Corneal Cupremia in Multiple Myeloma: A Clinicopathologic Correlation FREE

We describe the study of an eye from a patient with corneal cupremia secondary to multiple myeloma. An intercurrent episode of mucormycosis necessitated removal of this individual's eye, enabling this unique study.

A 71-year-old white woman with an 8-year history of refractory multiple myeloma had blurred vision. Her best-corrected visual acuity was 20/30 OU. In both eyes, the cornea manifested a remarkable golden-brown, metallic sheen that on slitlamp examination was determined to be at the level of the Descemet membrane (Figure 1). The remainder of her examination disclosed no abnormalities. Several months later, the patient's vision rapidly decreased and she was diagnosed with mucormycosis of the orbit and sinus. Despite aggressive sinus and orbit débridement as well as the use of antifungal agents, the patient required exenteration. The exenteration specimen provided a unique opportunity to study her eye.

Light microscopy demonstrated slightly granular, tan pigmentation of the anterior portion of the Descemet membrane in the central cornea. Copper-specific staining with rubeanic acid showed highly positive staining of the central cornea, primarily in the anterior Descemet membrane with some additional granular staining of the posterior Descemet membrane (Figure 2). Similar stains of the midperipheral and peripheral cornea revealed that copper was absent from these regions. No copper deposition was noted in the lens capsule as has been previously reported.^1- 6

Deposition of copper in ocular tissues has been reported in the context of multiple myeloma,^1- 3 IgG monoclonal gammopathy associated with pulmonary carcinoma,⁴ and benign monoclonal gammopathy of undetermined significance.⁵ The unifying factor in these conditions appears to be the presence of IgG light chains that bind copper with an unusually high affinity. Both κ and λ light chains have been reported to bind copper. Patients with these conditions have markedly elevated serum copper levels and normal to slightly elevated serum ceruloplasmin levels (in contrast to the low ceruloplasmin levels found in Wilson disease). Copper deposits have been reported in the cornea at the level of the Descemet membrane, within the anterior and posterior lens capsule, and within the trabecular meshwork.^1- 3,5

In multiple myeloma, the copper deposition is central and tends to spare the limbal region. The central cornea manifests a remarkable iridescent sheen secondary to fine, metallic particles at the level of the Descemet membrane. The diffuse central sheen may be supplemented by a radial pattern of spokes but is universally reported to stop within 2 to 3 mm of the limbus.

Various theories attempt to explain why copper is deposited centrally in monoclonal gammopathy and peripherally in Wilson disease. It has been hypothesized that the corneal copper is derived from the limbal circulation in Wilson disease, whereas in multiple myeloma the deposition is secondary to elevated levels of copper in the aqueous humor.¹

Interestingly, monoclonal IgG and IgG light chains appear to bind copper in these disease states but are not known to do so in vitro. In at least 1 case, the copper-carrying protein was sequenced in an attempt to determine whether it shared the N-terminal Asp-Ala-His amino acid sequence known to bind copper in albumin, but no such sequence was found.⁵ Sequences as simple as Gly-His are capable of binding copper under certain circumstances, especially if they are repeated, rendering it difficult to determine the location of a potential binding site based on sequence alone. Myeloma protein is known to accumulate in the eye as an amyloid, and although individual myeloma proteins do not appear to bind copper, closely packed myeloma proteins may be able to do so.

Correspondence: Dr Pomerleau, Department of Ophthalmology, California Pacific Medical Center, 2340 Clay St, Fifth Floor, San Francisco, CA 94115 (dustypomerleau@gmail.com).

Financial Disclosure: None reported.