Prostate

Prostate diseases, with few exceptions other than neoplasia, are diseases of intact male dogs. Most of these diseases evolve from endocrine-induced changes to the structure and integrity of the prostate. Resolution can often be achieved by medical management, hormone manipulation, or surgical intervention-including castration.

Anatomy

The canine prostate is a bilobed encapsulated organ composed of stromal cells, smooth muscle cells, and epithelial cells. It is closely associated with the neck of the urinary bladder, and encircles a portion of the urethra (prostatic urethra). Vasculature is supplied by the prostatic artery-a branch of the internal pudendal artery-and the prostatic vein [1]. Parasympathetic innervation, which stimulates glandular secretions, is supplied by the pelvic nerve [1]. Sympathetic innervation, which stimulates smooth muscle contraction during ejaculation, derives from the hypogastric nerve [1]. The blood vessels and nerves approach the prostate from the craniodorsal aspect.

The prostate is located at the cranioventral edge of the pelvic inlet. Post-pubertal maturation and advanced disease result in enlargement of the prostate and advancement cranioventrally into the abdomen where it is accessible to surgery. The prostate is a pharmacologically privileged organ protected by a blood-prostate barrier imposed by gap junctions between epithelial cells.

Physiology

The prostate is the only accessory sex gland in the dog. It produces ejaculatory fluid to increase seminal volume. The prostatic fluid may have some antibiotic effects and may play a role in activating spermatozoa for fertilization. Ironically, prolonged exposure to prostatic fluid is detrimental to sperm viability.

The canine ejaculate can be collected in three distinct fractions. The first fraction is of prostatic origin and is often an insignificant volume. The second fraction is concentrated sperm, derived from the epididymis. The third fraction is again prostatic and constitutes the most voluminous portion of the ejaculate. The total volume of the third fraction varies depending on the individual, breed, and duration of coitus (or collection); it can range from 1 milliliter to more than 20 milliliters. Normal prostatic fluid is clear, serous, and has a neutral to slightly acidic pH.

Clinical Presentation

The presentation of prostatic disease is primarily attributable to prostatic enlargement. The magnitude of space-occupying effects determines the type and severity of clinical signs. Dramatic enlargement of the prostate by hypertrophy or mass lesions may cause dorsal displacement of the colon, resulting in tenesmus or "ribbon-like" feces. Cranioventral displacement of the bladder may cause dysuria, increased urgency, and compromise of urinary tract defense mechanisms, predisposing to ascending cystitis and its associated clinical signs.

Other clinical signs are attributable to hyperplasia of the parenchyma and stroma. Increased vascularity and decreased stromal integrity predispose to microvascular hemorrhage, evidenced as hematospermia, hematuria, or hemorrhagic urethral discharge [1]. Occlusion of efferent ducts obstructs glandular secretions, forming cystic glands. These dilated acini may rupture, contributing to urethral discharge [1] or they may coalesce into large cavitations that contribute to the mass effect. Hyperplasia compromises natural defense mechanisms and immunity, predisposing to bacterial infection [1].

Finally, duration of onset of disease plays a major role in clinical presentation. Acute prostatic inflammation is often associated with severe rectal or abdominal pain as the prostatic capsule is unable to accommodate rapid swelling. Chronic disease is often asymptomatic as the body accommodates to the insidious course of disease; however, once a critical mass is attained (i.e., obstructive enlargement), space-occupying effects become evident.

Diagnosis

Thorough history and physical examination of the dog will provide important information for the interpretation of further diagnostic procedures. The presence of pain or pyrexia implicates an acute or septic disease process. Castrated dogs are at decreased risk of infectious disease and this may direct differential diagnosis toward neoplasia.

Rectal palpation is a highly subjective and nonspecific determinant of prostatic enlargement as only the caudal pole can be palpated. As the prostate enlarges and moves cranially and ventrally into the abdomen, abdominal palpation in conjunction with rectal palpation may be necessary in order to feel the prostate [1]. Symmetry of the bilobed prostate should be evaluated.

Cytologic evaluation of prostatic fluid can identify erythrocytes, neutrophils, bacteria, and normal or neoplastic epithelial cells (Fig. 72.1). Prostatic fluid is most easily obtained by manual ejaculation, isolating the third fraction. If the dog is not amenable to collection, prostatic massage and urethral flushing or the urethral brush method can be performed [1]. Blood or smegma from the prepuce or penis may contaminate the sample, complicating interpretation.

