*4.3.4 Differential diagnoses*

BPH and neoplasia of the prostate gland have to be considered.

#### *4.3.5 Therapy*

In acute canine prostatitis, typically, high-grade disturbance of the general conditions occurs; furthermore, acute urination and defecation problems require emergency measures. The rapid reduction of the prostate gland size is important, in addition to effective treatment of the infection. Intravenous infusions of physiological solutions are necessary for treatment of circulatory disturbances. Drugs against pain and inflammation such as NSAID and/or morphine derivates should be given (for example Carprofen 4 mg/kg SID i.v. or Buprenorphin 0.01–0.02 mg/kg every 6–8 h i. v.). In case of vomiting, metoclopramide injections are useful (0.5–1 mg/kg, BID-TID, s. c., i. m., i. v.) or maropitant (1 mg/kg SID s. c., i. v.). Dogs should be In-patient while treated until improvement.

Antibiotics have to be chosen according to a resistance test and according to the ability to penetrate the diseased tissue. In acute cases, the blood-prostate barrier is ruptured; therefore, each broad-spectrum antibiotic can be applied when effective according to the resistance test [97, 107]. Meanwhile, it is important to not only examine for bacteria but also for mycoplasms (M.) and ureaplasma (U.) inclusive specification and quantification; *M. canis*, *M. cynos,* and *U. canigenitalium* were isolated in semen, prostate secretions and urine of dogs with prostatitis. Even though it is not proven that they are causative agents, high-grade monocultures should be treated according to a resistance test [97, 99, 108]. Acute symptoms may be treated with broad-spectrum antibiotics before the resistance test is available [7]. In these cases, fluoroquinolones (for example Enrofloxacin s. c, i. v. SID or SOD 5–10 mg/kg) or erythromycins (for example Azithromycin 5–10 mg/kg SOD) can be given. These antibiotics are also effective against mycoplasms and ureaplasma.

In chronical canine prostatitis, the blood-prostate barrier is intact; therefore, antibiotics must be chosen according to the resistance test and the ability to penetrate the tissue. The latter is possible by using weak alkaline medicaments with a high pKavalue (acid-dissociations constant), good fat solubility, and weak protein binding [97]. In these cases, fluoroquinolones and erythromycins are good options as well, furthermore clindamycin and chloramphenicol.

In both acute and chronical prostatitis, the duration of treatment is important; in chronical cases, 4–6 weeks and up to 8–12 weeks are recommendable in dogs [19, 107]. One week after the end of the antibiotic treatment, another bacteriological examination should be done [19].

In dogs, prostate abscesses can be punctured and emptied; for this measure, a mild sedation is required. The needle should be carefully placed under sonographical control and samples for cytological and bacteriological examination obtained (**Figure 6**); sometimes one to four repetitions are required and in some cases, operative removal of the abscess is necessary [93]. Operative treatment is possible by marsupialization, a Penrose drain, or partial prostatectomy [109–112]; a further method with low recidivism rate is the operative drainage of the abscess cavity and consecutive filling with omentum (omentalization)[112]. The prostate has to be pulled out of the abdomen; the contents of the abscess are sucked off (**Figure 9a** and **b**), then the opening is enlarged and the cavity flushed. Another opening is cut into the opposite side of the gland (**Figure 9c**) and the omentum is pulled into and through the cavity. The omentum is fixed with a suture on the opposite side of the gland. Additional application of antiandrogens and antibiotics according to a resistance test are necessary measures.

#### **Figure 9.**

*Omentalisation of a paraprostatic cyst (a); The huge paraprostatic cyst was situated behind the urinary bladder (to the right, black arrow). The wall was high grade thickened. (b) The urinary bladder was emptied and the prostate cyst was pulled out of the abdomen (c) After puncture of the cyst the contents were sucked off, then a large piece of the wall was removed on both sides of the cyst by using a sealing device (LigaSure™, Medtronic, Vienna, A). The omentum was pulled into the cavity and fixed on both sides of the cyst by using resorbable material.*

#### *4.3.6 Prognosis*

The clinical symptoms can be effectively treated in both acute and chronical cases; however, the course of the disease is recurrent. Fertility prognosis is good when treated in time, with well-chosen medicaments, and over a sufficient period.

