4 Michael H. Goldschmidt1 and Kyle H. Goldschmidt2 1University of Pennsylvania, USA 2University of St. Thomas, USA Skin tumors are some of the more common neoplasms in veterinary medicine and probably the single most common histopathology specimen sent to diagnostic laboratories. Because they are easily seen by the owner, they are brought to the attention of the veterinarian and usually are fairly easy to remove. They are frequently submitted for histopathologic evaluation. In this chapter the tumors have been classified using the International Histological Classification of Epithelial and Melanocytic Tumors of the Skin of Domestic Animals, but with modifications and additions where appropriate.1–3 This classification system is similar to that found in several texts.1,4–6 These references will not be further cited in the text, but provide additional information on the clinical aspects and histopathology of skin tumors. The next chapter in this book is on mesenchymal tumors of the skin and subcutaneous tissues of domestic animals. The skin consists of the epidermis and its associated appendageal structures – the hair, the sebaceous glands and modified sebaceous glands, the apocrine glands and modified apocrine glands, and the eccrine glands – all supported by a dermis and panniculus. Melanocytes are present between the basal cells of the epidermis and between the germinative cells of the hair follicle bulb. Much of the information on incidence, age, sex, and breed predilection, and site of occurrence of these tumors in the dog and cat is from a database of surgical pathology accessions (1986–2011) in the Laboratory of Pathology, University of Pennsylvania, School of Veterinary Medicine. The canine database (331,000 cases) consisted of approximately 39,000 epithelial neoplasms, 6000 melanocytic neoplasms, 9000 hamartomas, 8000 cysts, and 9000 tumor‐like masses. The SAS/STAT® 9.2 program was used to run the statistical analysis. The Cochran–Mantel–Haenszel statistics were used to calculate the logit common odds ratio (OR) for breeds at increased risk for each specific tumor (see appendix on Canine breed predispositions, p. 976). Ninety‐five percent confidence limits (95% CL) were determined using the Greenland and Robins covariance estimate. P‐values were calculated using the Breslow–Day test for homogeneity of the odds ratio, which can be approximated by a Pearson chi‐squared distribution with q − 1 degrees of freedom. Statistical significance was defined as p < 0.05. In the text, the odds ratio is noted in parentheses (OR) after the breed. In most instances only the five breeds with the highest odds ratio are reported in the text. In some instances although a breed may have a very high odds ratio the 95% CL levels are very wide, either because of the small number of cases available for statistical analysis for a specific tumor or because this is an uncommon breed. An example of this is the otterhound which, according to our data, has a high risk of developing a pilomatricoma (OR = 27.4) but the 95% CL levels are very wide (8.3–90.5) and p = 1.2 × 10−16. When common tumors arise in popular breeds then the 95% CL levels are narrow. There are several breeds with high odds ratios that are well documented to be predisposed to developing specific epithelial neoplasms. Most significant are pilomatricomas and Kerry blue terriers (OR = 60, 95% CL = 48.0–75.0), infundibular keratinizing acanthomas and Norwegian elkhounds (OR = 33.2, 95% CL = 27.1–40.6), subungual squamous cell carcinoma and giant schnauzers (OR = 28.6, 95% CL = 21.5–37.8), and trichoepitheliomas and basset hounds (OR = 15.6, 95% CL = 14.3–17.0). In the appendix on Canine breed predispositions for epidermal and melanocytic tumors (p. 976) we have provided a table of breeds that are predisposed to developing epidermal or melanocytic tumors that have an odds ratio >3.0 along with the 95% CL levels and p‐values. Breeds with very wide 95% CL levels have been excluded even though p‐values are significant because of the very small number of cases in the database. It can be seen from the appendix on Canine breed predispositions that certain breeds are predisposed to developing neoplasms with follicular differentiation (e.g., bearded collies are prone to infundibular keratinizing acanthoma, trichoblastoma, and pilomatricoma), whereas other breeds have a very low incidence of epithelial and melanocytic tumors but are known to have a very high incidence of mesenchymal neoplasm (e.g., the boxer is prone to developing cutaneous mast cell tumors). There is most likely a genetic basis for the higher incidence of certain neoplasms in certain breeds and the decreased incidence in other breeds, which has arisen because these breeds have been selected to have specific traits. This work awaits further research. Basal cell neoplasms are epithelial neoplasms which show no epidermal or adnexal differentiation. The neoplastic cells morphologically resemble the normal basal cells of the epidermis from which they may arise. The neoplasm previously classified as a basal cell tumor in the dog, horse, and sheep and the spindle cell and trabecular variant of basal cell tumor in the cat, has been reclassified as a trichoblastoma.1 The neoplasm previously classified as a basal cell tumor in the cat that exhibits focal or multifocal ductal differentiation (lumen formation) has been reclassified as an apocrine ductal adenoma because the cells around the lumina stain positive on immunohistochemistry with CAM5.2, indicative of apocrine differentiation. Those basal cell neoplasms that do not show ductal differentiation have retained their basal cell tumor designation. The diagnosis basal cell carcinoma is used for a low‐grade malignant tumor. Table 4.1 Revised classification of basal cell neoplasms Basal cell tumors are common in the cat.2–4 Cats as young as 1 year of age may be affected with a peak incidence between 6 and 13 years. Himalayan, Persian, and domestic long hair cats are at increased risk and domestic short hair cats are at decreased risk for developing basal cell tumors. There is no sex predilection. In the cat basal cell tumors are most commonly found on the neck and head. Multicentric basal cell tumors have been reported to occur,5 but account for only 1% of cases. Most tumors present clinically as well circumscribed intradermal and subcutaneous masses. The overlying epidermis may show loss of hairs and ulceration. On cut section many of the tumors are pigmented brown/black. Central cystic degeneration with the accumulation of amorphous dark brown material within the center of the tumor may be found. The mass is frequently well demarcated from the surrounding dermal and subcutaneous tissue. Many