Chapter 138 Choroidal Nevi
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Introduction
Choroidal nevi are common tumors composed of benign-appearing atypical uveal melanocytes called nevus cells.1,2 When encountered clinically, they are widely regarded as trivial lesions; however, they have the potential to cause visual loss and, most importantly, they can resemble or transform into a choroidal melanoma. In fact, these lesions are the source of many unanswered questions, unresolved controversies, and much confusion as to their definition, incidence, histopathologic classification, and their relationship to uveal melanomas.
Definitions
Nevus
The term “nevus” in its historical context, is synonymous with hamartoma and denotes any congenital tumor-like tissue malformation.3 However, except in a few cases (e.g., nevus sebaceous or nevus flammeus), this word is now used restrictively to designate benign acquired or congenital tumors of neural crest-derived cells, including atypical melanocytes.2,3 A melanocyte is a mature melanin-producing and melanin-containing cell.2,3 Melanocytes derive embryologically from melanoblasts.2,4 These cells migrate during closure of the neural tube, and melanization starts between the 24th and 27th weeks of gestation, proceeding anteriorly until birth.4 Nevus cells are believed to be modified, or atypical, melanocytes.3 Zimmerman2 has emphasized that the morphologic appearance of cutaneous nevus cells may vary considerably, making it difficult to characterize a typical nevus cell.
Halo nevus
Halo nevus is a rarely encountered subgroup of choroidal nevus, and it is named after the depigmented annulus that surrounds the central pigmented portion of the nevus. It is believed that the halo is composed of large, polygonal cells with foamy cytoplasm, termed balloon nevus cells, similar to those found in halo nevi in other anatomic locations.5
Giant choroidal nevus
There are no definitive criteria to designate which nevus falls under the category of “giant” choroidal nevus; however, Shields et al.6 included those with a basal diameter greater than or equal to 10 mm. Based on their size, this rare subgroup of choroidal nevi may be particularly difficult to distinguish from malignant melanoma.6
Melanocytoma
Among nevi, melanocytomas are those that are composed mostly of uniform, densely pigmented, and plump polyhedral cells (magnocellular nevi).2,7
Ocular melanocytosis
Melanocytosis designates a congenital hyperpigmentation of the uveal tract caused by an increased number of uveal melanocytes.2,8 When accompanied by dermal melanocytosis in a distribution similar to that of the first or second division of the trigeminal nerve, this condition is termed oculodermal melanocytosis or nevus of Ota (nevus fuscoceruleus ophthalmomaxillaris (Fig. 138.1A).1,8
Fig. 138.1 (A) Nevus of Ota. (B) Cutaneous dysplastic nevi.
(Part A reproduced with permission from Gonder JR, Shields JA, Albert DM, et al. Uveal malignant melanoma associated with ocular and oculodermal melanocytosis. Ophthalmology 1982; 89:953–60. Part B reproduced with permission from Albert DM, Chang MA, Lamping K, et al. The dysplastic nevus syndrome. A pedigree with primary malignant melanomas of the choroid and skin. Ophthalmology 1985;92:1728–34.)
Prevalence
Nevus
The exact prevalence of choroidal nevi has been variably estimated in clinical and histopathologic studies (Table 138.1).9–21 The Blue Mountain Eye Study, a population-based study, demonstrated a 6.5% prevalence in an older, largely white population.21 Generally, higher rates are found in histopathologic studies. Naumann et al.22 attributed the clinical underevaluation to the obscuring of lesions by retinal pigment epithelium (RPE) and choriocapillaris, lack of adequate contrast between the nevus and the surrounding normal choroid, and the hypopigmentation of many nevi. In their series, only 10 out of 29 nevi were clinically detected in eyes with clear media. Other factors contributing to the discrepancy are probably related to the examining technique, variations in the criteria for identifying a nevus, and characteristics of the populations under study (Table 138.1). Like cutaneous nevi, uveal nevi are rare among blacks. Except for melanocytosis and, presumably, melanocytomas, choroidal nevi are not seen at birth and, like acquired cutaneous nevi, develop or become pigmented in the first three decades of life.14 No significant epidemiologic data establish a relation to sex or color of skin, hair, or iris.11–14,16 The influence of solar exposure, chemicals, and endogenous or therapeutic hormones on the formation of nevi is still to be established.16,23
Halo nevus
In a review of 3422 eyes with choroidal nevi by Shields et al., 4.7% were halo nevi.24 As with most other choroidal nevi, they were found almost exclusively in Caucasians. A predilection for women (71%) was also found.24
Giant choroidal nevus
In the Blue Mountain Eye Study, only 1.5% of choroidal nevi were larger than 4 mm, although measurements above this cutoff were not specified.21 In a review of 4100 patients with choroidal nevi by Shields et al., 8% met the criteria for giant choroidal nevus; however, this probably represents a referral bias as large nevi are likely to be referred to ocular oncology centers for melanoma evaluation.6
Melanocytoma
Melanocytomas represented only five of 907 pigmented intraocular tumors examined histopathologically by Howard and Forrest.25 Melanocytomas differ from choroidal nevi or melanomas in that they occur relatively more frequently in blacks and tend to grow more rapidly than typical nevi.25–28 Although probably congenital, they usually are not seen before the third decade of life.
