Evaluation of a patient with prostatitis is a complicated task, because the disease is defined only in terms of subjective symptoms and there is no objective, measurable parameter to divide the patients into diagnostic categories for clearly defined modes of treatment, in contrast to the treatment of other diseases of the prostate gland. Prostatitis means ”inflammation of the prostate” and inflammation is an accompaniment to an infection, but not all inflammatory reactions can be explained by an infection. This condition has caused great confusion over the treatment of prostatitis, a situation that continues to apply today. Pain or discomfort is the most severe and frequent symptom (Alexander & Trissel 1996, Krieger et al. 1996b, Nickel & Sorensen 1996, Egan & Krieger 1997), followed by voiding complaints (Alexander & Trissel 1996, Meares 1998) and not forgetting the importance and role of sexual dysfunction in these patients (Kretschmer 1937, Keltikangas-Järvinen et al. 1989, Egan & Krieger 1994, Alexander & Trissel 1996, Berghuis et al. 1996).
The oldest ”golden standard”, is the four-glass test proposed by Meares and Stamey (1968). This essential test for narrowing down the diagnosis of prostatitis is known to almost everybody but unfortunately used only by a few (Moon 1997, Nickel et al. 1998, McNaughton-Collins et al. 2000).
Symptoms of prostatitis include pain in the region of the lower abdomen or in the perineal, scrotal, inguinal and penile area, also accompanied by voiding disturbances of varying severity and related symptoms. Temporary sexual dysfunction and mental distress can be present (Krieger 1984, Roberts et al. 1997, Meares 1998). The baseline information is obtained by taking the history of all the facts related to urinary tract infections (Lipsky 1989, Krieger et al. 1993a) and any previous history of possible sexually transmitted disease (STD) and relating this to the number of sexual contacts (Kretschmer 1937, Stamey 1973, Drach 1976, Krieger et al. 1993a, Worm & Petterson 1989, Foxman et al. 1997), although still more important than this can be sexual preference and the latest exposure (Krieger et al. 1993a, Alexander & Trissel 1996). The history of previous urological procedures can provide some explanations on which to base a clinical conclusion, and similar importance can be given to comorbidity factors reflecting on the host defence mechanisms (diabetes, immunosuppression, etc.) (Meares 1998) and patients with hematuria require cystoscopy and urinary tract imaging (Nickel 1998b).
Clinical examination should include a careful assessment of the patient’s inguinal regions and scrotum (for hernias), penis for plaques suggestive of Peyronie´s disease, which can cause pain in the penis, a careful inspection of the perineum for evidence of perirectal diseases and a digital rectal examination (DRE), transrectal ultrasound (TRUS), noting any tenderness or other signs confirming an inflammation process or excluding malignancy of the prostate gland (Meares 1998, Nickel 1998b).
Several laboratory and related investigational procedures, more or less used for diagnosing CP/CPPS are available and are explained in detail below.
The cornerstone of the laboratory diagnostic methods for prostatitis is careful bacteriological assessment of cultures from the lower urinary tract and prostate gland and/or seminal vesicles (Meares & Stamey 1968). A microscopic work-up using several staining methods and a proper microbiological urine culture will reveal uropathogens and also any candida species (Krieger 1984, Krieger & McGonagle 1989). A careful urine analysis will exclude or define signs of inflammation, with or without bacteriuria and/or haematuria (Krieger 1984). Patients with haematuria should also undergo cystoscopy and a radiographic examination of the upper urogenital tract by intravenous pyelography or CT (Nickel 1998b). Transitional cell carcinomas, especially diffuse bladder carcinoma or a carcinoma in situ can cause clinical symptoms similar to prostatitis (Solsona et al. 1996, Montie et al. 1997, Luzzi & Cranston 2000).
In their famous article of 1968, Meares and Stamey launched a practical proposal for clinical differential diagnosis between several types of prostatitis (Meares & Stamey 1968). This method, which has never been validated, rose to the status of a ”golden standard” and was for many decades the only method for ascertaining a diagnosis of prostatitis. This is scientifically and historically an affront to such names as Young et al. (1906), von Lackum (1928), Nickel (1930) and Kretschmer (1937), all of whom pointed out many times in their publications that the basis for the diagnosis and treatment of prostatitis lies in microscopy of the prostate secretion.
