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Things That Go Bump in the Light. the Differential Diagnosis of Posterior Eye (2002) 16, 325–346 2002 Nature Publishing Group All rights reserved 0950-222X/02 $25.00 www.nature.com/eye IG Rennie Things that go bump THE DUKE ELDER LECTURE 2001 in the light. The differential diagnosis of posterior uveal melanomas Eye (2002) 16, 325–346. doi:10.1038/ The list of lesions that may simulate a sj.eye.6700117 malignant melanoma is extensive; Shields et al4 in a study of 400 patients referred to their service with a pseudomelanoma found these to encompass 40 different conditions at final diagnosis. Naturally, some lesions are Introduction mistaken for melanomas more frequently than The role of the ocular oncologist is two-fold: others. In this study over one quarter of the he must establish the correct diagnosis and patients referred with a diagnosis of a then institute the appropriate therapy, if presumed melanoma were subsequently found required. Prior to the establishment of ocular to have a suspicious naevus. We have recently oncology as a speciality in its own right, the examined the records of patients referred to majority of patients with a uveal melanoma the ocular oncology service in Sheffield with were treated by enucleation. It was recognised the diagnosis of a malignant melanoma. that inaccuracies in diagnosis occurred, but Patients with iris lesions or where the the frequency of these errors was not fully diagnosis of a melanoma was not mentioned appreciated until 1964 when Ferry studied a in the referral letter were excluded. During series of 7877 enucleation specimens. He the period 1985–1999 1154 patients were found that out of 529 eyes clinically diagnosed referred with a presumed melanoma and of as containing a melanoma, 100 harboured a these the diagnosis was confirmed in 936 lesion other than a malignant melanoma.1 cases (81%). In 218 patients (19%) a different Subsequent studies have shown a progressive final diagnosis was made. Over half of the improvement in the accuracy with which patients with pseudomelanomas (58%) were these tumours can be recognised. Shields and diagnosed as having an indeterminate McDonald in 1974 found the misdiagnosis rate melanocytic lesion (IML). This diagnosis will to have fallen to 1.9%.2 More recent studies be discussed in detail later. Choroidal naevi demonstrate a further improvement with the (8.7%), haemangiomas (6.9%), and choroidal COMS study group in 1990 reporting an neovascularization (macula and eccentric incidence of only 0.48%.3 These improvements disciforms) (5%) were the next most in the accuracy of diagnosis can be attributed to an increased awareness of lesions that may frequently misdiagnosed lesions. In all, 12 simulate malignant melanomas, improved different conditions were found to have diagnostic techniques and increased referral to simulated choroidal melanoma (see Table 1) units specializing in the treatment of ocular (manuscript in preparation). University of Sheffield Sheffield, UK tumours. Pseudomelanomas can be divided into pigmented and non-pigmented lesions. Many lesions that are mistaken for Correspondence: melanomas are non-malignant, nevertheless, Pigmented lesions may be melanocytic in Prof IG Rennie they may pose a serious threat to vision and origin or derived from the iris, ciliary body or Floor O require prompt treatment in their own right. retinal pigment epithelium (Figure 1). Non- Royal Hallamshire Hospital Others may be benign but have the potential pigmented lesions are more diverse in nature, Sheffield SI0 2JF, UK Tel: 0114 271 2902 but can be divided into neoplastic, to undergo malignant transformation and Fax: 0114 276 6381 occasionally a benign lesion may be the inflammatory or reactive, and vascular lesions E-mail: i.g.rennieȰ harbinger of a neoplasm elsewhere. (see Figure 2). shef.ac.uk Things that go bump in the light IG Rennie 326 Table 1 Diagnosis of pseudomelanomas 1985–1999. Figure 2 Classification of pseudomelanomas of the choroid (non pigmented lesions). approximately 1%.8 Whilst this variation may reflect sampling errors or improvements in clinical examination (for example the use of indirect ophthalmoscopy or fundus photography), it may also reflect the importance of age on the development of naevi. It is well recognised that choroidal naevi are uncommon in children and adolescents9 and are rarely observed in neonates. Naevi probably develop from nests of cells that are present at birth and then either proliferate or pigment at puberty. Tumour growth, although often taken as a sign of malignancy, may be observed in histologically proven benign nevi. 10 Figure 1 Classification of pseudomelanomas of the choroid MacIlwaine et al reported a case of a raised (pigmented lesions). pigmented choroidal lesion that enlarged over a 6.5- year period and after enucleation was found to be a choroidal naevus. Pigmented lesions Clinically, the typical choroidal naevus is a flat or minimally elevated pigmented lesion in the post Melanocytic origin equatorial choroid. The majority are brown to