Ocular melanocytosis
The prevalence of ocular melanocytosis in clinical series was determined to be 0.038% (two cases per 5251 persons) in whites, 0.014% in blacks (one case per 6915 persons), and 0.4% to 0.84% in Japanese.29–32 However, the diagnosis of melanocytosis in blacks is difficult to ascertain, and the prevalence of ocular melanocytosis in blacks is believed to be higher than the figure stated above.
Choroidal nevi and systemic disease
Uveal nevi and neurofibromatosis
Uveal nevi are considered to be quite common in association with neurofibromatosis. Melanocytes, composing the nevi, share a neural crest origin with the other tumors found in von Recklinghausen disease (neurocristopathies).33–35
Dysplastic nevus syndrome
Reese36 reported an association of uveal nevi with cutaneous nevi. The observation that cutaneous dysplastic nevi are related to increased risk of cutaneous melanoma gave a new impetus to the investigation of the association of ocular and cutaneous nevi. The importance of early diagnosis and prompt intervention in cutaneous melanoma made necessary an intensive evaluation of melanoma-prone patients.23,37 This led to the identification of families genetically predisposed to melanoma and to the characterization of clinicopathologically distinctive nevi – the dysplastic nevi. Clinically, a dysplastic nevus must be suspected if a melanocytic nevus harbors at least two of the following four features1,38,39: (1) ill-defined or irregular borders; (2) irregular pigmentation; (3) accentuated skin markings, and (4) large size (>5 mm).1 They tend to occur on sun-shielded skin (e.g., the scalp or bathing trunk area) (Fig. 138.1B).
Histopathologically, dysplastic nevi are divided into two types: (1) a mild type with aberrant differentiation (e.g., lentiginous melanocytic hyperplasia), and (2) a severe type with melanocytic nuclear atypia, in addition to aberrant differentiation.1 These dysplastic nevi are markers of both familial and nonfamilial melanoma risk.40
That the uvea might be involved in familial melanoma or dysplastic nevus patients is suggested by the following: (1) a report of a type of dysplastic nevus syndrome with primary malignant melanomas of the choroid and the uvea41; (2) an increased (although not statistically significant) frequency of iris nevi and choroidal nevi in patients with cutaneous melanoma,18 and (3) a statistically significant increase in the percentage of dysplastic nevus syndrome in patients harboring iris and choroidal nevi.19 Although inconclusive and controversial,42 these data should lead to an attentive ophthalmologic evaluation in patients with dysplastic nevi.
Paraneoplastic bilateral diffuse uveal melanocytic proliferations
Bilateral diffuse uveal melanocytic proliferation (BDUMP) is a rare paraneoplastic syndrome described in elderly patients with advanced systemic carcinomas.43–46 Gass47 does not consider these tumors to be malignant on the basis of the relatively benign appearance of spindle cells and the rare mitotic figures. However, Zimmerman32 mentions foci of plump spindle B and epithelioid cells in these tumors. No metastases from these uveal tumors have been found at autopsy. In these cases, patchy areas of degeneration of the RPE and photoreceptors account for the rapid irreversible visual loss, although a bilateral cataract is generally present. (Bilateral diffuse melanocytic proliferation is discussed in Chapter 154, Miscellaneous uveal tumors.)