### *4.3.7 Prophylaxis*

Regular clinical and sonographical examinations, starting when the dog reached 40% of the estimated life expectation, are recommendable [18].

#### **4.4 Squamous metaplasia**

Squamous metaplasia develops because of an endocrine active testicular tumor, secreting androgens and causing hyperestrogenemia, but in addition because of exogenous estrogens [113]. The metaplasia causes a morphological change in the gland, sonographically resembling an inflammation; sometimes cysts occur.

The disease is a side effect of hyperestrogenemia since this problem causes the clinically relevant changes in the blood picture and causes organ damages. Typical

#### *Diseases of the Canine Prostate Gland DOI: http://dx.doi.org/10.5772/intechopen.105835*

symptoms are alopecia, hyperpigmentation of the abdomen and inguinal region, gynecomastia, and in severe cases anemia.

The diagnosis can be made with FNA; however, rapid diagnosis and treatment of the hyperestrogenemia are more important. Mostly castration will solve the problem. However, it is important to know that the hyperestrogenemia can persist for months after the removal of the testicular tumor. Recurrence of the problem after castration may point toward metastasis.

#### *4.4.1 Prognosis*

When the dog is castrated, the estrogen concentration slowly decreases over weeks and months. During this time, infections frequently occur. Dependent on the degree of anemia and organ damage, a careful prognosis is appropriate. In case of low-grade changings and correct treatment, the prognosis is good.

#### **4.5 Tumors of the prostate gland**

#### *4.5.1 Causes*

Prostate gland tumors are seldom in dogs (<1%), [16, 114] and mostly malign adenocarcinomas or transitional cell carcinomas and seldom lymphomas [41]. The cells of origin sometimes are not identified [15, 115]. They are more frequently diagnosed in castrated than in intact dogs, the growth is not androgen-dependent [14, 15, 116]. Other diseases of the prostate gland are not predisposing [19]. It is not known, whether the age at castration plays a role [16]. However, the age itself is an important factor, since the disease mainly is diagnosed in dogs aged > 8 years [51, 117–119]. Medium to large size breeds are more frequently concerned than smaller or toy breeds [14, 114]. A breed disposition is not proven; however, a higher risk/odds ratio was found for Shetland Sheepdog, Scottish Terrier, Bouvier des Flandres, Doberman, and mongrels [9, 14, 120].

Recent studies investigated changes in the prostate gland during cancer development at the molecular level. A lack of androgen receptor and the overexpression of P-glycoprotein (P-gp) was described, indicating that androgens do not play an important role in pathogenesis [116]. P-glycoprotein regulates the influx and efflux of testosterone in prostatic cells. New findings suggest NF-kb dysregulation as a probable factor contributing to oncogenesis; chronic inflammations may trigger the change in precancerous cells causing DNA and epigenetic damage [121]. NF-kb is an inducible cytoplasmic transcription factor, able to activate genes for inflammatory cytokines, adhesion molecules, enzymes related to inflammation (such as cyclooxygenase-2), telomerase, antiapoptotic proteins, and cell cycle-regulatory genes [121].

The growth is most aggressive with an invasion of surrounding tissues and high metastatic potential. The incidence of metastases varies between 16% and 80%, dependent on age [119, 122]; the sites of metastasis are primary the lung, then regional lymph nodes, liver, urethra, spleen, colon and rectum, urinary bladder, bones, heart, kidney, and adrenal gland, but also the skin [123]. Metastases are mostly already present at the time of diagnosis of the prostate gland tumor [19].