basal cell tumors are well‐circumscribed intradermal masses that may extend into the subcutaneous adipose tissue as the tumor enlarges. There is often an association with the overlying epidermis, even in tumors that are ulcerated. The tumor is multilobulated with the individual lobules separated by a fibrous stroma. Central cystic degeneration of the tumor lobules is common with an accumulation of brown/black necrotic debris in the center of the cysts and a zone of viable tumor cells at the periphery (Figure 4.1B). The individual neoplastic cells are small, round to polyhedral in morphology. The nuclei are ovoid, nucleoli are inconspicuous and few mitotic figures are found. A small amount of cytoplasm is present. Melanocytes may be found interspersed between the basal cells, with transfer of melanin to the neoplastic cells. However, melanophages are often present in the interlobular connective tissue stroma (Figure 4.1B). Figure 4.1 (A,B) Basal cell tumor, cat. (A) The mass is multilobulated with central necrosis in the center of the lobules. (B) At the periphery of the mass the neoplastic cells are small, round with chromatic nuclei. These neoplastic cells exhibit no nuclear or cellular pleomorphism. Within the interstitial stroma are numerous melanophages. (C–F) Basal cell carcinoma – infiltrative type, cat. (C) There is an association with the overlying epidermis. The neoplastic cells are infiltrative of the dermis. (D) At the base of the neoplasm the invasive neoplastic basal cells incite a desmoplastic response. (E) There is an association with the overlying epidermis. (F) The neoplastic cells form large islands with central areas of necrosis similar to feline basal cell tumors (see Figure 4.1A). (G) Feline basal cell carcinoma – clear cell type. Basal cell tumors do not metastasize. They are usually slow‐growing intradermal masses. The treatment of choice is surgical excision. Incomplete excision may result in tumor recurrence. This is the low‐grade malignant counterpart of the neoplasm described above characterized by a lack of epidermal or adnexal differentiation. Basal cell carcinomas are relatively common in the cat. Cats between 3 and 16 years old are affected with the peak incidence between 12 and 16 years. Ragdolls (9.0) have a breed predilection. The head and neck are most often affected, but 3% of cases present with multiple cutaneous masses. The neoplasm, which often shows epidermal ulceration and extensive infiltration of the dermis and subcutaneous tissue, feels firm on palpation. Two variants of basal cell carcinoma are found: This neoplasm is locally invasive, but few cases with proven metastases have been reported. The infiltrative variant is more likely to recur at the surgical site and to show vascular/lymphatic invasion. This is a benign, exophytic proliferation of the epidermis (squamous epithelium) caused by an infection with a papillomavirus (PV), which are epitheliotropic, circular, double‐stranded DNA viruses within the family Papillomaviridae. Papillomaviruses are associated with benign and malignant tumors in humans and animals. A large number of different papillomaviruses have been identified. Each species may be infected by several papillomaviruses, with each virus subtype often associated with a specific tissue. Reviews covering this rapidly evolving topic can be found in the following: papillomaviruses and papillomavirus‐associated cutaneous neoplasia in equine,1,2 bovine,3,4 feline,5 and canine6,7 animals; a comparison between bovine and human papillomavirus infection;3 a review of the molecular biology of the papillomavirus and associated disease in humans.8 A list of canine papillomaviruses and associated clinical symptoms is given in Table 4.2. Table 4.2 Canine papillomaviruses and clinical symptoms Bovine papillomavirus DNA has been found in milk, blood, urine, semen, and spermatozoa of bovine papillomavirus‐infected animals.9 There is expression of bovine papilloma viral proteins in lymphocytes and productive infections of the placenta.4 Canine oral papillomas, bovine penile fibropapillomas, equine sarcoids, equine genital plaques, and equine penile neoplasms that are caused by papillomaviruses are discussed elsewhere. Cutaneous papillomas (papillomatosis) are common in dogs, horses, and cattle, uncommon in cats, sheep, and goats, and rare in pigs. In most species, except the goat, young animals are preferentially affected; in goats, adult females are most commonly affected. There are reports of congenital papillomas in foals, a calf, and a piglet. The lesions should be differentiated from a squamous papilloma (Table 4.3). Table 4.3 Points of differentiation between viral and squamous papillomas There is no known breed predilection for papillomas in horses or cattle. In goats, Saanen goats are primarily affected. More popular breeds of dog at increased risk are the French bulldog (9.5), Rhodesian ridgeback (6.5), whippet (6.4), vizsla (4.1), and bull mastiff (4.1). There is no known sex predilection in any species that develops cutaneous papillomas, except the goats, where white lactating animals are primarily affected. In cattle, papillomas occur most commonly at sites of abrasion where the virus can enter the epidermis and produce the cutaneous lesions, including the ears following tattooing and the teats. Thus the sites where the papillomas may be found are greatly dependent on husbandry practices used in agriculture. Lesions in cattle are most often multicentric and frequently tend to involve the head and neck (Figure 4.2A). Fibropapillomas are fairly common on the penis of bulls. Figure 4.2 (A) Bovine papillomavirus infection, multicentric. (Image courtesy of Perry Habecker.) (B) Equine papillomavirus infection, multicentric. (Image courtesy of Perry Habecker.) (C) Canine papilloma, cut surface of gross lesion. (D) Bovine papilloma, histopathology with epidermal hyperplasia, compact orthokeratotic hyperkeratosis, enlarged keratohyaline granules and several koilocytes. (E) Canine papilloma histopathology with cells in the upper spinous and granular cell layer with a viral cytopathic effect (see below). (F) Canine papilloma histopathology with parakeratosis and numerous cells in the upper spinous layer with basophilia to the cytoplasm of the cells (viral cytopathic effect). (G) Canine papilloma – infundibular subtype with marked viral cytopathic effect at the base of the infundibulum and accumulation of parakeratotic keratinocytes within the infundibular lumen. (H) Canine papilloma – infundibular subtype, immunohistochemistry (DAB). (I) Canine papilloma – Le Net subtype. (J) Canine papilloma – Le Net subtype with marked clumping of the cytoplasmic keratin tonofilaments and basophilic