Pathology in Practice

Jessica A. Fragola 1Comparative Ocular Pathology Laboratory of Wisconsin, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI 53706.

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Noelle C. La Croix 2Veterinary Medical Center of Long Island, 75 Sunrise Hwy, West Islip, NY 11795.

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Leandro B. C. Teixeira 1Comparative Ocular Pathology Laboratory of Wisconsin, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI 53706.

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Gillian C. Shaw 1Comparative Ocular Pathology Laboratory of Wisconsin, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI 53706.

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History

A 3-year-old 47.3-kg (104.1-lb) neutered male German Shepherd Dog was evaluated by a veterinary ophthalmologist because of blepharospasm of the left eye. One year prior to the evaluation, the dog had been transported to the United States from Egypt. At that time, the dog had a conjunctival and dermal transmissible venereal tumor (TVT). The patient was treated with vincristine chemotherapy and was reported by the owner to have achieved clinical remission.

Clinical and Gross Findings

With the exception of ocular abnormalities, findings on general physical examination were unremarkable. For the left eye, the pupillary light, menace, and dazzle reflexes were absent. There was marked conjunctival hyperemia, corneal edema, hyphema, hypopyon, and 4+ aqueous flare. The pupil was mydriatic with posterior synechiae. Because of the severe hyphema, hypopyon, and flare, no ocular structures posterior to the lens could be visualized. For the right eye, the pupillary light, menace, and dazzle reflexes were present. There were cellular opacities and fibrin strands in the vitreous humor, which obscured some of the temporal tapetal portion of the fundus.

Both the left-to-right and right-to-left indirect pupillary light reflexes were absent. The rest of the cranial nerve examination findings were considered normal. Results of a CBC, serum biochemical analysis, and thoracic radiography were unremarkable. A PCR assay failed to detect the DNA of Hepatozoon americanum and Hepatozoon canis in a blood sample obtained from the dog; results of serologic tests for circulating antibodies against Leishmania donovani, Babesia canis, Ehrlichia canis, Borrelia burgdorferi, Rickettsia rickettsii, and Aspergillus spp were all negative.

Because of the perceived pain and irreversible blindness associated with the dog's left eye, the left eye was enucleated, and the globe was submitted for histologic examination. Grossly, the external adnexal structures appeared normal and the cornea was cloudy. Hemisectioning of the globe revealed retinal detachment; hemorrhage in the anterior chamber, posterior chamber, vitreous humor, and subretinal space; and a soft tan-colored mass in the subretinal space (Figure 1)

Figure 1—
Figure 1—

Photograph of a parasagittal hemisection of the left globe of a 3-year-old German Shepherd Dog that was evaluated because of blepharospasm of the left eye. The globe was removed surgically because of intractable blindness, signs of pain, and glaucoma. Notice that the retina is detached (arrows) and there is a subretinal mass (asterisk). Severe intraocular hemorrhage is present. Bar = 1 cm.

Citation: Journal of the American Veterinary Medical Association 255, 12; 10.2460/javma.255.12.1343

Formulate differential diagnoses from the history, clinical findings, and Figure 1—then turn the page—

Histopathologic Findings

Histologically, a necrotic mass of neoplastic cells was present in the subretinal space of the enucleated left eye. The neoplastic cells multifocally carpeted the ciliary body, diffusely infiltrated the retina, and were mixed with the hemorrhage in the posterior chamber and vitreous humor (Figure 2) The neoplastic cells were round with distinct cell borders, and contained a small to moderate amount of finely vacuolated amphophilic cytoplasm, and a round to oval nucleus with clumped chromatin and a single variably prominent nucleolus. Cellular pleomorphism was mild. Mitotic figures were present in moderate numbers but difficult to quantify because of the multifocal distribution of the neoplasm throughout the globe. There was moderate hemorrhage in the anterior chamber, posterior chamber, vitreous humor, and subretinal space. Abundant lymphocytes and plasma cells had infiltrated the iris and ciliary body stroma. A fibrovascular membrane lined the anterior border of the iris and crossed the iridocorneal angle, forming peripheral anterior synechiae. The fibrovascular membrane continued across the anterior portion of the lens capsule resulting in posterior synechiae and formation of a pupillary membrane. There was severe liquefaction of cortical lens fibers that caused wrinkling of the lens capsule, and multifocal mineralization within the lens. The retina was diffusely detached and multifocally necrotic with perivascular accumulations of lymphocytes and plasma cells. A few lymphocytes and plasma cells diffusely had infiltrated the choroid. The optic nerve head was gliotic with mild hemorrhage.

