Sudden Growth of a Choroidal Melanoma and Multiplex Ligation-Dependent Probe Amplification Findings Suggesting Late Transformation to Monosomy 3 Type

Current wisdom is that uveal melanomas develop monosomy 3 very early.¹ It is hypothesized that metastatic spread commences years before presentation,² and therefore ocular treatment may not influence survival.³ We describe a melanoma with apparently delayed transformation from disomy 3 to monosomy 3.

In 2001, a 65-year-old woman was referred with an inferonasal, pigmented, choroidal tumor in her left eye. The lesion was 10.1 mm wide and 1.6 mm thick (Figure 1A and B). Scattered drusen were noted. Orange pigment and subretinal fluid were not seen. The differential diagnosis included nevus and melanoma. The patient was monitored every 6 months. She underwent photocoagulation for diabetic retinopathy in 2005 and epiretinal membrane peel in 2006. The tumor appeared unchanged in serial evaluations, but by December 2007 its thickness had increased to 2.3 mm (Figure 1C and D).

In 2009, the patient had an acutely painful left eye with visual acuity of light perception and an intraocular pressure of 40 mm Hg. Ophthalmoscopy and ultrasonography showed the tumor to have a collar-stud shape, measuring 14.0 mm basally and 10.5 mm in thickness (Figure 1E and F). The eye was enucleated.

Microscopy showed a choroidal melanoma with extensive necrosis but with viable epithelioid cells at its apex and spindle cells at its base (Figure 2A-C). The mitotic rate was 4 per 40 high-power fields. Closed connective tissue loops were not present and lymphocytic infiltrate was minimal. Melanoma cells were also present on the surface of the iris extending into the chamber angle. The ciliary body was infiltrated by a melanoma satellite. Following microdissection, molecular genetic evaluation using multiplex ligation-dependent probe amplification revealed monosomy 3 and chromosome 6p gains in the melanoma cells at the tumor apex and disomy 3 at the base (Figure 2D). The patient was well 6 months postoperatively with no evidence of metastasis.

We report the case of a melanoma that, after 8 years of apparent quiescence, suddenly enlarged. It developed a collar-stud shape, became necrotic, and made the eye acutely painful. It was still possible to recognize epithelioid cells at the tumor apex and spindle cells at the base. The apex melanoma cells were demonstrated to be monosomy 3, and the spindle cells at the base were demonstrated to be disomy 3. Our findings would suggest that after years of apparent dormancy, a choroidal melanoma suddenly enlarged because it had transformed from an indolent, disomy 3, spindle type to an aggressive, monosomy 3, epithelioid type. Genomic changes in other human cancers have been reported.⁴

An alternative explanation is that the indolent tumor was a choroidal nevus that transformed into a monosomy 3 melanoma; however, if this had been the case, one would have expected to see nevus cells in the basal part of the tumor and not the melanoma cells that predominated. Furthermore, slow growth of the tumor had been documented, which is rare with nevi. Whether the panretinal photocoagulation stimulated tumor growth is uncertain but, in our opinion, highly unlikely.

It has been suggested that disomy 3 and monosomy 3 melanomas are distinct from their inception.¹ Our case suggests, however, that monosomy 3 can arise at any stage during tumor development. This implies that if a small choroidal melanoma is not treated promptly, there is always the risk that the tumor may undergo transformation to the monosomy 3 type, developing rapid growth and a higher risk of metastatic spread. This case supports our current data indicating that intratumoral genetic heterogeneity exists in most uveal melanomas.⁵ The histologic and multiplex ligation-dependent probe amplification results suggest the emergence of a highly malignant clone of melanoma cells. This event is suggested by the following: (1) the sudden tumor growth; (2) the concurrence of epithelioid cells with chromosome 3 loss and chromosome 8q gain in the apical part of the tumor, which is where such rapid growth recently occurred; and (3) the absence of such high-grade morphological and genotypic features in the basal part of the tumor, which is oldest part of this neoplasm. Finally, the case also demonstrates how any opportunities for conserving the eye and vision may be lost if a melanoma is not immediately treated.

Further studies are needed to determine whether early treatment of uveal melanomas may prevent later conversion into a monosomy 3 genotype and, by implication, metastatic death.

Correspondence: Dr Callejo, Ocular Oncology Service, St Paul's Eye Clinic, Royal Liverpool University Hospital, Liverpool L7 8XP, England (guilleyso@hotmail.com).