This ”four-glass test” described by Meares and Stamey (1968), which is used to choose patients for therapy based on information received from urine and EPS samples, relies on finding excessive numbers of leukocytes in the EPS and/or post-prostatic massage urine (VB3), relative to those found in the first voided urine (VB1) and mid-stream urine (VB2). Since normal individuals have some leukocytes in their EPS, a consensus value of 10 leukocytes per high-power field serves as an upper normal limit (Meares & Stamey 1968, Drach et al. 1978, Anderson & Weller 1979). EPS cannot be obtained from all patients, however, and the diagnosis requires excessive numbers of leukocytes in the VB3 as well. Over 4 leukocytes per high-power field in centrifuged VB1 and/or VB2 urine specimens examined microscopically under 400x magnification is highly suggestive of prostatitis, and results over 10 leukocytes per high-power field are clearly pathognomic (Meares & Stamey 1968, Drach et al. 1978, Anderson & Weller 1979, Wright et al. 1994).
The diagnostic difficulties lie in the fact that uncircumcised men have a rich flora of commensals around the preputial skin and in the distal urethra, which can lead to misinterpretation in localisation studies. The possibility of such problems was illuminated by Meares and Stamey (1968), who advised that the bacterial colony count for a VB3 and/or EPS sample should be at least 10-fold greater than those in the VB1 and VB2 samples.
Krieger et al. (2000a) have recently shown that VB1 and VB2 samples have given low sensitivity as indicators of urethral inflammation, but that in combination with properly performed EPS and VB3 assessments, the four-glass test can be of significance for detecting urethral and prostate inflammation. Ludwig et al. (2000) have also pointed out that if the EPS search fails, leukocytes in the VB3 sample are a diagnostically more valuable sign of inflammation.
Everyday life has shown that this procedure is well known but seldom used (McNaughton et al. 2000), and in order to make up for this lack of accuracy and to meet the clinical need, J.C. Nickel has proposed a new, quicker screening pre-massage and post-massage test for the diagnosis of prostatitis (Nickel 1997).
Lacquaniti et al. (2000) and Strohmaier and Bichler (2000), in recently published articles, have questioned the meaning and usefulness of the Meares-Stamey test for the diagnosis or categorization of different forms of CP/CPPS. Lacquaniti et al. (2000) proposed an easier way to achieve 90% sensitivity in bacteriological examinations, by using a semen test, which is more tolerable for the patients.
The pre-massage and post-massage test (PPMT) is intended to be a simple, cost-effective and time-saving diagnostic tool for clinical use in cases of patients with an initial diagnosis of chronic prostatitis syndrome and with no clinical evidence of urethritis (no discharge from the urethra, no dysuria, no urethral irritation alone or in combination with dysuria). The patient gives a mid-stream urine sample (labelled pre-M) after careful cleansing of the glans penis with the foreskin retracted. A digital rectal examination is performed to assess the configuration and hardness of the prostate gland, and the prostate is massaged vigorously from the periphery towards the midline. The patient then immediately gives another urine sample of up to 10 ml (labelled post-M). These two specimens are properly checked for quantitative culture and microscopy of postcentrifugal sediment.
In the interpretation of the test, leukocytosis over 10 per high-power field in the post-M specimen, or a one log (x10) increase in leukocytes compared with the pre-M result is taken as suggesting the probability of clinically defined prostatitis. Significant bacteriuria in the post-M specimen (>10), or a one log greater colony count/ml compared with the pre-M specimen, given that the pre-M is sterile, suggests a possibility of chronic bacterial prostatitis. Significant bacteriuria in both the pre-M and post-M specimens is suggestive of prostatic inflammation, but may be associated with bacterial cystitis or bacterial inflammation proceeding from the upper urinary tracts. Another test should therefore be performed for these patients after 3 days of nitrofurantoin or trimethoprim therapy and the results compared with the previous ones. The calculated sensitivity and specifity of the PPMT in a selected population were both 91%, and it is thus recommended for use by urologists at the first meeting with the prostatitis patients, and ideally by general practitioners at primary visits (Nickel 1997).
