History
A 2-year-old 27.8-kg spayed female terrier mix was referred on emergency to North Carolina State University with a 4- to 5-day history of corneal opacity and blepharospasm in the left eye.
Clinical and Cytologic Findings
A thorough ophthalmologic examination and comprehensive ophthalmic database was performed. Pertaining to the left eye, there was mild to moderate blepharospasm; moderate conjunctival hyperemia; focal, ventronasal white to pink corneal infiltrate; aqueous flare with ≥ 2 large cells; fibrin; and moderate miosis. Vitreal hemorrhage was noted. The optic nerve and retina were unremarkable. Intraocular pressure of 41 mm Hg by rebound tonometry was noted in the left eye. Ophthalmic findings and ophthalmic database of the right eye was unremarkable. The general physical examination was otherwise within normal limits. Therapy included topical prednisolone acetate solution (1 drop in the left eye, q 8 h), dorzolamide-timolol solution (1 drop in the left eye, q 8 h), carprofen (2 mg/kg, PO, q 12 h), and doxycycline (6 mg/kg, PO, q 12 h).
Five days later, the patient was presented again to the ophthalmology department at North Carolina State University. The blepharospasm had improved in the left eye. However, the level of intraocular inflammation (cells and aqueous flare) had worsened, the intraocular pressure remained uncontrolled, and 4 pale-pink exophytic iris nodules were newly noted. The right eye remained unremarkable.
Due to the presence of the iris nodules, an aqueocentesis of the left eye was performed and the aqueous humor was examined cytologically (Figure 1). The sample consisted of clusters of large cells that were sometimes in acinar-like arrangements. They had large round nuclei, finely stippled chromatin, 0 to 3 prominent nucleoli that were variable sizes and shapes, and moderate amounts of moderately basophilic cytoplasm containing few small vacuoles and smooth pink material. The population displayed moderate pleomorphism and occasional mitotic figures. Scattered macrophages occasionally containing melanin, few lymphocytes, rare nondegenerate neutrophils, and rare RBCs were also present.
Cytologic Interpretation
Malignant neoplasia with mild mononuclear inflammation. The neoplastic population was most consistent with a carcinoma (iridociliary adenocarcinoma versus metastatic) or, less likely, amelanotic melanoma.
Histopathologic Findings
The patient underwent enucleation of the left eye, and the globe was submitted for histopathology (Figures 2 and 3). An unencapsulated, poorly demarcated, densely cellular, infiltrative neoplasm was found to line the iris and lateral lens, expand the ciliary body, and unilaterally invade under and separate the ciliary body and iris from the limbus, cornea, and sclera. The neoplasm was composed of cuboidal to columnar cells arranged in disorganized tubulopapillary projections, cords, or solid sheets, often resting on a variably thick basement membrane. Neoplastic cells had moderate amounts of occasionally vacuolated eosinophilic cytoplasm and a round basilar nucleus. Nuclei had finely stippled chromatin and 1 to 3 prominent nucleoli. Neoplastic cells exhibited moderate anisocytosis and anisokaryosis, and 32 mitotic figures were observed in 10 high-magnification fields (total area, 2.37 mm2). Scattered throughout the neoplasm were a few small areas of lytic necrosis and rare spicules of mature lamellar bone (not shown). In the examined section, the filtration angle was completely occluded from neoplastic invasion and compression. Glaucomatous change included loss of retinal ganglion cells. Application of periodic acid–Schiff stain revealed occasional formation of basal lamina throughout the neoplasm, and Alcian blue stain revealed rare cells with presumed intracellular hyaluronic acid. Neoplastic cells exhibited the following immunolabeling: strong cytoplasmic pancytokeratin positive (AE1/AE3), weak cytoplasmic vimentin, negative PNL2, negative Melan-A, and weak cytoplasmic neuron-specific enolase (NSE).
Morphologic Diagnosis and Case Summary
Morphologic diagnosis and case summary: iridociliary adenocarcinoma with secondary glaucoma in the left eye of a dog.
Comments
The patient showed no evidence of metastasis on abdominal ultrasound or thoracic radiographs at the time of enucleation and was treated postoperatively with amoxicillin–clavulanic acid (13 mg/kg, PO, q 12 h for 7 days) and carprofen (2 mg/kg, PO, q 12 h for 5 days). At 6 months postenucleation, the patient was doing well clinically, with no evidence of local recurrence or metastasis on abdominal ultrasound or thoracic radiographs.
