AFIP SYSTEMIC PATHOLOGY

JPC SYSTEMIC PATHOLOGY

INTEGUMENTAY SYSTEM

September 2019

I-N04

 

Signalment (JPC #1869901) Slide A: Age and breed unspecified dog

 

HISTORY: Mass from the toe

 

HISTOPATHOLOGIC DESCRIPTION: Digit (per contributor): Arising from the hyperplastic and ulcerated epidermis, extending to deep margins, and infiltrating preexisting bone is an unencapsulated, infiltrative neoplasm composed of anastomosing cords, trabeculae, and nests of polygonal cells supported by a moderate collagenous to desmoplastic stroma in which nests of neoplastic cells are surrounded by fibrous connective tissue and reactive fibroblasts. Neoplastic cells have distinct cell borders with prominent intercellular bridges, abundant brightly eosinophilic cytoplasm, and an irregularly round to oval nucleus with finely stippled chromatin and 1-3 magenta nucleoli. There is moderate anisokaryosis and anisocytosis. The mitotic rate averages 2 per 40x HPF with occasional bizarre mitotic figures. Frequent neoplastic cells exhibit dyskeratosis with brightly eosinophilic cytoplasm and pyknosis. There are multifocal keratin pearls characterized by brightly eosinophilic central accumulations of compact lamellations of keratin. Within the stroma of the neoplasm, there are low numbers of melanomacrophages, scattered lymphocytes, and plasma cells. Multifocally, neoplastic cells invade and replace preexisting bone in which existing bony trabeculae are lined by increased numbers of osteoclasts in Howship's lacunae (osteolysis) and multiple foci of woven bone lined by plump osteoblasts (reactive bone formation). Extensively the ulcerated epidermis is replaced by a serocellular crust composed of cellular debris, high numbers of neutrophils, hemorrhage, proteinaceous fluid, and fibrin.

 

MORPHOLOGIC DIAGNOSIS: Digit (per contributor): Squamous cell carcinoma, subungual, with osteolysis and reactive bone formation, breed not specified, canine.

 

Signalment (JPC #1619769), Slide B: Seven-year-old beagle

 

HISTORY: Abdominal skin from a beagle that was one of a large colony housed in outdoor kennels in Colorado

 

HISTOPATHOLOGIC DESCRIPTION: Haired skin, abdomen (per contributor): Arising from the hyperplastic and ulcerated epidermis and extending to the deep dermis is a poorly circumscribed, unencapsulated, infiltrative neoplasm composed of polygonal cells arranged in cords, trabeculae, and islands, with occasional individualized cells supported by moderate amounts of fibrovascular to often desmoplastic stroma. Neoplastic cells have variably distinct cell borders with prominent intercellular bridges and have abundant amphophilic to eosinophilic cytoplasm. Nuclei are irregularly round to oval with finely stippled chromatin and 1-4 distinct magenta nucleoli. The mitotic rate averages 3 per 40x HPF with occasional bizarre mitotic figures. There is moderate anisokaryosis and anisocytosis. Cords and islands often contain keratin pearls with central, compact, eosinophilic lamellations of keratin. Multifocally, follicles and adnexa are surrounded by many lymphocytes, plasma cells, and neutrophils. The epidermis is focally extensively ulcerated and replaced by a serocellular crust composed of fibrin, proteinaceous fluid, and neutrophils subtended by reactive fibroblasts, lymphocytes, plasma cells, histiocytes, and neutrophils. There is moderate parakeratotic and orthokeratotic hyperkeratosis. Within the subcutis, there is moderate multifocal hemorrhage, fibrin, and increased clear space (edema).

 

MORPHOLOGIC DIAGNOSIS: Haired skin, abdomen (per contributor): Squamous cell carcinoma, beagle, canine.