The prostate gland secretes various substances, including prostate-specific antigen (PSA), prostatic acid phosphatase (PAP), citric acid, cholesterol, zinc, etc., and some investigators have suggested that measurement of these in whole semen or in EPS may provide a useful marker for diagnosing prostatic inflammation (Fair & Cordonnnier 1978, Fair & Parrish 1981, Zaichick et al. 1996). Significant alterations in the secretory products of the prostate gland occur in patients with prostatitis. The pH of the prostatic fluid in normal men is slightly acidic, around 6.6–7.3 (Blacklock 1974, Fair & Parrish 1981), whereas in cases of bacterial inflammation an alkaline pH over 7.6 is detected (Fair & Cordonnier 1978, Huaijin et al. 1998).
Decreases in the citric acid concentration or in the specific gravity or zinc, spermine, cholesterol, PAF or enzyme (lyzozyme) concentrations (Fair & Cordonnier 1978, Fair & Parrish 1981, Meares 1998) have been reported, but no significant differences in zinc concentrations in the semen were found between patients with prostatitis and controls by either Leib et al. (1994) or Zaichick et al. (1996). The prostate fluid contains a potent antibacterial factor named prostate antimicrobial factor (PAF), which is bactericidal to most pathogens causing urinary tract infection (UTI) (Fair & Parrish 1981), but there is still some controversy concerning the role and importance of zinc or PAF in the inflammatory process (Fair & Cordonnier 1978, Leib et al. 1994, Zaichick et al. 1996, Meares 1998). It is proposed that semen functional analysis (SFA) should be taken by masturbation after 3–5 days abstinence from sexual intercourse and after careful washing of the hands and genitalia (Weidner et al. 1991a, Vicari 2000).
A leukocyte count over 10 per high-power field and/or over 2×106/ml in the semen may be regarded as pathognomic (Weidner et al. 1991a, Wolff 1995, Krieger et al. 1996a, Huaijin et al. 1998), or on some occasions only commensal (Aitken & Baker 1995).
The diagnostic sensitivity of the occurrence of bacteria or leukocytes in the seminal fluid relative to the Meares-Stamey test has been shown in a recently published prospective study (Lacquaniti et al. 2000) to be up to 90%. Krieger et al. (1996a) have pointed out that it is difficult or impossible to distinguish leukocytes from immature sperm without a specialized staining procedure, but patients have stated that giving seminal fluid is more tolerable than the Meares-Stamey test. Lacquaniti et al. (2000) also conclude that this diagnostic procedure is less expensive and more easily executed than the ”golden standard” test.
Serum prostate-specific antigen (PSA) levels can be elevated in prostatitis (Pansadoro et al. 1996, Potts 2000), reducing the diagnostic value of PSA for excluding prostatic cancer. On the other hand, Hasui et al. (1994) showed a relationship between PSA and the histological stage of inflammation in the prostate tissue, attributing this to a leak phenomenon. A PSA increase has also been reported to be present in acute inflammation of the prostate gland in experimental studies (Neal et al. 1992, van Iersel et al. 1995). There is no evidence, however, that in inflammatory cases a better diagnostic accuracy for differentiating between benign or malign processes in the prostate can be achieved using the PSA free-to-total (F/T) ratio (Nadler et al. 1995), at least not entirely (Jung et al. 1998).
Okada et al. (2000) have pointed out that PMNLs are responsible for the acute inflammatory reaction in the prostate tissue, and that they constitute a significant reason for the increase of PSA. A different point of view is represented by the conclusion of Ponniah et al. (2000) that one possible aetiological factor or reason for CP/CPPS is an autoimmune inflammatory process, findings which confirm the results of Alexander et al. (1997).
Wadström et al. (1984) showed that increased levels of PAP can be found after prostatic massage, perhaps caused by mechanical damage to the prostatic ducts, and this was supported by Brawn et al. (1994), who studied the influence of prostatic tissue infarction on the levels of PSA and PAP. Both rose, but PSA was elevated more frequently than PAP, the reason possibly lying in the different molecular weights of PSA and PAP, which influence penetration from the prostate tissue into the blood circulation.