While intraocular tumors are relatively uncommon, iridociliary epithelial tumors are the second most common primary intraocular tumor in the dog after melanocytic tumors.1–5 They arise from the nonpigmented or, less commonly, pigmented cells of the iris or ciliary body, which are derived from the neuroectoderm.1–3 Masses are pale pink to dark brown or black and typically located within the posterior chamber, though they may grow and invade into the anterior chamber.3 Because of their location, these masses can be difficult to detect on examination and may present for changes associated with glaucoma, hyphema, uveitis, or other secondary findings.1,3,4
Cytology of aqueous humor rarely gives a definitive diagnosis in patients with ophthalmologic disease. However, it may be highly valuable in cases with a neoplastic etiology and has been used to diagnose various exfoliating neoplasms including lymphoma, mast cell neoplasia, iridociliary neoplasia, and melanoma.6–9 In this case, an aqueocentesis was performed due to the presence of iris nodules and ≥ 2 cells in the anterior chamber. A cytospin of aqueous humor was prepared that concentrated the neoplastic cells sufficiently to make a diagnosis. Pleomorphism and mitotic figures in this sample supported the malignant nature, and the clustering of cells strongly supported epithelial origin including iridociliary, given the location, or metastatic carcinoma. However, melanomas may morphologically mimic several cell phenotypes and are not always well pigmented, particularly in cases of malignant melanoma.7 Because of this overlap in morphology and frequency of melanomas in the eye, an amelanotic melanoma was not ruled out but was considered less likely given the complete absence of pigment in the neoplastic cells. Overall, the cytologic morphology, clinical presentation, and lack of a separate primary tumor found during staging supported an iridociliary adenocarcinoma as the most likely diagnosis.
Histologically, these tumors may be solid, papillary, or cystic in appearance.1,3 Iridociliary adenomas are the benign variant that make up the majority of iridociliary epithelial tumors.1,4 Iridociliary adenocarcinomas are a malignant variant that are locally invasive with scleral invasion, as opposed to the rare, truly malignant variant with distant metastasis, which is termed pleomorphic iridociliary adenocarcinoma.1,3 Like normal neuroepithelium, iridociliary tumors are typically pancytokeratin (AE1/AE3) negative, vimentin positive, and NSE positive, which can help differentiate them from metastatic carcinomas.1,3,5,10 In this case, iridociliary adenocarcinoma and melanoma were the 2 primary considerations for the histologic findings. The tumor was pancytokeratin positive, weakly vimentin positive, and weakly NSE positive; while this is atypical for iridociliary neoplasms, these differences occur in highly aggressive cases.1,3 These findings may also occur with metastatic carcinoma, though the lack of other masses found during staging makes this far less likely. Additionally, PNL2 and Melan-A were negative, ruling out a melanoma. Overall, the authors felt that the uveal invasion, mitotic rate, and immunohistochemical staining patterns were most consistent with an iridociliary adenocarcinoma rather than an adenoma.
The treatment of choice, as elected in this case, is enucleation.2 Radiotherapy and chemotherapy are described but considered of minor importance by some authors.4,5 Other, far less common options for small tumors include laser ablation, intraocular resection, and photodynamic therapy.2 Overall, the prognosis for globe retention is generally poor in these cases. However, given the very low rate of metastasis of iridociliary tumors, the prognosis for life is typically good with appropriate treatment.5
References
- 1. ↑
Dubielzig RR, Steinberg H, Garvin H, Deehr AJ, Fischer B. Iridociliary epithelial tumors in 100 dogs and 17 cats: a morphological study. Vet Ophthalmol. 1998;1(4):223–231.
- 2. ↑
Lascelles BD, Davidson M. Eyelids, eye, and orbit. In: Kudnig ST, Seguin B, eds. Veterinary Surgical Oncology. Wiley-Blackwell; 2012:383–404.
- 3. ↑
Dubielzig RR. Tumors of the eye. In: Meuten DJ, ed. Tumors in Domestic Animals. 5th ed. Wiley-Blackwell; 2017:892–922.
- 4. ↑
Klopfleisch R. Ocular and periocular tumors. In: Klopfleisch R, ed. Veterinary Oncology: A Short Textbook. Springer International Publishing; 2016:273–279.
- 5. ↑
Labelle AL, Labelle P. Canine ocular neoplasia: a review. Vet Ophthalmol. 2013;16(Suppl 1):3–14.
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Wiggans KT, Vernau W, Lappin MR, Thomasy SM, Maggs DJ. Diagnostic utility of aqueocentesis and aqueous humor analysis in dogs and cats with anterior uveitis. Vet Ophthalmol. 2014;17(3):212–220.
- 7. ↑
Valenciano AC, Cowell RL. Diagnostic Cytology and Hematology of the Dog and Cat. 5th ed. Elsevier; 2020:151.
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Ferreira H, Scurrell E, Bass J, Salmon K. What is your diagnosis? Aqueous humor from a dog. Vet Clin Pathol. 2019;48(3):484–486.
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O’Brien PJ, Lumsden JH. The cytologic examination of body cavity fluids. Semin Vet Med Surg Small Anim. 1988;3(2):140–156.
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Labelle P, Reilly CM, Naydan DK, Labelle AL. Immunohistochemical characteristics of normal canine eyes. Vet Pathol. 2012;49(5):860–869.