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Toxicologic Pathology
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Brief Communication

Two Cases of Uveal Amelanotic Melanoma in Transgenic Tyr-HRAS+ Ink4a/Arf Heterozygous Mice

John R. Latendresse1, Levan Muskhelishvili1, Alan Warbritton1 and William H. Tolleson2

1 Toxicologic Pathology Associates
2 Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, Arkansas 72079 USA

Correspondence: Address correspondence to: John R. Latendresse, 3900 NCTR Road, Jefferson, AR 72079; e-mail:John.latendresse{at}fda.hhs.gov

Uveal melanoma (UM) is uncommon among wild type mice. Efforts to develop transgenic mice to study this disease have resulted in pigmented tumors derived from the retinal pigment epithelium (RPE) or mixed tumors of RPE and UM complicating the study of UM specifically. Reported here are two early stage intraocular amelanotic melanomas discovered in 2 Tyr-HRAS+ Ink4a/Arf heterozygous (1 normal CKDN2A allele) transgenic FVB/n mice. These tumors were morphologically and immunohistochemically similar to spontaneous UM recently reported in the Ink4a/Arf homozygous (CKDN2A knockout) parent strain. The tumors originated in the posterior uveal tract. The neoplasms were comprised of bundles of spindle-shaped melanocytes admixed with some epithelioid cells. Tumors were immunohistochemically positive for neuron-specific enolase, S-100, pan-ras, but negative for cytokeratin and Melan-A. The development of early lenticular opacity and bilateral cataracts is a consistent phenotype of transgenic mice in which the retinoblastoma signaling pathway has been disrupted. Lenticular opacity and cataracts are rarely observed clinically in Tyr-HRAS+ Ink4a/Arf heterozygotes, rendering this strain suitable for ophthalmoscopy. Consequently, Tyr-HRAS+ Ink4a/Arf heterozygotes provide practical advantages, compared to the cataract-prone CKDN2A knockout strains, for real-time ophthalomoscopic detection and monitoring of UM while developing chemotherapeutic regimens and other research to understand the biology of UM.

Key Words: Uveal melanoma • amelanotic • transgenic animals • mouse pathology • animal models • Ink4a/Arf • immunohistochemistry

Abbreviations: DAB, diaminobenzidine hydrochloride • HD, high dose • IHC, immunohistochemical • LD, low dose • LO, lenticular opacity • NSE, neuron-specific enolase • PBS, phosphate-buffered saline • PND, postnatal day • RB, retinoblastoma • RPE, retinal pigment epithelium • TBS, Tris-buffered saline • UM, uveal melanoma • UV, ultraviolet

Toxicologic Pathology, Vol. 35, No. 6, 825-830 (2007)
DOI: 10.1080/01926230701584221
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