#### *4.5.2 Clinical symptoms*

The symptoms vary independently on castration status; in some dogs, gastrointestinal symptoms are predominant (defecation problems, tenesmus), in others, symptoms of the urogenital tract occur first (stranguria, hematuria, incontinence, dysuria, pollakisuria, and polydipsia). Enlargement of the gland was observed in only 45% of cases [119]. In some dogs, lameness, loss of weight, and abdominal pain become obvious, especially, when metastases occur [9, 114].

Since the symptoms are unspecific, a prostate gland tumor must be considered in aged dogs with severe symptoms of a disease of the urogenital tract and gastrointestinal symptoms [16].

#### *4.5.3 Diagnosis*

Prostate gland tumors are frequently diagnosed too late when the aggressive invasive growth already caused massive tissue damage and metastases. Accompanying inflammation and secondary infections of the urogenital tract complicate the diagnosis. However, early detection is an important factor for survival.

Digital rectal palpation may reveal an uneven surface, immobility, asymmetry, and/or painfulness. A blood picture can show neutrophilia, leucocytosis and in 70% an increase in alkaline phosphatase concentration. Pyuria and hematuria are possible; in the sediment, tumor cells can be detected [119].

However, cytological examination of urine or prostate secretion sediment is unreliable, even when the cytobrush method was used. For the final diagnosis, a biopsy and histological examination of the tissue are obligatory. Transcutaneous FNA has a sensitivity of 80% [119], which can be increased to 89% by punch-biopsy or excisional biopsy [102, 103, 124]. For punch-biopsy or excisional biopsy, total anesthesia is required. The gland has to be pulled forward to be able to perform the biopsy on the ventrolateral surface. The wound is closed with single sutures, including the capsule and parenchyma [125]. Histologically, a prostatic adenocarcinoma can be differentiated from a prostatic carcinoma, urothelial, and tumors of mixed morphology [124, 126]. A possible side effect is the spread of tumor cells [103].

Sonography is not useful to differentiate between inflammation and neoplasia; however, can be helpful [45, 63]. With B-mode, the gland appears inhomogeneous, with hyperechoic areas; mineralizations are frequent and the borders in > 80% of cases appear irregular and diffuse against the rectum, and sometimes even rupture. In many cases, the regional lymph nodes are changed [119] (**Figure 10**).

Some imaging methods were improved. With contrast-enhanced-Doppler sonography it is possible to visualize the perfusion in the normal prostate tissue and to compare it with prostate neoplasia; in case of adenocarcinoma, the perfusion was significantly higher [81]. Elastography was used in one Labrador dog with prostatic adenocarcinoma, and the histological result of the FNA correlated well with the findings of the elastography [121]. A new experimental method is a combination of simultaneous magnet-resonance spectroscopy (MRS), positron-emission-tomography (PET), and multiparametric magnet-resonance (mpMR). In one study, the results were compared with findings from transrectal sonography and prostate biopsy. In 3/3 dogs, tumor growth was diagnosed by using the combined method; the diagnosis was verified by biopsy [71].

An X-ray of thorax and abdomen should be done to diagnose metastases in the lymph nodes, pelvic bones, and the lung [11, 41].

Recent studies focus on the detection and development of biomarkers for canine prostate cancer [126, 127]. Markers are not easy to find in case of canine prostate cancer since the tumor growth is aggressive and the pattern variable, the basal cell layer is discontinuous and markers are frequently absent. A combination of markers might

#### **Figure 10.**

*Sonography of a carcinoma of the prostate gland (B-mode). The male dog showed chronical prostatitis, loss of weight, and a matt coat. The prostate gland was only low-grade enlarged, but high-grade inhomogeneous, with mineralizations. The margin was not well defined and could not be separated optically from the wall of the rectum. Small intraprostatic cysts were visible. FNA of the gland was performed and revealed the diagnosis of prostate carcinoma.*

increase the diagnostic accuracy [127]. For a precise immunohistochemical analysis, different markers are necessary to differentiate between urethral, glandular, or ductal origin of the tumor, which is possible in human medicine but not sufficiently investigated in the dog. In dogs, the prostate cancer most probably originates mainly from collecting ducts [128]. In one study, qPCR revealed increased expression of PSMA in all cancer tissues [128].