Figure 2—
Figure 2—

Photomicrographs of a subgross parasagittal hemisection (A) of the left enucleated globe and sections of a necrotic subretinal mass identified in the globe (B and C) of the dog in Figure 1. A—A necrotic subretinal mass (asterisk) and a carpet of neoplastic cells on the ciliary body (black outline) are visible. H&E stain; bar = 1 cm. B—In the necrotic subretinal mass, there are a few viable, neoplastic round cells mixed with hemorrhage and a mixed inflammatory cell population. H&E stain; bar = 50 μm. C—The neoplastic cells carpeting the ciliary body are round with distinct cell borders and have moderate amounts of vacuolated amphophilic cytoplasm and round nuclei with coarsely clumped chromatin. H&E stain; bar = 20 μm.

Citation: Journal of the American Veterinary Medical Association 255, 12; 10.2460/javma.255.12.1343

Immunohistochemical Findings

Immunohistochemical analyses for CD3, CD20, CD204, CD117, and lysozyme were performed on specimens of the necrotic subretinal mass in the left globe. More than 90% of the neoplastic cells had moderately strong cytoplasmic reactivity to anti-lysozyme antibodies, and cells were uniformly negative for CD3, CD20, CD204, and CD117 (Figure 3), which strongly supported a diagnosis of TVT.

Figure 3—
Figure 3—

Photomicrographs of neoplastic cells from the necrotic subretinal mass in the left globe of the dog in Figure 1 following staining with immunohistochemical markers for CD3 (A), CD20 (B), CD204 (C), CD117 (D), and lysozyme (E). A—The neoplastic cells do not express CD3. CD3-specific immunohistochemical stain; bar = 20 μm. B—The neoplastic cells are uniformly negative for CD20. Several stained normal B lymphocytes are mingled with the neoplastic cells. CD20-specific immunohistochemical stain; bar = 20 μm. C—The neoplastic cells are uniformly negative for CD204, whereas scattered, infiltrating, nonneoplastic macrophages are positive for CD204. CD204-specific immunohistochemical stain; bar = 20 μm. D—The neoplastic cells are uniformly negative for CD117. CD117-specific immunohistochemical stain; bar = 20 μm. E—Most neoplastic cells have moderate cytoplasmic staining for lysozyme. Lysozyme-specific stain; bar = 20 μm.

Citation: Journal of the American Veterinary Medical Association 255, 12; 10.2460/javma.255.12.1343

Morphologic Diagnosis and Case Summary

Morphologic diagnosis: metastatic TVT in the left eye, along with marked lymphoplasmacytic panuveitis with fibrovascular membrane and synechia formation, hypermature cataract, intraocular hemorrhage, retinal detachment and necrosis with lymphoplasmacytic retinitis, and chronic secondary glaucoma.

Case summary: intraocular metastasis of TVT in a dog.

Comments

Transmissible venereal tumor is 1 of 3 transmissible tumors known to develop in mammals; the others are contagious reticulum cell sarcoma of Syrian hamsters and devil facial tumor disease of Tasmanian devils. Transmissible venereal tumor is spread by implantation of tumor cells in a new host, most commonly during coitus.1 Most TVTs develop on genitalia, but these tumor cells can also be implanted on other mucosal surfaces (eg, oral, nasal, and conjunctival mucosae) and skin.2–4 The primary tumor forms cauliflower-like nodules that are often firm but friable, ulcerated, and hemorrhagic and are prone to secondary infection.1 For affected animals, the treatment of choice is IV administration of vincristine sulfate, which achieves permanent remission in most cases.5 Immunity against tumor cells generally prevents recurrence.1 Metastasis is uncommon (occurring in 5% of affected dogs) and usually transiently affects nearby lymph nodes.1 There are few case reports of intraocular metastasis of TVT.6,7 The tumor is endemic in at least 90 countries, but within the United States, cases are confined to populations of feral dogs in the Southwest.8