Figure 72.1. Prostatic fluid

Culture of prostatic fluid must be interpreted carefully. Prostatic fluid is collected as described above for cytologic evaluation. It must be noted that these techniques do not provide an aseptic means of fluid collection [1]; normal bacterial flora of the urethra or prepuce may contaminate the sample.

Survey radiographs are often nondiagnostic for mild to moderate prostatic disease [1]. With advanced prostatic disease and significant enlargement, radiographs may demonstrate a soft-tissue density in the caudal abdomen, space-occupying lesion of the urinary bladder, or dorsal displacement of the colon [1]. However, they do not localize the lesion to the prostate or differentiate prostatic pathologies.

Retrograde cystourethrograms may more readily demarcate the borders of the prostate and its association to the bladder. Infiltration of contrast media into the prostate via the prostatic urethra may implicate specific prostatic diseases [1].

Ultrasonography is the most effective, noninvasive technique to differentiate prostatic diseases. Evaluation of prostatic size, symmetry, and echogenicity implicates specific disease processes; however, definitive diagnosis cannot be made by ultrasonography alone.

Ultrasound-guided fine-needle aspiration (US-FNA) of prostatic lesions may provide the most definitive diagnosis of prostatic disease. One study demonstrated 80% agreement in diagnosis comparing US-FNA to histopathologic findings at necropsy [2]. Potential complications include seeding bacteria along the needle tract and leakage of suppurative material into the abdomen [2].

Prostatic biopsy can be performed via laparotomy, transabdominally by ultrasound guidance, or by perirectal biopsy [1]. Again concerns arise for seeding bacteria along the needle tract and abdominal contamination.

Serology and hematology have limited application in diagnosing prostatic disease other than to rule out systemic infection. Mild elevations in alkaline phosphatase (ALP) are commonly seen, but are nonspecific for prostate disease [3].

Prostate-specific markers have been used extensively in human medicine for early diagnosis of prostate cancer. To date, no such substance has been shown to reliably diagnose or differentiate prostatic diseases in the dog. The most promising marker, canine prostate-specific arginine esterase (CPSE), is produced by epithelial cells in response to androgens and is secreted in prostatic fluid [3]. CPSE serum levels are increased in dogs with benign prostatic hypertrophy compared with those in normal dogs; however this does not differentiate prostatic neoplasia [3].

Pathophysiology

Benign Prostatic Hypertrophy (Hyperplasia)

Benign prostatic hyperplasia/hypertrophy (BPH) is a normal, senile, usually asymptomatic condition of aging, intact dogs. Fifty percent of intact dogs over the age of 5 years, and 95% of intact dogs older than 9 years have gross or histologic signs of BPH [1].

Enlargement of the prostate is hormonally driven, as evidenced by prostatic atrophy after castration. The hypothalamic-pituitary-testicular axis is predominantly responsible for the production of male sex hormones. The hypothalamus produces gonadotropin releasing hormone (GnRH), which induces pituitary secretion of the gonadotropins-luteinizing hormone (LH) and follicle stimulating hormone (FSH). LH stimulates testicular Leydig cell production of testosterone. Dihydrotestosterone (DHT) is the primary mediator of prostate growth [1,4]. It is synthesized in the prostate by the metabolism of testosterone under the influence of the enzyme 5a-reductase [1,4]. Both testosterone and DHT induce growth factors in stromal and epithelial (glandular) cells, which increase cell size (hypertrophy) and cell numbers (hyperplasia), and decrease normal rates of apoptosis (programmed cell death) [1,4,5]. However, DHT binds to the cells with 10 times greater affinity and dissociates much slower, exerting exponentially greater effects on prostatic growth than does testosterone [1,4]. Estrogen (E2) plays a significant, yet uncertain role in the development of BPH [1,4]. It may increase receptors or receptor affinity to DHT [4].

BPH is generally eccentric (away from the center), so the prostatic urethra is not occluded, and stranguria is rarely seen as a presenting complaint in dogs [1]. BPH induces symmetrical enlargement that, if extreme enough, will produce symptoms of space occupying effects. Hematospermia is often an incidental finding during routine semen evaluation.