slate- grey in colour and range in size from 0.5–4.5 mm in Naevi The commonest pigmented intraocular diameter.5 The edges of the lesion may be distinct or lesion is the naevus. Estimates of their frequency vary blend slightly into the surrounding choroid. The from 1 to 9% of the population. In 1998 Sumich5 et al surface is usually uniform in colour, although retinal examined a total of 3654 individuals aged 49–79 years pigment epithelial changes are common.11 Drusen may using six standard field fundus photography and be observed on the surface of naevi, particularly in the found that choroidal naevi were present in 6.5% of the central portions of the larger lesions (Figure 3). study cohort. Correction of the data to account for Occasionally, large solitary drusen are present on the possible naevi missed by the photography gave surface of the naevus.12 prevalence rates of 8.9% for women and 8.3% for men. Whilst many naevi have a typical appearance, These figures agree closely with post-mortem studies, several clinical variants can be recognised; partial or which found that almost 9% of the eyes examined even totally amelanotic nevi occur. One rather peculiar contained a nevus of either the ciliary body or variant is the halo naevus where there is a yellowish choroid.6 ring surrounding the lesion. Interestingly, this latter Previous clinical studies have found a lower variant has been observed in a patient with vitiligo.13 incidence. Ganley and Comstock7 found an incidence Abnormalities of visual function have in the past been of 3.1% in a sample of individuals aged over 30 years. taken as an indication that a pigmented fundal lesion Earlier clinical studies have found an incidence of is malignant and whilst visual symptoms undoubtedly Eye Things that go bump in the light IG Rennie 327 occur more frequently in malignant pigmented lesions, growth appears to dramatically slow down or stop they may also be associated with benign naevi. mitigates against them having the unrestrained growth Asymptomatic scotomas corresponding to the of a malignant lesion. It is now recognized that anatomical sites of the lesions can be demonstrated malignant neoplasms arise by virtue of genetic using careful perimetry.14–16 Reduced central visual mutations in the cell that in turn leads to a loss of acuity may be present if the naevus is subfoveal.17 regulation in cell cycling, leading to unrestrained Presumably these abnormalities of visual function are growth. Furthermore, it is apparent from studies of attributable to photoreceptor dysfunction either in the other malignancies that tumours do not develop absence of or secondary to retinal pigment epithelial because of a single genetic mutation; but rather as a degeneration. Visual loss can also result from the result of a series of, often sequential, changes which development of either a serous retinal detachment or ultimately result in a lesion with unrestrained growth, choroidal neovascularization.17–19 Serous retinal invasiveness and metastatic capability. Indeed, studies detachments can arise as a direct result of a retinal in our own laboratory and those of others have pigment epithelial disturbance, or secondary to identified specific chromosome alterations in uveal choroidal neovascularization. Similarly, choroidal melanomas.20–23 Moreover, it would appear that some neovascularization can lead to visual loss as a result of of these changes (notably alterations of 3 and 8) subretinal haemorrhage and scarring or serous retinal correlate strongly with prognosis,24–26 suggesting that detachment. these particular changes are relatively late changes in the progression to a metastatic phenotype. Thus if one Indeterminate melanocytic lesions The majority of accepts that uveal melanomas arise as a result of a melanocytic lesions of the choroid are either benign sequence of several genetic mutations, then it is naevi or malignant melanomas; they are a group of possible to speculate that some early genetic mutations lesions that clearly do not fit comfortably in either may have occurred in IMLs; but that the process has category. Such lesions are larger than normal naevi arrested before a complete malignant phenotype has and often significantly elevated, and yet if merely developed. Whilst this possible hypothesis remains observed, remain indolent for many years. I use the unproven, it is at least in part supported by clinical term indeterminate melanocytic lesions (IMLs) to observation; for although the majority of such lesions describe such lesions. As such they probably are indolent, I have observed growth in at least two correspond to lesions described as low-grade tumours (in each instance manifest by a small melanomas or suspicious naevi. Typically, IMLs appear herniation through Bruch’s membrane) after many as pigmented, elevated lesions in the mid-peripheral years of apparent dormancy (Figure 5): suggesting the choroid. They vary considerably in size with the eventual acquisition of further mutations which in largest attaining 3–4 mm in thickness.
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