In dogs, both urothelial carcinoma of the lower urinary tract and prostate cancer may occur. In both cancer types, *canine (c) BRAF V595E* gene mutations were found. The *BRAF* genes belong to the *RAF* gene family known to contribute to the MAPK pathway; mutations promote growth of cancer cells during oncogenesis [129]. *Canine(c)BRAF V595E* gene mutations were recently detected by means of droplet digital PCR (ddPCR) in approximately 80% of urogenital cancer in dogs. The *cBRAF* mutation was detectable in urine samples with the same sensitive assay and in 75% of the cancer patients [129, 130]. However, since in approximately 20% of canine urogenital cancer the *cBRAF* mutation is not detectable, the sensitivity of the ddPCR assay does not exceed 80%.

To differentiate between urothelial and prostate carcinoma, a combination of markers will be necessary. In a recent study [131], the chemokine CCL17 was found to contribute to regulatory T cell (Treg) recruitment in prostate tumors. In dogs with prostate cancer, tumor-infiltrating Tregs were found to be associated with bad prognosis [132]. In urine samples of dogs with urothelial cancer, increased concentrations of CCL17 were found in comparison to healthy dogs. The *cBRAF* mutation is believed to induce the COX-2/PGE2/EP2 pathway, thereby triggering the CCL17 production and the Treg infiltration in canine urothelial carcinomas; however, a direct relation between *cBRAF* mutation and prognosis was not possible [131]. Recently, the concentration of another chemokine, named CCL2, was found to be increased in urine

of dogs with urothelial carcinoma [133]. The combined measurement of CCL17 and CCL2 in urine might improve the sensitivity and specificity of each biomarker for detection of canine urothelial cancer [131].

In one study, RNA-Sequencing of canine normal prostate gland tissue and malignant tissues was performed to find differentially expressed genes (DEGs) and deregulated pathways. The detected DEGs were grouped into the superior pathways (1) inflammatory response and cytokines; (2) regulation of the immune system and cell death; (3) cell surface and PI3K signaling; (4) cell cycle; and (5) phagosome and autophagy. Meanwhile, some genes were listed in relevant databases and might improve diagnosis and therapy in future.

Furthermore, canine prostate cancer cell lines have been developed making investigation of molecular mechanisms easier [134]; one cell line expressing redfluorescence proteins was developed to improve in-vivo imaging [135].

#### *4.5.4 Differential diagnosis*

BPH, chronical prostatitis, or other tumor diseases must be considered, especially in case of weight loss.

### *4.5.5 Therapy*

Conservative therapy comprises chemotherapy and palliative measures and shall improve the median survival time (MST) and well-being. Surgical treatment is possible; partial and total prostatectomy followed by chemo- and radiotherapy, photodynamic therapy and COX inhibitors [15] are possible methods. Castration is not useful and should not be recommended [19, 119].

Prostate surgery is mostly recommended in case of intracapsular growth and early-stage cancer. For total prostatectomy, the prostate-inclusive prostatic urethra has to be removed; thereafter, the urethra is reconstructed. Subtotal intracapsular prostatectomy proved to prolongue the MST more than 5fold in comparison to total prostatectomy (112 ± 63.3 days vs 19.9 ± 10.67 days) [136]. Most frequent postoperative complication is a permanent incontinence, occurring in 33–100% of cases; however, less frequent after subtotal intracapsular prostatectomy [136–138]. In one retrospective study [139], the postoperative survival time (time between operation and death) was 231 days (median; range: 24–1255 days). In the evaluated studies, ureter-urethral anastomoses (14), cysto-urethral anastomoses (9), anastomoses between ureter and colon (1), and anastomoses between urinary bladder neck and pelvic part of the urethra were described (1). The dogs in addition received mitoxantrone, NSAID, metronomic thalidomide, cyclophosphamide, piroxicam, carboplatin, and/or deracoxib. In 8/23 dogs, postoperative incontinence occurred. Further complications were dehiscence of sutures, uroabdomen, and prepubic herniation. In 3/23 dogs a recidive occurred, in 4/23 metastases were diagnosed [139].