intranuclear viral inclusion bodies. (K) Canine papilloma – regressing, with extensive infiltration of the basal and suprabasal epidermis by small lymphocytes and several apoptotic keratinocytes in the spinous layer. In horses lesions are found on the face, primarily around the nose and lips, especially in young horses; in goats they are found on the udder and in sheep the head and ears (Figure 4.2B). Lesions in affected dogs may be solitary or multicentric and the head is most commonly involved (Figure 4.2.C). Cutaneous papillomavirus infection may also present as multiple plaques (see Pigmented viral plaques) and nodules in dogs. The histopathologic features of cutaneous papillomas were studied in the horse by Hamada et al.10 who subdivided the naturally developing lesions into three phases: a growing phase, a developing phase, and a regressing phase. The growing phase was characterized by basal cell hyperplasia, mild to moderate acanthosis, hyperkeratosis and parakeratosis, and a few intranuclear inclusion bodies. The developing phase was characterized by severe acanthosis with cell swelling and marked hyperkeratosis and parakeratosis. Many intranuclear inclusion bodies were present in swollen or degenerating cells of the upper spinous and granular cell layer. The regressing phase was characterized by slight epidermal hyperplasia, accentuation of the rete, moderate proliferation of fibroblasts, and collagen deposition along with an infiltrate of T lymphocytes at the epidermal–dermal interface. Papillomas in horses show hypopigmentation of the affected skin which is due to decreased numbers of melanocytes in the basal layer, abnormal melanosome formation during melanin synthesis and abnormal interactions between melanocytes and keratinocytes. Langerhans cells in the epidermis are decreased in number and size during the developing phase, but are increased in number and are hyperfunctional in the regressing phase. There are also abnormalities in the expression of cytokeratins in the papillomavirus‐infected cells, with expression of a 54 kDa keratin by the suprabasilar keratinocytes in the infected epidermis.11 Electron microscopy showed decreased intracytoplasmic tonofilaments and desmosome–tonofilament complexes due to an abnormality in the proliferation and terminal differentiation of keratinocytes in the papilloma (viral cytopathic effect). In dogs, cutaneous papillomas are associated with CPV‐2, CPV‐6, and CPV‐7 (personal communication, J.A. Luff). Three different histopathologic variants of papillomavirus are found.12 Immunohistochemistry may be required to identify the papillomavirus and will detect the papillomavirus L1 protein in the stratum granulosum and corneum. Spontaneous regression of papillomavirus infection due to a cell‐mediated immune response has been noted, with protection from subsequent infection by neutralizing antibodies.14 Cell‐mediated immunity is of greater importance in producing regression of papillomas. Therefore, several prophylactic vaccines have been developed; however, “self‐vaccination” from traumatized lesions often leads to regression of lesions without recurrence. In regressing papillomas there is a lymphocytic infiltrate at the epidermal–dermal interface and within the epidermis (Figure 4.2K). Lymphoid cells are often found adjacent to apoptotic keratinocytes (satellitosis). These lymphoid cells are associated with upregulation of ICAM‐1 on keratinocytes and E‐selectin and VCAM‐1 on endothelial cells at the site of infection.14 This is a benign, endophytic proliferation of the epidermis that is caused by infection with a papillomavirus (CPV‐1, CPV‐2, CPV‐6). This neoplasm has only been reported in the dog and is uncommon.15 These are uncommon skin neoplasms with no known age, breed, or sex predilection. Lesions are most commonly found on the forelimbs and abdomen as solitary lesions and are 1–2 cm in diameter, located within the dermis, extending into the subcutaneous tissue as the lesions increase in size. On cut section the invaginated mass shows proliferation of thin filiform projections into the center of the mass, where keratin accumulates (Figure 4.3A). There is a well‐demarcated border. Figure 4.3 (A) Canine inverted papilloma, cut surface of gross lesion. (B) Canine inverted papilloma with papilliform projections extending into the center of the mass. The histological features are the same as those described for papillomas, with a supporting stroma of connective tissue covered by a hyperplastic epidermis, enlarged keratohyaline granules, gray/blue cytoplasmic pallor (viral cytopathic effect), and in some cases eosinophilic intranuclear inclusions (Figure 4.3B). Inverted papillomas should be differentiated histologically from the infundibular variant of cutaneous papilloma (see above). The latter arise from the infundibulum of a single follicle and are often multicentric, whereas inverted papillomas are an invagination of the entire epidermis and are usually solitary lesions. In the literature infundibular variants of cutaneous papilloma have been referred to as inverted papillomas. The masses are slow growing and amenable to surgical excision. These are papillomavirus‐induced lesions. In dogs, CPV‐3, 4, 5, 8, 9, 10, 11, 12, 14, and 16 have been associated with viral plaque formation with focal or multifocal epidermal hyperplasia and hyperpigmentation. In cats, infection of the epidermis by FdPV‐1, FdPV‐2, results in the formation of a feline viral plaque (FVP). Canine viral plaques are usually multicentric and are mostly found on the ventral abdomen and limbs. In many instances the animals are immunosuppressed. The hyperpigmented lesions are oval and vary from 0.5 to 3 cm in diameter (Figure 4.4A). A multifocal filiform variant of pigmented plaques has also been seen. Lesions may occur at any age with a peak incidence between 6 and 8 years old and are more frequently seen in the pug, Italian greyhound, Welsh terrier, miniature dachshund, and miniature schnauzer. No sex predisposition has been noted. Figure 4.4 (A–D) Canine pigmented plaques. (B) With an abrupt transition from normal to hyperplastic epidermis. (C) Transition zone between normal and hyperplastic epidermis with occasional koilocytes and enlarged keratohyaline granules. (D) Immunohistochemistry to demonstrate papillomavirus within the granular cell layer (DAB). (E) Equine aural plaque with histopathology. Feline viral plaques typically appear as multiple, scaly, flat, variably pigmented lesions.5 Plaques can develop anywhere on the body. Immunosuppression (FIV infection or long‐term immunosuppressive therapy) may predispose to plaque formation but most cats are immunocompetent. The lesions are sharply demarcated from the normal