Halo nevi
The development of the depigmented halo has been postulated to be secondary to an immune response, such as that incited by prior antigenic exposure to cutaneous melanoma, as there is a higher association of a prior diagnosis of cutaneous melanoma in patients with choroidal halo nevi. No increased association with systemic autoimmune diseases has been found.1,5,48
Histopathology
Cytology
Adult melanocytes are normally found in the suprachoroidal lamellae, around blood vessels and in the outer layer of the choroidal stroma.4 These stellate cells with long processes contain oval membrane-bound melanin granules.49 Immunohistochemical staining against S-100 antigen is the most sensitive way to label melanocytic cells of neural crest origin, such as nevus and melanoma cells. Nevus cells are larger and show other morphologic differences from normal melanocytes.4 Naumann et al.50 classified nevus cells into four main cell types.
Plump polyhedral nevus cells
Plump polyhedral nevus cells are the most common nevus cells and usually represent about two-thirds of the mass. Their voluminous cytoplasm is filled with melanin. Bleaching with potassium permanganate is necessary to visualize the small, round, and uniform basophilic nuclei that lack prominent nucleoli (Fig. 138.2A).22
Electron microscopic studies have demonstrated ultrastructural differences in the cells composing melanocytomas. Juarez and Tso,51 studying enlarging melanocytomas of the optic disc or uvea, disclosed the following two cell types:
1. Type 1 cells are large, polyhedral, and heavily pigmented. They possess round nuclei without nucleoli, few cytoplasmic organelles, and prominent giant melanosomes. These characteristics suggest an inactive state.
2. Type 2 cells are small, spindle-shaped, and sparsely pigmented. They possess marked infoldings of the nuclear membrane, conspicuous nucleoli, abundant cytoplasmic organelles, and small melanosomes. These characteristics suggest high metabolic activity.
Slender spindle nevus cells
Slender spindle nevus cells are the second most common cell type. These small, spindle-shaped, lightly pigmented or unpigmented cells have a slender, intensely basophilic nucleus, and are often distributed in the outer portions of nevi (Fig. 138.2B).1,22 When they make up the bulk of a nevus, the nevus is often amelanotic.1,22,52
Intermediate nevus cells
Between plump polyhedral and slender spindle-shaped nevus cells, there exists a spectrum of cells with larger nuclei showing a less marked chromatin pattern and occasionally small nucleoli. The cytoplasmic volume and pigmentation are at intermediate amounts between those of the principal nevus cell types. According to the shape of their cytoplasmic border, they are called either plump fusiform or plump dendritic nevus cells (Fig. 138.2B,C).1,22
Balloon cells
Balloon cells are large, nonpigmented cells with abundant foamy cytoplasm (Fig. 138.2B,C). They are found in the peripheral halo surrounding skin nevi, cutaneous and choroidal melanomas, and, presumably, halo nevi in the choroid.1,5,53 The significance of the cytoplasmic lipoid content is not certain.1 Some authors,48 reviewed by Green,1 have interpreted balloon cell transformation and halo nevi as the consequence of an autoimmune response to the antigens of abnormal melanocytic cells. The finding of a halo nevus associated with cutaneous melanoma and vitiligo-like leukoderma is consistent with these hypotheses.53,54
Secondary histologic changes in the neighboring tissues
Choriocapillaris
Thick nevi induce slight narrowing and, in some cases, complete obliteration of the choriocapillaris.22,55
Drusen
Drusen formation is frequently seen in the overlying Bruch’s membrane; it was seen in 27 of the 101 nevi reported by Naumann et al.22 Drusen most often are an indication of chronicity and an inactive tumor.14
Retina and retinal pigment epithelium
The RPE overlying nevi can either degenerate or proliferate slightly. In choroidal nevi and melanomas, clumps of lipofuscin have been shown in the RPE and in macrophages overlying the tumor.22,56–58 This is more likely to occur in melanomas,22,56–58 the orange pigment being most commonly associated with risk for tumor growth. Serous detachment of the RPE15,59 and the neurosensory retina can be observed. In rare instances, choroidal neovascularization may cause these detachments.1,22,57,60–62 Disturbances of the retina are sometimes seen, which include thinning, loss of photoreceptors, and intraretinal edema.22,63
Controversial aspects
Do all choroidal melanomas arise from nevi?
