JPC SYSTEMIC PATHOLOGY

SPECIAL SENSES SYSTEM

APRIL 2024

S-N01 (NP)

 

SLIDE A: SIGNALMENT(JPC #2051261): Tissue from a 9-year-old ox

 

HISTORY: None

 

HISTOPATHOLOGIC DESCRIPTION: 1. Conjunctiva: Arising from the mucosal epithelium, effacing the subepithelial connective tissue, and extending to all margins is an unencapsulated, densely cellular, infiltrative neoplasm composed of polygonal cells arranged in islands, cords, and anastomosing trabeculae on a moderate fibrovascular stroma. Neoplastic cells mature in a disorganized manner; they multifocally mature through a granular cell layer, and neoplastic cells occasionally surround concentric lamellations of keratin (keratin pearls). Neoplastic cells have variably distinct cell borders, a moderate amount of eosinophilic cytoplasm that is often vacuolated, and a round to oval nucleus with coarsely clumped chromatin and up to three distinct nucleoli. There are approximately 2 mitotic figures per 2.37mm². Neoplastic cells exhibit widespread scattered individual cell necrosis. Many lymphocytes, plasma cells, macrophages, and neutrophils are admixed with hemorrhage, fibrin, and edema and diffusely infiltrate the fibrovascular stroma and extend into the superficial conjunctival subepithelial connective tissue. There are multifocal large areas of lytic necrosis.  Multifocally, few vessels contain fibrin thrombi. Focally the epithelium is eroded or ulcerated and replaced by a serocellular crust, and subepithelial lymphatics are diffusely dilated.

2. Lymph node, site unspecified: No significant lesions.

 

MORPHOLOGIC DIAGNOSES: 

1. Conjunctiva: Squamous cell carcinoma, breed unspecified, bovine.

2. Lymph node, site unspecified: Essentially normal tissue.

 

SLIDE B: SIGNALMENT (JPC# 4057684): 13-year-old quarter/paint mare (Equus ferus caballus), equine.  

 

HISTORY: The horse presented with a small flat plaque on the surface of the left eye that had begun to grow rapidly. The mass was 0.7 cm, well-demarcated and bulged from the corneal surface and focally effaced the medial limbus. Incisional biopsy was performed and diagnosed as squamous cell carcinoma. Over six months, the mass grew to 3 x 1.5 cm in size, covering the cornea and impeding vision. The eye was enucleated and submitted for histopathological examination. 

 

HISTOPATHOLOGIC DESCRIPTION: Arising from the bulbar conjunctiva and covering the corneal epithelium is an unencapsulated, well-demarcated, infiltrative, moderately cellular neoplasm composed of stratified epithelial cells arranged in variably sized nests, cords, and trabeculae on variably dense fibrovascular stroma. The neoplastic cells have distinct cell borders, an abundant amount of pale eosinophilic cytoplasm, and vesiculate nuclei with one distinct nucleolus. Anisocytosis and anisokaryosis are mild and there are 5 mitotic figures per 2.37mm². Occasionally, cellular islands and nests contain central areas of intensely eosinophilic keratinized cells. There is scattered, multifocal single cell necrosis. The neoplastic cells grow over and partially efface and compress the corneal epithelium. The corneal epithelium is multifocally ulcerated, with ulceration accompanied by a moderate lymphoplasmacytic and occasionally neutrophilic inflammatory infiltrate. The corneal stroma multifocally contains small caliber blood vessels(vascularization) and multifocally displays loss of stromal clefting (edema). 

 

MORPHOLOGIC DIAGNOSIS: Conjunctiva: Squamous cell carcinoma, mixed breed, equine. 