epidermis. There is mild papillary epidermal hyperplasia with synchronous differentiation of keratinocytes, accentuation of the rete, hyperkeratosis, hypergranulosis, acanthosis, and hyperpigmentation of all levels of the epidermis with melanophages in the superficial dermis. Angulated, enlarged keratohyaline granules, koilocytosis (nuclear shrinkage with perinuclear clearing), and cytoplasmic basophilia (viral cytopathic effect) are often seen. There is no nuclear atypia (Figure 4.4B,C). Immunohistochemistry to identify a papillomavirus may be required for a definitive diagnosis. Immunohistochemistry detects the papillomavirus L1 protein, which is produced only in the late stages of viral replication and in terminally differentiated keratinocytes, so that positive staining is present in the stratum granulosum of the viral plaque15 (Figure 4.4D). As these growths have a viral association additional lesions may occur at other sites. In both dogs and cats lesions can progress to squamous cell carcinoma in situ and invasive squamous cell carcinoma.16 Equine aural plaques are papillomavirus‐induced lesions (EcPV3, EcPV4)17 that occur on the inner aspects of the pinna as round, raised, well‐demarcated, hyperplastic, nonpigmented, papillomatous cutaneous lesions (Figure 4.4E). No age or breed predilection has been noted. This is a neoplasm of epidermal cells that has cytologic features of malignant transformation of the squamous epithelial cells, but does not at the time of histopathologic evaluation show evidence of invasion through the basement membrane. The neoplasm is not associated with prolonged exposure to ultraviolet light. As noted above, in the dog and cat there is an association with papillomaviruses (see Table 4.3) and many lesions are more advanced stages of pigmented plaques. The neoplasm is most often seen in cats. Middle‐aged to old cats are primarily affected. Immunosuppression may predispose the cat to the development of lesions. Although no breed predilection has been noted, most cases have been described in domestic shorthaired cats with a variety of hair‐coat colors. However, hairless breeds may be predisposed to developing lesions and they are more severe in these breeds.1 No sex predilection has been found, although neutered animals appear to be more commonly affected. Areas of haired, pigmented skin, including the trunk, limbs, feet, head, and neck, are the primary sites of occurrence, although the lesions are found at multiple sites in most cats (Figure 4.5A). The sites of the neoplasms and the color coats of affected cats indicate that development of the neoplasm is not related to exposure to ultraviolet light. Figure 4.5 (A–E) Feline squamous cell carcinoma in situ. (B) Proliferation of neoplastic keratinocytes within the epidermis and follicular infundibulum but without invasion through the basement membrane into the dermis. (C) Disorganized keratinocytes within the epidermis and follicular infundibulum. (D) Keratinocytes exhibiting viral cytopathic effects. (E) Progression to invasive squamous cell carcinoma. Lesions may be either irregular, slightly raised, hyperpigmented, and plaque‐like or papillated and alopecic, and vary in size from 0.5 to 3.0 cm in diameter. Several cases with a cutaneous horn overlying the skin neoplasm have been described. The lesions consist of sharply demarcated regions of moderate to severe epidermal hyperplasia with accentuation of the rete and in some cases hyperpigmentation of all layers of the epidermis. Neoplastic keratinocytes affect the epidermis and follicular infundibular epithelium without invasion through the basal lamina into the dermis. Two histological subclasses of multicentric squamous cell carcinoma in situ are described: an irregular nonhyperkeratotic type and a verrucous hyperkeratotic type.2 The irregular nonhyperkeratotic lesions have moderate to severe acanthosis of the epidermis and follicular infundibulum and a mildly undulating surface to the epidermis. The verrucous hyperkeratotic lesions, as the name implies, show the formation of elongated spires of orthokeratin arising from the follicular ostium in addition to hyperkeratosis and dilation of the follicular infundibulum. The neoplastic cells give the epidermis and infundibulum a disorganized appearance, with loss of polarity of the keratinocytes and loss of normal keratinocyte maturation. The neoplastic cells are very variable in their morphology. Some cells are large with euchromatic nuclei, prominent nucleoli, and an extensive clear or vacuolated eosinophilic cytoplasm, whereas others have small hyperchromatic, round to elongated nuclei with only a small amount of cytoplasm. Mitotic figures may be found in the suprabasal cells and may be quite numerous. Increased melanin may be present within the cells. Cells in the granular layer may have cytological features indicative of papillomavirus infection (see previous description). These are most often found in early lesions but are absent in more mature lesions2 (Figure 4.5B–D). In some cases immunohistochemistry for papillomavirus antigen is positive. The lesions continue to enlarge slowly. Local recurrence has not been reported following surgical excision of the masses, but similar lesions may develop at new sites in these cats. Some cases will progress to invasive squamous cell carcinomas (Figure 4.5E). These invasive neoplasms often exhibit minimal or no squamous differentiation but the epidermis still retains features of squamous cell carcinoma in situ. Invasive lesions remain localized with no reported cases of metastasis. Squamous cell carcinoma (SCC) is a malignant neoplasm of epidermal cells in which the cells show differentiation to keratinocytes. It is one of the most common malignant skin tumors of all domestic animals, including chickens. There are several factors that are associated with the development of SCC, including prolonged exposure to ultraviolet light, lack of pigment within the epidermis at the sites of tumor development, and lack of hair or a very sparse hair coat at the affected sites. Therefore, geographic location and climate (ultraviolet light exposure) and anatomic location (conjunctiva, vulva, perineum) will greatly influence the incidence. Recent studies have linked papillomavirus with SCC in several species1 (also see previous section). The neoplasm is common in horses, cows, cats, and dogs, relatively uncommon in sheep, and rare in goats and pigs. In all species SCCs may occur in young animals, but the incidence increases with age. The peak incidence of SCC in cats is between 9 and 14 years of age, in dogs between 6 and 13 years of age, and in horses between 13 and 21 years of age. When exposed to solar radiation and higher