On ultrasound evaluation, BPH is diagnosed when the prostate exceeds normal parameters. In some cases of BPH, prostate size can be within normal parameters; however, changes in the appearance of the stroma and parenchyma indicate pathologic changes consistent with BPH [1]. These changes include diffuse echogenicity ("moth eaten appearance") or the presence of parenchymal cysts [1].

Castration is the definitive treatment for BPH.1 Elimination of testosterone induces complete regression of prostatic growth to near pre-pubertal size [1,4]. In valuable breeding animals, or when castration is not an option, life-long hormonal regulation aimed at decreasing concentrations of testosterone or DHT can dramatically reduce BPH. Finasteride ("Proscar", Merck; 5 mg PO daily) blocks the enzyme 5a-reductase, preventing conversion of testosterone to DHT [1,5]. It has demonstrated good efficacy in reducing prostatic size [1,5]. It has a high margin of safety, maintains fertility, and has no reported side effects [1,5]. Megestrol acetate (MGA, "Ovaban," Schering 0.5 mg/kg PO daily), a synthetic progestin, inhibits gonadotropin release (LH) by negative feedback inhibition to the pituitary, resulting in decreased levels of testosterone and E2 production [1]. Lower levels of testosterone correlate to lower levels of DHT and reduction of BPH. No detrimental effects on fertility or side effects have been reported. A gonadotropin releasing hormone (GnRH) vaccine ("Canine Gonadotropin Releasing Factor (GnRF) Immunotherapeutic," Pfizer Animal Health; 1 ml SQ, repeat in 4 to 6 weeks, booster every 6 months) has recently received conditional licensing for the treatment of BPH in dogs. Preliminary studies show an increase in anti-GnRH antibodies, a decrease in serum testosterone concentration, and a decrease in prostate and testicular size [6]. Effects on fertility have not been evaluated, but the decrease in testicular size is suggestive of decreased sperm production.

Prostatitis

BPH is the inciting cause of prostatitis [1,4]. BPH disrupts the integrity of the prostate and affects natural immunity and resistance to infection, lymphatic drainage, and the normal vascularity of the gland [1,4]. Two distinct forms of prostatitis are recognized: aseptic prostatitis and septic prostatitis [4]. Aseptic prostatitis is a noninfectious inflammatory reaction characterized by prostatic infiltration with neutrophils. Septic prostatitis develops as bacteria from the normal flora of the urogenital tract opportunistically invade the prostate [1,4]. Escherichia coli is the most common isolate; Pseudomonas, Staphylococcus, Streptococcus, and Proteus are other common pathogens [1,4]. Septic prostatitis can further be categorized as acute or chronic. The fundamental difference is duration of onset and presenting clinical signs. Chronic prostatitis is often subclinical or symptomatic of low-grade infection [1]. Acute prostatitis presents as a sudden onset of severe abdominal pain and pyrexia [1].

Diagnosis of prostatitis is made by demonstration of inflammatory cells in prostatic fluid. In the case of septic prostatitis, presence of intracellular bacteria or a positive bacterial culture should be confirmed. Culture and histology of a prostatic biopsy or fine-needle aspirate may provide definitive diagnosis.

Successful treatment of prostatitis requires resolution of any infectious component and removal of the inciting cause, BPH. First, treatment of the bacterial infection requires use of antibiotics that are able to penetrate the prostatic barrier. Appropriate antibiotics must be lipophilic to penetrate the lipid bilayer, slightly basic as the normal and infected pH of the prostate is usually neutral to slightly acidic, and should have low protein-binding affinity to dissociate from the circulation [1]. Current antibiotic options (enrofloxacin, trimethoprim-sulfa, erythromycin, and chloramphenicol)1 should be selected based on safety and antibiotic sensitivity. Secondly, effective treatment of chronic prostatitis requires treatment of BPH (see above).

Prostatic Abscess

Septic prostatitis may progress to purulent vacuolization of the prostate or infection of parenchymal cysts [1,4,7]. The vacuoles or cysts may coalesce and form large intracapsular abscesses, causing asymmetric enlargement of the prostate [1]. Clinical signs vary from chronic, nondescript symptoms to acute onset with abdominal pain and pyrexia. If an abscess ruptures, presentation may be an acute abdomen and septic shock [1]. A presumptive diagnosis is made by sonogram. History, clinical signs, and hematology help differentiate prostatic abscesses from intraprostatic cysts. Conclusive diagnosis is made by demonstration of suppurative fluid obtained by biopsy, fine-needle aspiration, or exploratory surgery [1].