In the case described in the present report, the morphology of the TVT cells and the multifocal distribution of the neoplasm along with the carpeting of intraocular surfaces were highly suggestive of round cell tumor metastasis to the eye.9 The most common metastatic round cell tumors of the eye in dogs are histiocytic sarcoma and lymphoma. Cytologic examination is the preferred diagnostic test for TVT. For the dog of the present report, such testing was not performed prior to enucleation of the left eye because the owner elected to have the painful nonfunctional eye removed surgically independent of the diagnosis. Cytologically, TVT cells are round to oval with multiple clear cytoplasmic vacuoles, frequent mitotic figures, clumped chromatin, and 1 or 2 prominent nucleoli.10 The histologic appearance of TVT is more variable and cannot be solely used as the basis for a definitive diagnosis; immunohistochemical analyses of neoplastic tissue is required to rule out other round cell neoplasms.11

Immunohistochemical analyses for CD3, CD20, CD204, CD117, and lysozyme were performed in the case described in the present report. CD204 is expressed by tissue-resident macrophages and is a highly specific and sensitive marker for canine histiocytic sarcomas.12 CD3 is expressed by T lymphocytes, CD20 is expressed by B lymphocytes, CD117 is expressed by mast cells, and lysozyme is expressed by both TVT cells and histiocytes. For the dog of the present report, the neoplastic cells were positive for lysozyme but negative for CD3, CD20, CD204, and CD117. The immunohistochemical characteristics and morphology of the neoplastic cells and the dog's history of conjunctival TVT supported the diagnosis of ocular metastasis of TVT.

The neoplasm within the left globe led to numerous secondary intraocular changes. First, neoplastic cells and hemorrhage in the subretinal space resulted in retinal detachment. Because the lens is highly sensitive to changes in the aqueous humor and vitreous humor, neoplastic cells and necrosis within the posterior chamber and vitreous humor may have promoted cataract formation. The marked uveitis may have been secondary to the necrotic neoplasm or the cataract, or both. Fibrovascular membrane formation can occur secondary to uveitis, intraocular neoplasia, or retinal detachment, all of which were present in this dog. In the left globe, fibrovascular membranes extended from the base of the iris and across the iridocorneal angle (peripheral anterior synechiae), causing obstruction of the normal aqueous humor outflow with subsequent elevation of intraocular pressure and development of glaucoma.

The case described in the present report highlighted the importance of careful inspection for masses during gross examination of dogs with ocular problems; if an ocular mass is detected, histologic examination of the lesion for neoplastic cells should be undertaken. Thorough examination of ocular structures is especially important when a globe is filled with hemorrhage, which can obscure subtle abnormalities. In the case described in the present report, the mass was initially obscured by a pool of blood in the subretinal space. The mass was detected grossly only after blood had been cleared from the hemisected globe. Furthermore, the mass was small and largely necrotic, and viable neoplastic cells were sparsely distributed throughout the globe. Neoplastic cells that metasta-size to a globe are frequently sparsely distributed, and examination of deeper sections of the tumor are often required to fully evaluate the neoplastic cells.

For the dog of the present report, the postoperative recovery was without complication until approximately 3 months after globe enucleation, when the dog developed uveitis and acute blindness in its remaining right eye. The dog was treated with doxorubicin chemotherapy every 3 weeks along with systemic and intraocular administration of corticosteroids. Initially, the dog regained its sight, and clinical signs improved; however, 1.5 months after initiating chemotherapy, the dog developed intractable blindness in the right eye. Enucleation of the right eye was elected, and the globe was submitted for histologic examination. Histologically, a population of neoplastic cells morphologically identical to the neoplastic cells in the previously enucleated eye were found. A diagnosis of metastatic TVT to the right eye was made. Five months after the second surgery, the dog was apparently healthy and had no evidence of TVT recurrence.

For the dog of the present report, it is unclear why vincristine chemotherapy failed to achieve permanent remission of the TVT. Although permanent remission is achieved in most dogs with TVT following vincristine treatment, some authors have noted that the biological behavior of TVT is more aggressive in immunosuppressed dogs.1,6 However, the dog of the present report was systemically healthy and had no known evidence of immunosuppression. It is also possible that the intraocular concentration of chemotherapeutic agents was not adequate. To the authors' knowledge, intraocular concentrations of vincristine and doxorubicin following IV administration have not been evaluated in dogs. The specific sequence of events leading to bilateral intraocular metastasis of TVT in the dog of the present report was not known.

Acknowledgments

The authors declare that there were no conflicts of interest.

References

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