altitude, cattle breeds at increased risk are those that lack circumocular or mucocutaneous pigmentation, including the Hereford and Simmental (Figure 4.6A). Figure 4.6 (A) Bovine squamous cell carcinoma, multifocal. Note the lack of periocular epidermal pigment. (B) Feline SCC, focal, early lesion involving nonpigmented, sparsely haired skin. (C) Feline SCC, advanced lesion with destruction of the pinnal cartilage and extensive hemorrhage. (D) Canine SCC, advanced lesion with marked ulceration and destruction of the nasal planum. (E) Well‐differentiated SCC. (F) Well‐differentiated SCC with parakeratosis. (G) Invasive SCC with desmoplasia and focal neural invasion. (H) Acantholytic variant of SCC. Horse breeds at increased risk are the Belgian, Clydesdale, Shire, American paint horse, and Appaloosa. The more popular dog breeds at increased risk are the bloodhound (5.3), giant schnauzer (3.7), keeshond (3.3), Kerry blue terrier (3.2), and bull mastiff (3.2). No sex predilection has been noted. In horses and cattle, SCC occurs primarily at mucocutaneous junctions, particularly the eyelids and conjunctiva, vulva, and perineum. In cats, the most common sites are the pinna, eyelids, and planum nasale (Figure 4.6B,C). SCC at the tips of the ears of white cats has a characteristic presentation. In dogs, the neoplasm most frequently occurs on the head (Figure 4.6.D), abdomen, forelimbs, rear limbs, perineum, and digits (see Subungual squamous cell carcinoma in the section on Nailbed (subungual) neoplasms). Short‐coated dogs with a white or piebald coat color that spend an extended period of time outdoors also have a higher incidence of cutaneous SCC that tend to occur on the ventral abdomen and head. Occasional cases will arise from the wall of the anal sacs which is lined by a stratified squamous epithelium. In sheep, the ears are affected. However, in any species this neoplasm may arise at any site. Oral SCC is discussed in Chapter 13. Solar dermatosis (actinic keratosis) is the first recognizable change at mucocutaneous junctions or on skin that is sparsely haired and lacks pigment. Erythema, edema, and scaling are followed by crusting and thickening of the epidermis with subsequent ulceration. As the neoplasm invades the dermis, the lesion feels more indurated. With time, the ulcerated lesion increases in size and depth, and secondary bacterial infection results in a purulent exudate on the surface of the mass. SCC of the eyelid often is associated with a purulent conjunctivitis, while epistaxis, sneezing, ulceration, or swelling are the clinical signs associated with neoplasms arising from the planum nasale. In dogs, cases of invasive SCC within the subcutaneous tissue have been identified at the site of prior vaccination with an autogenous papillomavirus vaccine.2 The latency period reported in these cases is 11–34 months. The neoplasm exhibits no unique features that allow it to be differentiated from other cases of SCC other than a rather uncommon location. As noted previously in immunosuppressed or immunocompromised animals papillomavirus infection may progress to invasive SCC. In cats, SCCs are also associated with UV radiation and approximately half of SCCs in the nasal planum of cats will have papillomavirus DNA, suggesting that it is also a causative factor. Immunostaining using p16 protein antibodies was used as evidence that papillomavirus is the etiology of papillomas and SCC. A recent study looked at 51 cats with nasal SCC; 32 stained positively for p16 protein and 19 did not. The cats with p16‐positive SCC survived longer (mean 643 days) than cats that were p16‐negative (217 days). The authors suggested that p16‐positive SCC may have a less aggressive clinical behavior and this could prove useful to predict survival and possibly help select treatment protocols.3,4 Fully developed SCCs are easy to diagnose, however, early or pre‐neoplastic changes may be subtle. The early neoplastic lesions, referred to as actinic keratosis, show epidermal hyperplasia, hyperkeratosis, parakeratosis, acanthosis, accentuation of the epidermal rete, and keratinocyte dysplasia. The affected keratinocytes, which are mostly found in the basal and spinous layer, show loss of polarity, karyomegaly, nuclear hyperchromatism, enlarged and prominent nucleoli, and mitotic figures of basal and suprabasal keratinocytes. Because this lesion is induced by prolonged UV light exposure, some cases may show solar elastosis, with degeneration and fragmentation of elastic and collagen fibers in the superficial dermis and deposition of thickened, basophilic fibrillar material that stains positive with the van Gieson elastin stain. At this stage there is no invasion through the basement membrane by the dysplastic keratinocytes, such as occurs with SCC described below. SCCs have an association with the overlying epidermis although this may not always be found on microscopic examination. Islands, cords, and trabeculae of neoplastic squamous epithelial cells invade the dermis and subcutis. The amount of keratin, seen as intracytoplasmic, eosinophilic fibrillar material (keratin tonofilaments), produced by the neoplastic cells is quite variable. When there is extensive keratinization, which may be orthokeratotic (Figure 4.6E) or parakeratotic (Figure 4.6 F), and in well‐differentiated neoplasms there is the formation of distinct keratin “pearls.” In poorly differentiated neoplasms only a few cells may have intracytoplasmic eosinophilic keratin tonofilaments. Individual neoplastic cells have large, ovoid, often vesicular nuclei with a single, central, prominent nucleolus, abundant cytoplasm that varies from pale to brightly eosinophilic, and distinct cell borders. In more differentiated neoplasms it is possible to find intercellular desmosomes, particularly in areas where intercellular edema allows them to be more readily identified. The number of mitotic figures is variable, but they are more frequent in less well‐differentiated neoplasms. Invasion of the dermis and subcutaneous tissue may evoke a desmoplastic response. There is often an infiltrate of neutrophils into the islands of neoplastic squamous epithelium, while plasma cells and lymphocytes are found in the connective tissue stroma that surrounds the neoplastic epithelium. The invasive margins of the neoplasm may show neurotropism (Figure 4.6G) as well as invasion of dermal and subcutaneous lymphatics. Several uncommon variants of SCC have been described. The spindle cell variant is often difficult to differentiate from the surrounding stromal cells. However, the neoplastic cells stain positive with antikeratin antibodies on immunohistochemical evaluation. Acantholytic SCCs are characterized by marked dyshesion