 

GENERAL DISCUSSION:

·      Squamous cell carcinoma (SCC) is the most common malignant skin neoplasm in cats; it is the second most common in dogs, following mast cell tumor

·      SCC is the second most common oral tumor in dogs

·      Arises from keratinocytes and occurs commonly in sun-damaged skin

·      SCC is usually preceded by actinic keratosis; other factors that can influence its occurrence include carcinogens, genetic factors, papillomaviruses and epidermal trauma (e.g. ear notching, branding, burns and chronic inflammation)

·      Highest incidence among short haired breeds with little skin pigmentation in both dogs and cats (predisposed dog breeds include Dalmatians, pit bull terriers, harlequin great Danes and beagles); SCC in pigmented areas more often are associated with papillomavirus (see chart below)

·      Claw bed (subungual): Most common neoplasm of the digit in dogs and cats; often more aggressive with multiple digits affected and usually associated with large breed, black-coated dogs (especially Labrador retriever, standard poodles, giant schnauzers, dachshunds, Briards, Beaucerons and Bouvier de Flanders)

·      SCC of the nasal planum arising in chronic cutaneous lesions of discoid lupus erythematosus has been reported in dogs

 

PATHOGENESIS:

·      Ultraviolet (UVB) radiation is the most important carcinogenic stimulus for cutaneous SCC

·      UV light > pyrimidine dimers (cytosine, uracil, thymine) in DNA > nucleotide repair pathway is overwhelmed > some DNA damage remains unrepaired > transcriptional errors (e.g. leading to overexpression of p53) > neoplasia

·      Action of sunlight may be related to overexpression of p53 protein as a result of UV-induced mutations of the p53 tumor suppressor gene

·      There is usually a progression, over months to years, from epidermal plaques, solar keratosis, and papillomas to carcinoma in situ, and finally to SCC

·      Other associated carcinogens include tobacco, coal tar, soot, arsenic, and smegma

·      Structural antigens from papillomavirus have been found in canine SCC suggesting a possible etiologic role

·      Proposed pathogenesis: UV light damage to DNA of a papillomavirus-infected epithelial cell > viral inhibition of p53 prevents DNA repair and apoptosis > viral-induced epithelial proliferation > increased replication of neoplasia-prone cells

·      Cox-2 was immunohistochemically detected in all canine and feline SCC in a study of 36 SCC cases

 

TYPICAL CLINICAL FINDINGS:

·      Typically locally invasive and slow to metastasize; however, SCCs arising from internal sites such as tonsil, stomach, and urinary bladder are more prone to metastasize

·      May metastasize to the lungs and regional lymph nodes

 

TYPICAL GROSS FINDINGS:

·      Variably sized; poorly demarcated; firm; white; nodular; papillary, plaque-like, or crateriform masses that are often ulcerated and red

·      Common sites in dogs include ventral trunk, limbs, digits, scrotum, and lips

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

·      Tumor cells breach the basement membrane to form islands, cords, and trabeculae within the dermis that are usually contiguous with the overlying epidermis; there is often formation of keratin pearls (concentric lamellae of keratin) and prominent intercellular bridges; poorly differentiated tumors may only show keratinization of individual cells (dyskeratosis)

·      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

·      Uncommon histologic variants of SCC:

·      Acantholytic SCC: There is dyshesion and degeneration of neoplastic cells (dropout) resulting in a pseudoglandular to pseudocyst formation with a single peripheral layer of neoplastic cells.