 

GENERAL DISCUSSION:

• Squamous cell carcinoma (SCC) arises from the conjunctival epithelium of the limbus, nictitating membrane, or eyelid in cattle, horses, cats, and dogs, in that order of frequency
• Bovine ocular SCC (BOSCC) is the most common and economically important neoplasm of North American cattle
• Etiology is multifactorial; predisposing factor is lack of periocular pigment (Hereford breed); incidence increases with age and exposure to ultraviolet light; Bos taurus cattle are more often affected than are Bos indicus 
• Metastatic or invasive potential has not been correlated with histologic criteria, but there is a correlation between site of origin and subsequent behavior; parotid lymph node is the initial site of metastasis; intraocular invasion is uncommon

• Site of origin (order of prevalence):
  • Bulbar conjunctiva of the limbus (70% of all occurrences)
  • Nictitating membrane 
  • Palpebral conjunctiva of the true eyelid

 

PATHOGENESIS:

• Ultraviolet light (wavelength B) induces cutaneous neoplasia through genomic damage through the formation of pyrimidine dimers in DNA; an attempt to repair this damage occurs through nucleotide excision repair (NER), but when NER is overwhelmed, some DNA escapes repair, leading to transcriptional errors and neoplasia 
• Ocular SCC in all species develops through a series of premalignant stages: epidermal plaque (acanthosis) > keratoses (localized focal hyperkeratosis) > papilloma (before malignant transformation over months or years) > dysplasia > carcinoma in situ > SCC
• No viral particles or viral genomes have been demonstrated in ocular SCC yet
• Spontaneous regression of precancerous lesions may occur in an estimated 25-50% of cases; rarely, ocular SCC regresses spontaneously 
• Systemic metastasis occurs late, and local invasion may be aggressive 
• Associated with increased p53 immunohistochemical staining

 

TYPICAL CLINICAL FINDINGS:

• In general, premalignant squamous cell tumors are small, white, and elevated with hyperplastic plaques or papilloma-like structures; in contrast, malignant tumors are more irregular, nodular, pink, erosive, and are often necrotic
• The bulbar conjunctiva at the limbus is the most frequent site of origin in cattle

 

TYPICAL GROSS FINDINGS:

• Variably sized, poorly demarcated, firm, white, nodular, papillary, plaque-like, or crateriform masses that are often ulcerated and red
• Neoplasm may protrude through the palpebral fissure, invade anterior chamber, infiltrate entire globe
• Secondary changes of hemorrhage, necrosis, ulceration, and inflammation are present in more than 40% of invasive carcinomas

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Tumor cells breach the basement membrane (only absolute proof of malignancy) to form islands, cords, and trabeculae within the subepithelial connective tissue and are usually contiguous with the overlying epidermis 
• Tumor cells have vesicular nuclei with one or multiple very prominent nucleoli; cytoplasm is typically abundant and eosinophilic
• Tumor cell invasion is usually associated with marked desmoplasia 
• Mitotic figures are often numerous and in proportion with the degree of anaplasia
• Range from well-differentiated carcinoma with prominent intercellular bridges and keratin pearl formation (concentric lamellae of keratin) to anaplastic carcinoma; poorly differentiated tumors may only show keratinization of individual cells
• Marked lymphoplasmacytic infiltration may be present
• Progression of histologic lesions in the development of SCC:

• Epidermal plaque: Marked acanthosis with variable keratinization and dyskeratosis, and epidermal down-growth into subconjunctival connective tissue
• Papilloma: Acanthosis and parakeratosis/ hyperkeratosis with papillary projections supported by vascularized connective tissue core
• Carcinoma in situ: Increasing dysplastic cell nests in deeper layers of plaques or papillomas
• Carcinoma: Squamous cell invasion across the basement membrane; often accompanied by lymphocytic-plasmacytic infiltration

 

ADDITIONAL DIAGNOSTICS:

 

DIFFERENTIAL DIAGNOSIS:

Gross

• Epidermal plaque - Single or multiple; opaque or gray/white; raised; variable shape; smooth or irregular surface
• Papilloma - Sessile or pedunculated mass that is an exophytic growth of papillary projections; merges with underlying plaque  
• Carcinoma in situ (noninvasive carcinoma) resembles the papilloma grossly 

 

Microscopic:

• Epidermal plaque - Epithelial hyperplasia with atypia, marked acanthosis, variable hyperkeratosis, dyskeratosis, and epidermal downgrowth into subconjuctival connective tissue; no invasion through basement membrane
• Papilloma - Multiple papillary projections (fronds) that are covered by hyperplastic and hyperkeratotic epithelium and supported by a vascularized connective tissue core; there is marked para- and hyperkeratosis 
• Carcinoma in situ arises by focal or multifocal transformation of dysplastic cell nests in the deep layers of plaques or papillomas; there is lack of invasion across the basement membrane (i.e. “in situ”)