of the neoplastic cells, which results in a pseudoglandular pattern (the basal neoplastic cells having remained attached to the basal lamina), but there is individualization and often dyskeratosis of the neoplastic keratinocytes that make up the centers of the islands of neoplastic squamous cells (Figure 4.6H). SCCs are usually slow growing. Most neoplasms, although invasive, do not show metastatic spread to regional lymph nodes; regional lymph node metastasis is most often found with poorly differentiated neoplasms or neoplasms that have been present for a considerable time before they are diagnosed or excised. Overall, metastasis to regional lymph nodes and other organs is uncommon when compared to oral SCCs. In cats with nasal planum SCC, p16 helps predict survival.3,4 SCCs vary considerably in their histologic appearance. This feature has been used to grade these tumors (Broder’s grading system). Well‐differentiated SCC (grade 1) is characterized by neoplastic cells with abundant eosinophilic cytoplasm, intercellular bridges, and concentric laminated masses of keratin, the keratin pearls. Nuclear pleomorphism and mitotic activity is minimal. Invasion into the dermis and subcutis is accompanied by a fibrous connective tissue proliferation. Moderately differentiated SCC (grade 2 and 3) is characterized by tumor cells with less eosinophilic cytoplasm, nuclei showing greater pleomorphism and hyperchromatism and more numerous mitotic figures, some of which may be quite bizarre. Fewer keratin pearls will be found and intercellular bridges may be difficult to identify. Invasion is more prominent with the islands of neoplastic cells appearing smaller than with a well‐differentiated SCC. Poorly differentiated SCC (grade 4) may show little squamous differentiation. The cytoplasm appears amphophilic and the nuclei are extremely pleomorphic with hyperchromatism and marked mitotic activity. Neoplastic cells are deeply invasive, often appearing as single cells or small groups of cells in a desmoplastic matrix. This is a low‐grade malignancy composed primarily of basal cells with foci of squamous differentiation. The neoplasm is uncommon and is diagnosed most often in dogs. The peak incidence is between 6 and 12 years of age. Breeds at increased risk are the Saint Bernard (7.6), bloodhound (6.2), Samoyed (3.0), and old English sheepdog (3.0). No sex predilection has been noted. Basosquamous carcinoma occurs most often on the head, neck and limbs. The neoplasm is intradermal to subcutaneous, often with foci of epidermal ulceration and hair loss. On cut section the neoplasm may be pigmented brown/black, and is subdivided by connective tissue trabeculae into variably sized lobules, which may show central cyst formation. It may not always be possible to identify the borders of the neoplasm on gross examination. At the periphery of the neoplastic lobules are undifferentiated basaloid cells. In the center of the lobules the cells show abrupt differentiation and the formation of keratinocytes, which exhibit modest nuclear pleomorphism, mitotic activity, and dyskeratosis. Melanin is often present within the peripheral basaloid cells (Figure 4.7A,B). Because basal cell carcinomas do not show squamous differentiation they are readily differentiated from basosquamous carcinomas. Figure 4.7 Basosquamous carcinoma, canine. (A) Low magnification. The peripheral neoplastic cells are basaloid with central squamous differentiation. (B) High magnification. The squamous cells show mild pleomorphism and there are occasional interspersed melanocytes. Although relatively slow growing, these neoplasms may recur at the surgical site if inadequately excised, but metastasis has not been reported. The normal hair follicle is divided dorsoventrally into three parts: the infundibulum, which extends from the epidermis to the sebaceous duct; the isthmus from the sebaceous duct to the insertion of the arrector pili muscles; and the inferior segment from the arrector pili muscles to the bulb. The external root sheath (ERS) joins the epidermis and in the infundibular region cannot be differentiated from the epidermis. In the isthmus and inferior portion of the follicle the ERS varies in thickness and is composed of cells with very pale eosinophilic cytoplasm that becomes more eosinophilic as the cells mature towards the epidermal surface. This portion of the ERS is referred to as the trichilemma. The internal root sheath (IRS) lies between ERS and the hair shaft and cells contain large eosinophilic trichohyaline granules. The cells of the bulb, which surround the dermal papillum, have large basophilic nuclei, little cytoplasm, and variable amounts of melanin. These are the mitotically active cells. The anatomic structures described above are the basis for separating this group of skin neoplasms into distinct entities, as they differentiate to or arise from the infundibular, isthmic, or bulbar regions of the hair follicle (Figure 4.8). Figure 4.8 Normal canine hair follicle histology. Considerable effort is placed on the correct histologic diagnosis of hair follicle neoplasms in this chapter and by practicing veterinary pathologists. Generally, almost all the hair follicle neoplasms are benign and complete surgical excision is curative. Malignant trichoepitheliomas and malignant pilomatricomas are rare neoplasms that can metastasize. However, until a histologic diagnosis is provided the biologic behavior of the excised neoplasm is unknown. These may be more aggressive skin neoplasms in animals and therefore require accurate histologic evaluation. Infundibular keratinizing acanthoma (IKA) is a benign neoplasm showing differentiation to the squamous epithelium of the follicular isthmus and infundibulum. This neoplasm has been previously referred to as an intracutaneous cornifying epithelioma, intracutaneous keratinizing epithelioma, keratoacanthoma, and squamous papilloma. The dog is the only species affected. The neoplasm is common in dogs, with a peak incidence between 4 and 10 years of age, but in our database 13% of cases are found in dogs less than 4 years old. The breeds at increased risk are the Norwegian elkhound (33.2), Tibetan terrier (15.7), Bedlington terrier (9.9), Kerry blue terrier (9.0), and Pekingese (6.5). The increased risk for the Norwegian elkhound (33.2) is one of the highest risks for any tumor and breed and multiple tumors are often found on affected dogs. No sex predilection has been noted. IKA occurs commonly on the back (15%), neck (11%), tail (10%), and limbs (31%). Multiple neoplasms (10%) on the same dog are common, especially in the Norwegian elkhound, German shepherd (5.3), Lhasa apso (3.5), and keeshond (2.3). The neoplasms are located in the dermis