In 1966, Yanoff and Zimmerman,64 reviewing the previous literature and 100 consecutive malignant melanomas of the choroid or ciliary body, found a significant component of small, benign-appearing, and spindle-shaped nevus cells at the periphery and along the scleral edge in 73 cases. They inferred that “most malignant melanomas, perhaps all such neoplasms, have their origin in pre-existing nevi”.64 Subsequent additional cases of uveal melanomas associated with nevi have been reported.32 This has led many clinicians to undertake follow-up of quiescent nevi.
In 1972, Albert et al.65 examined the eyes of a 36-year-old white man with multiple bilateral choroidal metastases of a skin melanoma and found a nevus-like configuration at the base of the metastatic lesion. On previous fundus examination, no nevus was seen. Albert et al.66 subsequently induced nevus-like structures at the base of experimental choroidal tumors. In a case report,67 a large choroid melanoma arose over a 16-month period. Previous fundus photographs and angiograms documented the absence of any pigmented tumor in this fundus. A pigmented nevus-like structure again was found at the base of the tumor (Fig. 138.2D).67 The possibility that pre-existent nevi had escaped clinical examination, as claimed in a similar case by Yanoff and Zimmerman,64 was unlikely.67
A nevus-like configuration associated with a melanoma may have several interpretations:
1. In many instances, including skin melanomas, melanomas may arise from nevi.
2. In other instances, choroidal or skin melanomas arise de novo. At their base and periphery, these can induce a nevus-like structure by flattening normal uveal melanocytes or by the modification of the tumor cells while they infiltrate the sclera (Fig. 138.2D).
3. Nevus-like structures may result as a secondary proliferative effect of the malignancy or because of a common oncogenic stimulus.32 These mechanisms have been postulated in a few cases of bilateral diffuse melanocytic tumors of the uvea composed of relatively benign-looking, spindle-shaped cells in patients with systemic carcinoma.68,69
Ocular and oculodermal melanocytosis are conditions that predispose to choroidal melanoma. Malignant transformation was described in 4.6% of the reported cases of nevus of Ota8,29,35,70–72 and, with rare exception,70 the melanoma occurred in the pigmented eye. Orbital, meningeal, and cerebral melanomas have also been reported in patients with oculodermal melanocytosis.35,49,73–76 Zimmerman2 states that ocular melanocytosis, unlike racial uveal pigmentation, is associated with an increased risk of melanomas, even in blacks.
The occurrence of uveal melanomas in patients with neurofibromatosis has been reported in rare cases34,35; one of these was associated with nevus of Ota.33
Malignant changes in melanocytomas are unusual; these tumors are described as being at the more benign end of the nevus spectrum.1,32 Zimmerman called attention to Roth’s report, of eight uveal melanomas arising from melanocytomas and questioned the reported presence of plump polyhedral cells in these tumors. He suggested that the melanomas probably arose from populations of spindle-shaped nevus cells. Yet, a few reports of malignant transformation of melanocytomas do exist.32,34,77–79 In these cases, the type 1 cell population described in the section on plump polyhedral nevus cells is more likely to account for the malignant potential. (Additional material concerning the malignant transformation of melanocytomas is included in Chapter 135, Melanocytoma of the optic disc.)
Reappraisal of the Callender classification
The second controversial point is related to the modification of the Callender classification in which the spindle A and spindle B subgroups were combined as the spindle cell type.14,80 The usefulness of Callender’s classification of choroidal melanomas into the categories of spindle A, spindle B, epithelioid, or mixed tumors has been called into question by Jensen,81 Gass,14 and McLean et al.45 for many reasons. One of the criticisms was that, although none of the initial spindle A melanomas proved fatal, Callender did not classify them as benign or describe a spindle cell nevus type.82 Gass14 was reluctant to accept the survival curve reported by Paul et al.83 from the mortality data of the spindle A portion of 2652 patients (i.e., 81.2% were survivors at 15 years). He argued that: (1) only a small sample of the tumor is generally studied, leaving many areas that could contain epithelioid cells unexamined; (2) many differences exist in the interpretation of the cell types by pathologists; (3) no more than 50% of the deaths are tumor-related because most patients are elderly and are prone to multiple neoplasms.14 McLean et al.80