·      Spindle cell SCC: Neoplastic cells are large pleomorphic, fusiform to polygonal, and difficult to differentiate from stromal cells but are often positive for cytokeratin

·      Verrucous SCC: Rare; observed only in dogs; very low-grade malignancy with both exophytic and endophytic architecture characterized by broad papillary proliferations, trabeculae with rounded ends, and large tubular invaginations

 

ADDITIONAL DIAGNOSTIC TESTS:

·      Immunohistochemistry:

·      Most carcinomas are positive for cytokeratin which may be helpful in differentiating SCC from other anaplastic neoplasms

·      SCCs in dogs are positive for cytokeratin 6 and 10, which can be helpful in distinguishing them from some basosquamous variants

 

DIFFERENTIAL DIAGNOSIS:

Histologic differential diagnosis:

·      Cutaneous location:

·      Squamous cell carcinoma in situ: Confined by the basement membrane

·      Basosquamous carcinoma: Low-grade malignant tumor comprised primarily of dermal lobules of basaloid cells with centralized foci of atypical abruptly keratinized cells

·      Papilloma (I-V01)

·      Subungual location: Keratoacanthoma (I-N31)

 

COMPARATIVE PATHOLOGY:

·      Cats:

·      SCC:

·      White cats are predisposed to solar induced damage;

·      Common sites include the nasal planum, pinnae, and eyelid

·      High numbers of stromal cancer-associated fibroblasts are associated with a shorter survival time in cats with oral SCC

·      Multicentric squamous cell carcinoma in situ ("Bowen-like disease"):

·      Affects middle aged to older mixed-breed cats

·      Found in haired-pigmented skin and is unrelated to sunlight exposure, but has been associated with papillomavirus

·      Malignant change that is confined to the epidermis without breaking through the basement membrane

·      Microscopically, there is abrupt hyperplasia and dysplasia of the epidermis and follicular outer root sheath

·      Caused predominantly by Felis catus papillomavirus 2 (FcaPV-2)

·      More common and more aggressive in Devon Rex cats.

·      Loss of retinoblastoma protein, and subsequent increase in p16, is associated with papilloma viral DNA in viral plaques, bowenoid in situ carcinoma and SCC

·      Cattle:

·      SCC: Common on eyelids, conjunctiva, pinna, back, distal limbs, and vulva; Herefords and Ayrshires are at increased risk

·      Carcinoma of the horn of cattle: Uncommon; almost exclusive to castrated male adult cattle in India and neighboring countries; infiltrates and destroys the horn core and may invade adjacent sinuses and cranial bone

·      Horses: Common on penis, prepuce, periocular, perianal

·      Appaloosa, American paint horse, quarter horse, and males are predisposed

·      SCC is also found in the nonglandular stomach (this is the most common gastric neoplasm in horses, D-N08)

·      A report of SCC with clear cell differentiation in eyelid (Stein 2019)

·      Rodents, pigs: SCC of the nonglandular (pars esophagea) stomach

·      Sheep: Muzzle, lips, eyelids, perineum, vulva (in recently sheared sheep), pinnae; Merinos may be at risk

·      Goats:

·      Udder, perianal, horn base, pinnae, eyelid, vulva

·      Angoras and Boers may be at increased risk

·      SCC was the second most common neoplasm in goats (lymphoma was #1) in a study of 102 goat neoplasms

·      Rabbits: Subungual, eyelid, and extremities

·      SCC also can occur at brand sites in livestock, especially freeze brand sites

·      California sea lion: Zalophus californianus papillomavirus-1 associated with cutaneous SCC (Luff 2018)

·      Captive reptiles: Papillomaviral DNA amplified via PCR from SCC lesion in a Dumeril’s boa (Eleni 2017)

 

Papilloma viruses associated with pre-neoplastic and neoplastic skin lesions in animals (adapted from Munday 2016, Mauldin 2016, and Vitiello 2017):

 

Animal species

Skin lesion

Papillomavirus

Cat

Feline viral plaque progressing to BISC

FcaPV-1, -2, -3

Cat

SCC

FcaPV-2

Dog

Canine pigmented viral plaque progressing to ISC and SCC

CfPV-3

Dog

Endophytic papilloma and SCC in immunosuppressed dogs

CfPV-2

Dog

In situ SCC

CfPV-7

Horse

Equine sarcoid

BPV-1, -2

Horse

Equine papillomas, ISC and SCC

EcPV2

Sheep

SCC

OaPV-3

Rabbit

Cutaneous SCC

CRPV

 