and subcutis and vary in size from 0.3 to 5 cm in diameter. Many have a central pore, which extends to the skin surface and represents the preexisting follicular infundibulum, from the base of which the neoplasm arises and grows. The pore may be filled with inspissated keratinous material. Applying gentle digital pressure to the mass often results in expulsion of a gray‐white keratinous material through the pore onto the skin surface. Those neoplasms having no epidermal communication arise as encapsulated intradermal masses. On cut section there is accumulation of keratin in the center of the mass, with the neoplastic cells at the periphery forming a red‐brown zone of viable cells that varies in thickness. The mass is well demarcated from the surrounding dermis and subcutaneous tissue. Any breach in the wall of the mass will allow keratin to extend into the adjacent dermis and subcutaneous tissue, where it will evoke a severe inflammatory response. The pore is lined by a stratified squamous keratinizing epithelium with prominent intracytoplasmic keratohyaline granules. From the base of the pore the tumor extends into the dermis and subcutis. There is central aggregation of keratin, which often forms concentric lamellae. Beneath the keratin, the wall of the neoplasm consists of large, pale‐staining keratinocytes that may contain small basophilic keratohyaline granules (Figure 4.9A). These cells have normochromatic nuclei, cell borders are very distinct, and no desmosomes can be seen. Extending outward from the lining cells of the central cavity are cords of epithelial cells, which are only two cells thick. These cords, which also form the peripheral zone of neoplastic cells, will anastomose and form small horn cysts with concentric lamellar aggregates of keratin within the cyst lumina (Figure 4.9B). The cells have central nuclei that are more chromatic than those of the luminal cells, a moderate amount of eosinophilic cytoplasm, and distinct cell borders. Cellular and nuclear pleomorphism and mitotic activity is minimal (Figure 4.9C). A fibrovascular stroma surrounds the mass and also extends into the neoplasm between the anastomosing cords of epithelial cells. The stroma may be mucinous and in some cases will show chondroid or osseous metaplasia, a feature also noted with mixed apocrine gland neoplasms, from which IKA must be differentiated by the morphology of the keratinocytes with their abundant eosinophilic cytoplasm and lack of glandular tissue within the IKA. Occasional lymphocytes and plasma cells may be present within the stroma. Compression of the surrounding dermal collagen produces a pseudocapsule. Figure 4.9 (A–C) Infundibular keratinizing acanthoma, canine. Note the accumulation of keratin in the lumen of the cyst (A). Rupture of the wall of the neoplasm with release of keratin into the surrounding dermal and subcutaneous tissue will evoke a pyogranulomatous and granulomatous inflammatory response. Owners or referring veterinarians may indicate the mass has increased rapidly in size. This probably reflects rupture of the tumor wall and infiltration by the inflammatory component induced by the free keratin rather than actual growth of the tumor. These neoplasms do not recur following adequate surgical removal. Surgical removal is recommended for solitary masses or in those cases where only a few masses are present. In dogs with multiple neoplasms, treatment with synthetic retinoids has been helpful but these drugs are no longer available. This is a benign neoplasm showing differentiation to either the isthmic segment or the inferior segment of the external root sheath of the hair follicle. It is uncommon in the dog and rare or not described in other species. Too few cases have been seen to determine any age, breed, or sex predilection. No site predilection has been established for tricholemmomas. The neoplasms are well‐encapsulated intradermal and subcutaneous masses, with hair loss from the overlying skin. Two variants of tricholemmomas are described: the isthmus type and the inferior type. The isthmus type, as its name implies, shows differentiation to the isthmus segment of the hair follicle. There is often an association with the epidermis. The tumor consists of cords and trabeculae of epithelial cells extending between islands of epithelial cells which exhibit central tricholemmal (no keratohyaline or trichohyaline granules are formed) keratinization. The neoplastic cells are small and have a moderate amount of pale eosinophilic cytoplasm and small euchromatic nuclei (Figure 4.10A,B). Melanin may be found within the neoplastic cells. There is some interstitial stroma which may contain a small amount of mucin. The isthmus type of tricholemmoma shares many features with the infundibular keratinizing acanthoma. However, the isthmus tricholemmoma has an association with the epidermis, shows no central cyst formation and exhibits tricholemmal keratinization, whereas the IKA shows central cyst formation and infundibular keratinization, with occasional keratohyaline granules within the cytoplasm of the cells which line the central cyst. Figure 4.10 (A,B) Tricholemmoma – isthmus type, canine, at low (A) and higher (B) magnification. (C,D) Tricholemmoma – inferior type, canine, at low (C) and high (D) magnification. The inferior type shows differentiation to the inferior segment of the hair follicle with islands of epithelial cells surrounded by a fine fibrillar collagenous stroma. The central epithelial cells have a moderate amount of eosinophilic cytoplasm, while the peripheral cells are arranged in a palisaded fashion on a thickened, eosinophilic basal lamina and have an abundant, pale, vacuolated cytoplasm (Figure 4.10C,D). These neoplasms are amenable to wide surgical excision; recurrence is unlikely and metastases have never been reported. This is a benign neoplasm, which is either derived from or shows differentiation to the hair germ of the developing follicle. Several of these neoplasms were previously classified as basal cell tumors (see Table 4.1). Trichoblastoma is a common neoplasm in dogs and cats, uncommon in horses, and rare in other species. In dogs, the neoplasm occurs predominantly between 4 and 10 years of age. Breeds at increased risk are Kerry blue terrier (11.4), puli (5.8), bichon frise (4.7), Shetland sheepdog (3.5), and Bedlington terrier (3.4). A slight male sex predilection has been noted. The head and neck are the primary sites of occurrence of trichoblastomas in dogs and cats. The neoplasms, which are often exophytic masses, may vary from 0.5 to 18 cm in diameter. Most extend from the epidermal–dermal interface into the dermis and subcutis. They are well demarcated from the surrounding tissue