 

COMPARATIVE PATHOLOGY:

• Horses: Ocular SCC is common, especially in horses with unpigmented palpebrae; in contrast to cattle, SCCs in horses arise most commonly at the edge of the third eyelid followed by limbic bulbar conjunctiva; bilateral involvement is seen in 15-20% of cases; 10-15% of cases have regional to distant spread; most common in paints and quarter horses; morphologic variants include one report of clear cell SCC
• Dogs - SCC infrequently involves the eye; SCC accounts for approximately 2% of ocular neoplasms  
• Cats - Ocular SCC is rare and often affects skin of the eyelid 

 

REFERENCES:

1. Deschuillers PL, Raskin RE. Eyes and Ears. In: Raskin RE, Meyer DJ, Boes KM eds. Canine and Feline Cytopathology: A Color Atlas and Interpretation Guide. 4th ed. St. Louis, MO: Elsevier; 2023:567-568. 
2. Dubielzig RR. Tumors of the eye. In: Meuten DJ, ed. Tumors in Domestic Animals. 5th ed. Ames, IA: Iowa State Press; 2017:893-895.
3. Fisher DJ. Cutaneous and Subcutaneous Lesions. In: Valenciano AC, Cowell RL, eds. Diagnostic Cytology and Hematology of the Dog and Cat. 5th ed. St. Louis, MO: Elsevier Mosby; 2014:92-93. 
4. Grahn BH, Peiffer RL. Veterinary Ophthalmic Pathology. In: Gelatt KN, Gilger BC, Kern TJ, eds. Veterinary Ophthalmology. 5th ed. Baltimore, MD: Lippincott Williams & Wilkins; 2013:503-508.
5. Labelle P. The Eye. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO:Mosby; 2022:1409-1410, 1413.
6. Maggs DJ. Diseases of the eye. In: Smith BP, ed. Large Animal Internal Medicine. 4th ed. St. Louis, MO: Mosby Elsevier; 2009:1301.
7. Raskin RE, Conrado FO. Integumentary System. In: Raskin RE, Meyer DJ, Boes KM eds. Canine and Feline Cytopathology: A Color Atlas and Interpretation Guide. 4th ed. St. Louis, MO: Elsevier; 2023:67-70. 
8. Schmidt R, Reavill DR, Phalen DN. Pathology of Pet and Aviary Birds. 2nd ed. Ames, IA: John Wiley & Sons, Inc.; 2015: 274.
9. Sozmen M, Devrim AK, Sudagidan M, Kabak YB, Beytut E, Ozba B.  Significance of angiogenic growth factors in bovine ocular squamous cell carcinoma. J Comp Pathol. 2019;170:60-69.
10. Stein L, Sledge D, Smedley, R, Kuipel M, Thaiwong T. Squamous cell carcinoma with clear cell differentiation in an equine eyelid. J Vet Diagn Invest. 2019;31(2):259-262.
11. Whitaker CJG, Gelatt KN, Wilkie DA. Food animal ophthalmology. In: Gelatt KN, ed. Veterinary Ophthalmology. 3 rd ed. Baltimore, MD: Lippincott Williams & Wilkins; 1999:1140-51.
12. Wilcock BP: Special Senses. In: Maxie MG, ed. Jubb, Kennedy and Palmers Pathology of Domestic Animals, Vol 1. 6th ed. Philadelphia, PA: Elsevier-Saunders; 2016:479-480.
13. Wilcock B, Dubielzig RR, Render JA. Histological classification of ocular and otic tumors of domestic animals. In: Schulman FY, ed. World Health Organization International Histological Classification of Tumors of Domestic Animals. 2 nd series, vol. IX, Washington, DC:Armed Forces Institute of Pathology; 2002:16, 18.
14. Young KM and Teizeira LBC. Eyes and associated structures. In: Valenciano AC and Cowell RL, eds. Cowell and Tyler’s Diagnostic Cytology and Hematology of the Dog and Cat. 5th ed. St. Louis, MO: Elsevier; 2020:153-154.

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