FcaPV, Felis catus papillomavirus; CfPV, Canis familiaris papillomavirus; COPV, canine oral papillomavirus; BPV, bovine papillomavirus; CRPV, cotton-tail rabbit papillomavirus; RaPV, rousettus aegyptiacus papillomavirus type I; MnPV, Mastomys natalensis papillomavirus; EcPV2, equine papillomavirus type 2; OaPV, Ovine aries papilloma virus

 

REFERENCES:

1.    Goldschmidt MH, Kiupel M, Klopfleisch R, Munday JS, Scruggs JL. Epithelial Tumors of the Skin. Surgical Pathology of Tumors of Domestic Animals. Vol 1. Gurnee, IL: Davis-Thompson DVM Foundation; 2018:47-51, 54-70.

2.    Gross TL, Ihrke PJ, Walder EJ, Affolter VK: Epithelial neoplasms and other tumors. In: Skin Diseases of the Dog and Cat. 2nd ed. Ames, IA: Blackwell Science; 2005:581-589.

3.    Hargis AM, Myers S. The integument. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 6th ed. St. Louis, MO: Elsevier; 2017: 1061-3,1107.

4.    Mauldin EA and Peters-Kennedy J. Integumentary system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 1. 6th ed. St. Louis, MO: Elsevier; 2016:706-714.

5.    Mestrinho LA, et al. p63 and E-cadherin expression in canine oral squamous cell carcinoma. Vet Pathol. 2015;52(4):614-20.

6.    Millanta F, Andreani G, et al. Correlation between cyclo-oxygenase-2 and vascular endothelial growth factor expression in canine and feline squamous cell carcinomas. J Comp Path. 2016;154:297-303.

7.    Munday JS, Fairley R, Atkinson K. The detection of Felis catus papillomavirus 3 DNA in a feline bowenoid in situ carcinoma with novel histologic features and benign clinical behavior. J Vet Diagn Invest. 2016;28(5):612-5.

8.    Zhu KW, Affolter VK, et al. Equine genital squamous cell carcinoma: In situ hybridization identifies a distinct subset containing Equus caballus papillomavirus 2. Vet Pathol. 2015;52(6):1067-1072.

9.    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.

10. Luff JA, Burns RE, et al. Cutaneous squamous cell carcinoma associated with Zalophus californianus papillomavirus 1 in a California sea lion. J Vet Diagn Invest. 2018;30(4):572-575.

11. Munday JS, Thomson NA, et al. Identification of Felis catus papillomavirus 3 in skin neoplasms from four cats. J Vet Diagn Invest. 2018;30(2):324-328.

12. Hoggard N, Munday JS, Luff J. Localization of Felis catus papillomavirus type 2 E6 and E7 RNA in feline cutaneous squamous cell carcinoma. Vet Pathol. 2018;55(3):409-416.

13. Eleni C, Corteggio A, et al. Detection of Papillomavirus DNA in cutaneous squamous cell carcinoma and multiple papillomas in captive reptiles. J Comp Path. 2017;157:23-26.

14. Vitiello V, Burrai GP et al. Ovis aries papillomavirus 3 in ovine cutaneous squamous cell carcinoma. Vet Pathol. 2017;54(5):775-782.

15. Nagamine E, Hirayama K, et al. Invasive front grading and epithelial-mesenchymal transition in canine oral and cutaneous squamous cell carcinomas. Vet Pathol. 2017;54(5):783-791.

16. Sozmen M, Devrim AK, et al. Significance of angiogenic growth factors in bovine ocular squamous cell carcinoma. J Comp Path. 2019;170:60-69.

17. Njaa BL. The Ear. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 6th ed. St. Louis, MO: Elsevier; 2017: 1249.

18. Labelle P. The Eye. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 6th ed. St. Louis, MO: Elsevier; 2017: 1295-6.


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