by a pseudocapsule of compressed collagen. The overlying epidermis is devoid of hair and may be secondarily ulcerated. On cut section the mass is often subdivided into multiple lobules of varying size by connective tissue trabeculae. Some neoplasms are melanized, and others may show focal or multifocal cystic degeneration. There are several histological subtypes of trichoblastoma, including the ribbon, medusoid, granular cell, trabecular, and spindle subtypes (Figure 4.11A–F). However, the considerable variability of these neoplasms on histological evaluation in no way affects their prognosis, since they are all benign. Figure 4.11 Trichoblastoma. (A) Ribbon type, canine. (B) Medusoid type, canine. (C) Solid type, canine. (D) Granular cell type, canine. (E) Trabecular type, feline. (F) Spindle cell type, feline. Ribbon type trichoblastoma consists of long cords of branching and anastomosing cells (Figure 4.11A). These cords are two or sometimes three cells thick. The cells often have a palisaded appearance with prominent nuclei and little cytoplasm. The nuclei may appear normochromatic or hyperchromatic, and the nucleoli are inconspicuous. The small amount of cytoplasm is eosinophilic, and cell borders are indistinct. The number of mitotic figures may be quite variable, with some neoplasms showing marked mitotic activity. The adjacent stoma can vary from mucinous to collagenous, and the amount of stroma found between the cords of cells is also quite variable. This subtype is most frequently seen in dogs. Medusoid type trichoblastoma is similar to the ribbon type. However, the cords of cells stream outward from a central aggregation of cells, which have a more extensive amount of eosinophilic cytoplasm (Figure 4.11B). This subtype is most frequently seen in dogs. The solid type consists of variably sized islands of cells surrounded by a moderate to extensive connective tissue stroma (Figure 4.11C). The nuclei may appear normochromatic or hyperchromatic, and the nucleoli are inconspicuous. The cytoplasm is lightly eosinophilic, and cell borders are indistinct. Granular cell type trichoblastoma consists of islands and sheets of neoplastic cells that have an abundant, eosinophilic, granular cytoplasm with distinct cell borders (Figure 4.11D). The nuclei are small and chromatic, and few mitoses are found. The amount of interstitial collagenous stroma is variable. This subtype is most frequently seen in dogs. Trabecular type trichoblastoma consists of multiple lobules of neoplastic cells surrounded by thin bands of interlobular collagenous stroma (Figure 4.11E). The cells at the periphery of the lobules are distinctly palisaded, while the cells in the center of the lobules have ovoid to elongated nuclei and a more abundant eosinophilic cytoplasm. This subtype is most frequently seen in cats. Spindle type trichoblastoma may have an association with the overlying epidermis (Figure 4.11 F). The neoplasm is multilobulated with little interlobular stroma. The morphology of the neoplastic cell varies depending on whether the cells are cut longitudinally, when they have a spindle cell morphology, or transversely, when they appear more ovoid. The fusiform cells often have an interwoven pattern. The neoplasm may have melanin within the neoplastic cells and within melanophages. This subtype is most frequently seen in cats. Most trichoblastomas are slow growing. They recur only after incomplete surgical excision. This is a very uncommon neoplasm that resembles the folliculosebaceous unit. Most cases are found in cats. No predilection for age, breed, sex, or site has been determined.
Epithelial and Melanocytic Tumors of the Skin
General references
EPITHELIAL NEOPLASMS WITHOUT SQUAMOUS AND ADNEXAL DIFFERENTIATION
Basal cell neoplasms (Table 4.1)
Previous nomenclature
Revised nomenclature
Canine basal cell tumors
Canine trichoblastoma
Granular cell type
Granular cell type
Ribbon type
Ribbon type
Medusa head type
Medusa head type
Feline basal cell tumor with lumen formation (tubules)
Feline apocrine ductal adenoma
Feline basal cell tumor
Feline trichoblastoma
Spindle cell type
Spindle cell type
Trabecular type
Trabecular type
Basal cell tumor – feline
Incidence, age, breed, and sex
Sites and gross morphology
Histological features
Growth
Basal cell carcinoma
Incidence, age, breed, and sex
Sites and gross morphology
Histological features
Growth and metastasis
References
NEOPLASMS OF THE EPIDERMIS
Papilloma (cutaneous papillomatosis)
General considerations
Clinical symptoms
CPV‐1
Asymptomatic infections
Exophytic papilloma
Endophytic papilloma
Invasive squamous cell carcinoma
CPV‐2
Exophytic papilloma
Endophytic papilloma
Invasive squamous cell carcinoma
CPV‐3
Pigmented plaque
In situ squamous cell carcinoma
Invasive squamous cell carcinoma
CPV‐4
Pigmented plaque
CPV‐5
Pigmented plaque
CPV‐6
Endophytic papilloma
CPV‐7
Exophytic papilloma
CPV‐8
Pigmented plaque
CPV‐9
Pigmented plaque
CPV‐10
Pigmented plaque
CPV‐11
Pigmented plaque
CPV‐12
Pigmented plaque
CPV‐13
Oral mucosal papilloma
CPV‐14
Pigmented plaque
CPV‐16
Pigmented plaque
Incidence, age, breed, and sex
Viral papillomas
Squamous papillomas
Epidermal differentiation may show orthokeratosis or parakeratosis
Epidermal differentiation is normal
Enlarged keratohyaline granules
Normal size keratohyaline granules
Koilocytes present
Koilocytes absent
Keratinocytes show viral cytopathic effect
Keratinocytes normal
Intranuclear inclusions may be present
No intranuclear inclusions
Elongated rete slant inward
Elongated rete slant outward
Sites and gross morphology
Histological features and growth
Immunity and regression
Inverted papilloma
Incidence, age, breed, and sex
Sites and gross morphology
Histological features and growth
Growth
Pigmented viral plaques
Sites and gross morphology
Histological features
Growth
Equine aural plaques
References
Multicentric squamous cell carcinoma in situ (Bowen’s disease, bowenoid in situ carcinoma)
Incidence, age, breed, and sex
Sites and gross morphology
Histological features
Growth
References
Squamous cell carcinoma
General considerations
Incidence, age, breed, and sex
Sites and gross morphology
Histological features
Growth and metastasis
Grading
References
Basosquamous carcinoma
Histological features
NEOPLASMS WITH ADNEXAL DIFFERENTIATION
Follicular neoplasms
General considerations
Infundibular keratinizing acanthoma
Sites and gross morphology
Histological features
Growth
Tricholemmoma
Histological features
Growth
Trichoblastoma
Incidence, age, breed, and sex
Sites and gross morphology
Histological features
Ribbon type
Medusoid type
Solid type
Granular cell type
Trabecular type
Spindle cell type
Growth
Trichofolliculoma
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