Page 376 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

354 PART IV Specific Malignancies in the Small Animal Patient

situ in a dog receiving long-term immunosuppressive therapy with SCCs (48%) positive for p53 expression in three studies. 56,57,62 In
prednisone and cyclosporine also demonstrated positive staining for addition, feline actinic keratosis was found to be highly positive for
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p53 expression (79%), whereas BISC lesions were less commonly
PPV antigens. Interestingly, the lesions persisted and new lesions
VetBooks.ir developed even after discontinuation of the drug therapy. The suc- positive (18%). These studies have raised questions about the rela-
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tive roles of PPV infection and UV irradiation in the development
cessful use of immune stimulants for early cancer lesions, such as
imiquimod for carcinoma in situ, supports the role of the immune of different subtypes of feline SCC, because both mechanisms of
system in controlling skin cancer. The ability of the immune system tumorigenesis can result in increased identification of p53.
of dogs to cause regression of histiocytomas and papillomas also Several studies have used IHC to evaluate changes in selected
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illustrates the role of immune surveillance in veterinary patients. protein expression. For example, IHC staining of p27, a protein
thought important in maintaining cells in G0, showed SCC to
Genetic Abnormalities in Skin Cancer have much lower levels than benign cutaneous neoplasms.
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β-Catenin is a protein that is responsible for normal skin homeo-
Cancer is a genetic disease (see Chapter 1, Section A). The accu- stasis. When dysregulated, β-catenin can be oncogenic. A study
mulation of multiple alterations in critical genes is usually neces- of β-catenin expression in normal skin and in benign and malig-
sary for full neoplastic transformation. An understanding of these nant tumors demonstrated nuclear presence of this protein, rep-
genetic abnormalities, which can include both genetic and epi- resenting pathway activation, in 100% of trichoepitheliomas and
genetic modifications in a particular cancer type, allows for the pilomatricomas; no nuclear expression was found in any of the
formulation of therapeutics to circumvent these critical muta- other malignant tumors or normal skin. This finding led the
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tions and their pathways. The accumulation of such genetic data authors to suggest a role for aberrantly activated β-catenin in the
is only beginning in veterinary oncology. The discovery of acti- formation of tumors of the hair follicle. Evaluation for the presence
vating mutations in the stem cell factor receptor, c-kit in canine of cyclin D1 and cyclin A, proteins important in the regulation of
MCTs, and the subsequent successful targeting of this mutation the cell cycle, demonstrated that cyclin A was present in 90% of
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with tyrosine kinase inhibitors, is the first step in applying this feline SCCs and 44% of canine SCCs. Cyclin D1 was rarely
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approach in veterinary oncology. The current understanding of expressed in skin tumors of any type. Staining for these proteins
mutations in the most common forms of skin cancer and their in normal skin and benign tumors showed rare or weak staining.
role in either tumorigenesis or prognosis/response to treatment are The investigators suggested a role for cyclin A in the regulation
presented according to tumor type. of proliferation and neoplastic transformation in cutaneous SCC.
The syndrome of renal cystadenocarcinoma and nodular der-
Basal Cell Carcinomas matofibrosis deserves mention, because this disease often presents
to the veterinarian as the result of manifestation of multiple firm,
In people, basal cell carcinomas (BCCs) are thought to arise from cutaneous nodules. The disorder was first described as a genetic dis-
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critical mutations in the hedgehog signaling pathway. Limited ease in the mid-1980s, and it was not until 2003 that the causative
genetic evaluation of BCTs has been performed in veterinary mutation in the Birt-Hogg-Dubé (BHD) gene was described. 66,67
medicine. One study demonstrated a reciprocal translocation in The BHD gene codes for the tumor suppressor protein folliculin
a canine BCT of t(10:35). In the dog, chromosome 10 con- and mutations in this gene are thought to lead to loss of function.
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tains the gene GLI1, which is the effector transcription factor of This disease is primarily seen in German shepherd dogs. 66,69
the hedgehog signaling cascade. Two aberrant karyotypes were Identification of the driver mutations underlying neoplastic
found in feline BCTs: trisomy E3 and monosomy E3, although transformation in the skin will be the key to optimizing the use
the significance of these findings is unknown. 55,56 IHC for p53 of drugs that target these pathways and of avoiding unwanted
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in five feline BCTs were negative. Likewise, IHC evaluation for cutaneous side effects. The use of pathway-specific drugs may
the presence of the apoptotic regulatory proteins Bcl-2 and Bax have unanticipated effects in the skin. Sorafenib, a tyrosine kinase
showed 23 of 24 tumors expressed Bcl-2, but only seven of the inhibitor of Raf and VEGF/PDGFR, has been associated with
BCTs expressed Bax. Interestingly, Bcl-2 staining is considered the rapid development of actinic keratosis and invasive SCC in
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fairly specific for human BCC. people. 70,71 As understanding of these pathways and their role in
normal skin homeostasis develops, preventing these types of unin-
Squamous Cell Carcinoma tended consequences may become possible.
The genetic abnormalities responsible for the development of Pathologic Classification of Skin Tumors
cutaneous SCC are incompletely understood in human oncology.
One common finding is mutations in p53. A pathway of sequen- Skin tumors arise from the epidermis and associated structures.
tially necessary mutations has been proposed. In addition, sev- For ease of use, these tumors are categorized based on their dif-
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eral genetic changes in cutaneous SCC have been suggested to be ferentiation into specific subelements of the skin. Some histolo-
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of prognostic value in people with this disease. gies are divided into benign and malignant forms based on known
A number of studies have evaluated p53 in canine and feline clinical and histologic predictors of behavior. In other tumor
cutaneous SCC. When p53 is present in the wild-type form, its short types, such clear-cut division may not be possible.
half-life prevents detection of the protein with IHC. The presence The World Health Organization’s classification system of
of a detectable form of the p53 protein correlates with mutations tumor-node-metastasis (TNM) can be applied to skin tumors
within the coding sequence. Three IHC studies of p53 in canine in the clinical setting. Location is also prognostic for particular
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cutaneous SCC revealed that 30% were positive for p53 overexpres- tumor types; for example, digit and oral melanomas are highly
sion. 32,57,61 Interestingly, two of six cutaneous papillomas were also malignant tumors, whereas cutaneous melanomas are often
positive for p53 expression by IHC. Detectable expression is even benign. Therefore this information should be included in the clin-
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more prevalent in feline cutaneous SCCs, with 19 of 40 cutaneous ical description of the tumor at presentation.