Treatment requires abscess drainage and long-term antimicrobial therapy and resolution of BPH. Surgical drainage and omentalization is the preferred surgical technique [1]. Other surgical options include complete or partial prostatectomy, marsupialization, or placement of Penrose drains. Successful, nonsurgical drainage by ultrasound-guided aspiration has been reported.8 Regardless of the treatment method, concurrent castration is highly recommended.

Cystic Lesions of the Prostate

Prostatic abscesses must be differentiated from prostatic cysts. Parenchymal (retention) cysts are diffuse hypoechoic structures within the parenchyma of the prostate that develop subsequent to BPH and are the most common cystic condition seen in the canine prostate [1,7]. "Squamous metaplasia," epithelial hyperplasia in response to estrogen exposure, is responsible for formation of some parenchymal cysts [1,7]. Epithelial hyperplasia and stromal fibrosis block the efferent ductules of the glands, resulting in the accumulation of serosanguinous fluid and subsequent dilatation and destruction of the acini.1,4,7,8 Cysts are lined by a single layer of epithelial cells [1,4,7]. Chronic prostatitis may lead to fibrosis and dissolution of the cystic lining, forming giant cavities (cavitary prostatitis) (Fig. 72.2) [7].

Figure 72.2. Prostatic cyst in ultrasound (A) and in surgery (B).

Extremely large parenchymal cavities may extend beyond the margins of the prostate. Cavities or cysts may be asymptomatic or they may contribute to symptoms of hematuria or hematospermia if they rupture. They may cause space-occupying symptoms or predispose to prostatic abscessation from ascending or hematogenous spread of bacteria.

Treatment of parenchymal cysts requires treatment of BPH pharmacologically or by castration. In squamous metaplasia, elimination of the estrogen source (e.g., exogenous estrogen therapy or endogenous estrogen production by Sertoli cell or adrenal tumors) is necessary [1,7]. Small cysts may regress, but large cysts and cavities may require surgical drainage if they are clinically significant. Drainage by US-FNA has been described [8]. Surgical excision and omentalization is the procedure of choice when surgery is warranted [1].

Paraprostatic cysts (Müllerian duct cysts) lie outside the prostatic capsule, distinguishing them from parenchymal cysts. They are not hormonally controlled, are not associated with BPH, and do not regress post-castration. They develop late in life from the remnants of the Müllerian (paramesonephric) duct [1,7]. During embryogenesis, male sexual differentiation induces regression of the Müllerian duct by secretion of Müllerian inhibiting substance (MIS) [1]. In females, the Müllerian duct gives rise to the oviducts, uterus, and cranial vagina [1]. Incomplete regression of the Müllerian duct can result in fluid-filled cysts located adjacent to the prostate, with variable degrees of prostatic involvement. The cysts generally do not communicate with the prostate or the urethra. Paraprostatic cysts require drainage or surgical resection only if they are symptomatic.

Prostatic Neoplasia

The highest incidence of prostatic neoplasia occurs in castrated dogs [9,10]. There does not appear to be any association with age at time of castration [10]. Adenocarcinoma is the most commonly diagnosed neoplasia [9,10]. Transitional cell carcinoma is also common, presumably from the close association of the prostate to the bladder [9].

Presenting complaints may include stranguria, which is more common with prostatic neoplasia than with other prostatic conditions because of the invasive nature of the tumor into the lumen of the urethra [1]. Rectal palpation or ultrasonography commonly demonstrates asymmetry of the prostate. Ultrasonography may also identify echogenic mass lesions within the parenchyma. Definitive diagnosis is made by biopsy or fine-needle aspiration.

Prostatic cancers are highly malignant and metastasis has usually occurred by the time of diagnosis [1,9,10]. Prognosis is grave to guarded at diagnosis and treatment is generally palliative, focusing on maintaining a patent urethra [11]. Therapeutic options that have been described include complete prostatectomy, chemotherapeutic and radiation therapy [12] and transurethral resection (TUR) [11]. All treatment modalities have been associated with significant side effects including incontinence and death; and none have prolonged or maintained the patients' quality of life.