Another study compared the outcome of medical therapy (n=12) and surgery in dogs with adenocarcinoma of the prostate gland [140]. The surgery comprised total prostatectomy (TP, n=20) and prostatocystectomy (TPC, n=9). In the surgical group, the overall MST was longer than in the medical treatment group (337 vs. 90.5 days). Within the surgical group, the postoperative MST was longer in the TP group (510 vs. 83 days). In case of aggressive prostate cancer, TPC is preferred, therefore more severe complications occur, explaining the shorter MST.

#### *Diseases of the Canine Prostate Gland DOI: http://dx.doi.org/10.5772/intechopen.105835*

In recent years, the surgery was improved by use of Light-Amplification by Stimulated-Emission-of-Radiation (laser). Meanwhile, the method is used for prostatectomy. The laser (Diode, Nd:YAG or CO2) must be adapted to the predominating tissue, i.e. the vascularization and the pigment since the absorption spectrum can be influenced by melanin, hemoglobin, and water. For prostatectomy, the CO2 laser in combination with electrocautery was proven advantageous [141].

Immunotherapy is under intense investigation in human medicine and recently, a promising study in dogs with naturally occurring prostate cancer was published [132]. In this study, the presence and molecular mechanism of targeting regulatory T-cells (Tregs) were studied in canine cancer cells and an anti-Treg treatment (anti-human CCR4, mogamulizumab) in combination with Piroxicam tested in dogs with prostate cancer. The tumor response was evaluated according to canine response evaluation criteria [142]. The presence of tumor-infiltrating CCR4 Tregs was found to be associated with bad prognosis. The anti-CCR4 compound reduced circulating CD4+ Foxp3+ Tregs and CCR4+ Tregs, furthermore, the number of local CCR4 cells was reduced. The combined treatment with piroxicam better reduced the tumor size than piroxicam alone. The median progression-free survival time (PFS) was 204 (21–573)days and 57 (6–210)days in mogamulizumab/piroxicam dogs and piroxicam dogs, respectively; the respective OS time was 312 (86–1000)days and 99 (6–468)days. Observed clinical side effects were grade 1 or 2 (vomiting, anorexia, pancreatitis, urticaria, rash, and infusion reaction).

Modern studies investigate molecular targets like tight junction proteins. A recent in vitro approach used prostate adenocarcinoma (PAC) and transitional cell carcinoma (TCC) cell lines to investigate whether it is possible to destroy tumor cells by gold-nanoparticle-mediated laser perforation (GNOME-LP [143]), a noninvasive thermotherapy. The gold-nanoparticles (AuNPs) were conjugated to *Clostridium perfringens* enterotoxin (C-CPE); the latter are known to bind to claudins, which are tight junction proteins frequently expressed in tumors. They are of interest since they regulate the transfer of molecules through tight junctions and in case of deregulation because cancer might contribute to metastase spreading [144]. The targeted AuNPs enter the tumor and the laser activation leads to protein thermodenaturation. The successful laser perforation was recognized by red fluorescence signals. When the combination of functionalized AuNPs and GNOME-LP was used, cell survival was significantly reduced in comparison to non-treated control cells. The targeted treatment is a promising new approach.

In human medicine, *BRAF* inhibitors have been developed for targeted treatment of *BRAF* mutant tumors [145]; respective investigations concerning prostate cancer cell lines are ongoing in veterinary medicine [131].

Another interesting method is the prostate artery chemoembolization, causing necrosis of prostate gland and tumor tissue and a decrease in prostate volume of approximately 70% in one study [146]. The method is promising; however, since all dogs died because of metastases within 9 months, improvement of early diagnosis of the disease is most important.

#### *4.5.6 Prognosis*

The prognosis of maligne prostate cancer is poor; the median survival time (MST) is still 0–6.9 months and better in case of intracapsular growth and early-stage cancer [15, 115].
