Page 654 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

632 PART IV Specific Malignancies in the Small Animal Patient

Natural Behavior defined, although nuclear estrogen receptor expression appears to
be decreased in PCA tissue compared with normal and hyperplas-
158,190
tic prostate tissue.
At the time of diagnosis, most canine prostatic tumors are char-
VetBooks.ir acterized by local invasion with a high propensity for regional some investigators have considered mechanisms that may con-
Because of its aggressive behavior at the time of diagnosis,
and distant metastasis. In one postmortem study of 76 dogs,
80% of dogs with PCA had evidence of measurable metastatic tribute to PCA progression and metastasis. Activating mutations
disease, with lung and LNs being the most common sites of in the BRAF gene, which lead to constitutive MAPK signaling,
spread. 134 Importantly, similar to high-grade PCA in men, were found in the majority of PCA in dogs. Moreover, the muta-
canine PCA has a tendency to metastasize to bone: 22% to 42% tion frequency was similar between PCA and urothelial (blad-
of dogs develop skeletal metastasis, predominantly to the lum- der) TCC. 191,192 This is uncommon in nonmetastatic human
bar vertebrae and pelvis. 134,159,177,178 Younger dogs diagnosed prostate cancer, but may support the current hypothesis that
with PCA may be at increased risk for metastasis than older most canine PCAs arise from the prostatic ducts or prostatic
dogs, although the role of castration status in these two groups urethra. 134,154,157,193–196
is unclear. 134,179 As long-term studies in dogs with evidence of Cyclooxgyenase-2 (COX-2) expression may play a role in car-
PIN but without PCA are not available, it is unclear if PCA in cinogenesis and progression in PCA. Expression of COX-2 was
dogs can behave in a slowly progressive fashion in its early phase noted in 75% of PCAs in one study, whereas none of the normal
of development. It is presumed that most dogs are diagnosed at prostate tissue stained positively. 197 Two other studies have sup-
an advanced stage of disease because of the high metastatic rate; ported the notion that COX-2 and downstream prostaglandin E
2
however, the true behavior from time of onset is not definitively production may play a role in PCA development. 198,199 Indeed, a
known and PCA may behave differently in intact and castrated clinical study identified COX-2 protein expression in 88% of 16
dogs. 146,147 PCAs examined and was further able to show a survival benefit in
dogs treated with either piroxicam or carprofen. 200
Pathogenesis PCA has a predilection for bone, which may be mediated in
part by TGF-β, parathyroid hormone–related protein (PTHrp),
The underlying cause of prostate tumors is unknown, and it is and endothelin. 201–203 PTHrp mediates pathologic bone resorp-
possible that both genetic and environmental factors contrib- tion in many different tumors, including PCA, which may
ute to tumor development. HGPIN is considered a precursor encourage release of TGF-β into the microenvironment. In
of human PCA and occurs under the influence of androgenic a positive feedback loop, canine PCA cells can increase gene
stimulation in those patients at risk for carcinoma. 180 Although transcription for PTHrp in response to exogenous TGF-β. 202
PIN has been detected in dogs with existing PCA, it has also Although PTHrp and TGF-β may be important in establishing
been detected in dogs without evidence of prostatic disease, skeletal metastases, it is interesting to note that PCA metasta-
making its role in the dog less clear. 149–151 HGPIN as a predic- ses are more commonly osteoblastic in nature. 173,204,205 In a rat
tor of carcinoma occurrence may not be as reliable in the dog model, osteoblast activation was increased after incubation with
as it is in men. 150,173 It is not known with certainty if low- and normal canine prostate protein homogenates through an endo-
intermediate-grade PIN occurs in dogs, although one IHC thelin-dependent pathway, suggesting a possible contribution
study suggested the presence of low-grade PIN. 181 Investigators to bone metastasis formation. 203 Recent gene expression profil-
evaluated five prostates from middle-aged to older intact dogs ing work in human castration-resistant prostate cancer (CRPC)
containing lesions of PIN and compared nuclear protein p63 has shown high AR expression is correlated to genes controlling
(marker of prostatic basal cells), androgen receptor expression, osteoblast/osteoclast activity, cellular metabolism (i.e., choles-
and PCNA to normal prostatic tissue also obtained from intact terol synthesis, fatty acid oxidation, pyrimidine synthesis), and
dogs. PIN foci had higher p63 expression, higher PCNA index, immune cell infiltration, all of which may influence therapeutic
and heterogeneous androgen receptor (AR) expression, suggest- regimens. 206,207
ing similarities to human low-grade PIN. 181 Prostatic inflam-
matory atrophy has also been identified in dogs and humans, History and Clinical Signs
which may be a precursor of PIN lesions or PCA. 143,152,182–185
Several studies have attempted to elucidate key changes in gene Clinical signs in dogs with PCA are variable and may be reflec-
and protein expression in prostate carcinogenesis to develop and tive of local and/or metastatic disease. Common historical find-
investigate targeted approaches that interrupt carcinogenesis and ings and clinical examination signs include hematuria, dysuria,
progression. 143,163,182,183,186–188 stranguria, dyschezia, tenesmus, bacteriuria, and altered stool
The role of hormones in prostate development and tumor shape (flattened or ribbonlike stools). 134,147,155,178,208 With com-
progression is unclear in the dog. Castration does not provide a plete obstruction of urinary outflow due to prostatic compres-
protective effect and, in fact, may contribute to tumor develop- sion or direct tumor extension into the urethra, hydroureter,
ment and/or progression, although PCA may behave differently hyrdronephrosis, and renal failure may occur. Local invasion into
in the intact male compared with the neutered male. 146,147 Nor- the lumbar vertebrae or nerve roots may cause signs of pain, gait
mal prostate development and regulation in humans and dogs is abnormalities, lameness, and/or constipation. Nonspecific sys-
androgen dependent; however, neoplastic human prostate most temic illness, typically associated with advanced disease, include
commonly remains androgen dependent as opposed to the dog. lethargy, exercise intolerance, tachypnea or dyspnea, hyporexia,
AR expression within the nuclei can be identified in 90% to 95% and weight loss. Dogs with skeletal metastasis may present with
of normal (intact) prostatic secretory epithelial cells and in the signs of severe bone pain, pathologic fracture, or rarely with
majority of acinar basal cells. 159,160,189,190 In neutered dogs and a palpable mass. 134,178,209 Dogs may present with a history of
in dogs with PCA, nuclear AR expression decreases and is usually clinical signs that partially improved with empiric therapy for
lost. 159,160 The role of estrogen and progesterone has yet to be fully prostatitis.