The last five years have yielded investigations into the basic behaviour of proinflammatory cytokines in the semen of patients with CP/CPPS. The cytokines are soluble proteins secreted by cells of the human immune system that principally regulate the inflammatory and immune responses of the host to microbes, and measuring the level of cytokines may give a more objective measure of disease severity in CP/CPPS patients (Alexander et al. 1998, Nadler et al. 2000, John et al. 2001). The production of cytokines IL-1ra and IL-1b, commonly IL-1 (secreted by macrophages) has an influence on the host response, on the severity and prolongation of the inflammatory reaction in tissues and on the response to tissue repair (Alexander et al. 1998, Nishimura et al. 1998).
Tumor necrosis factor (TNF-a) is synthetized by cell lines of monocytes / macrophages and induced by bacterial proteins, viruses and fungal antigens, and is of considerable importance for the process of inflammation and angiogenesis (Alexander et al. 1998, Nadler et al. 2000). The cytokines have a mediatory effect on nitric oxide production and through this an effect on endogenous vasodilatation and the response to inflammatory reactions, but the cytokines studied so far represent only a small part of the whole group of inflammation mediator molecules (Galley et al. 1997, Alexander et al. 1998, Nishimura et al. 1998, Nadler et al. 2000)
The use of polymerase chain reaction (PCR) techniques, a highly sensitive molecular radio-assay method for bacterial detection, has opened up a ”Pandora’s box”, showing that a situation shown to be sterile by conventional methods is actually not sterile at all. The prostate can harbour bacteria that are undetectable by traditional everyday approaches, and PCR will confirm the sterility of a tissue with a high level of confidence and can trace small numbers of microbial agents/particles and bacterial DNA sequences which may represent the presence of pathogens or parts of these (Wilson 1994, Riley et al. 1998, Keay et al. 1999, Tanner et al. 1999, Hochreiter et al. 2000, Krieger et al. 2000c).
The latest method, prostate-specific membrane antigen (PSMA) (measured by RT-PCR), is so sensitive that it can even detect prostate epithelial cells in the circulating blood, but we do not know the clinical relevance of this finding (Dumas et al. 1997).
There are no transrectal ultrasound findings that are specific to prostatitis, but certain publications give a general characterization of ultrasonic patterns and their possible clinical implications, e.g. irregular internal echoes and overall alterations of the shape of the gland in cases of prostatitis, dilatation of the vessels and oedema due to acute inflammation (Veneziano et al. 1995, Ulleryd et al. 1999, Wasserman 1999).
Increased blood flow to the prostate capsule and parenchyma has been demonstrated in cases of CP/CPPS (Cho et al. 2000), while asymmetry and/or overdistension of the seminal vesicles may be a local sign of inflammation, and also cystic lesions in the region of bladder neck (Christiansen & Purvis 1990, Ludwig et al. 1994, Wasserman 1999).
The finding of prostatic stones is often taken as a basis for a diagnosis of prostatitis, but such calcifications are very common and are also present in men without symptoms of prostatitis (Wasserman 1999, Zackrisson et al. 2000). The usefulness of transrectal ultrasound (TRUS) lies in determining the volume of prostate gland, changes in the volume being related to inflammation, and in finding possible ejaculatory duct cysts and ruling out possible hypoechoic lesions in the periphery of the gland that might lead to a suspicion of prostate cancer and also in diagnosing prostatic granulomas (Terris et al. 1997, Ulleryd et al. 1999, Wasserman 1999).
Targeted biopsies taken from suspicious areas and/or diagnostic/treatment procedures performed on the prostate (cyst, abscess drainage) are also very conveniently managed under TRUS control (Doble et al. 1989a, Doble et al. 1989b, de la Rosette et al. 1995, Aarnink et al. 1998, Ludwig et al. 1998, Wasserman 1999). In relation to biopsy and/or other invasive procedures performed with TRUS, one should not forget antibiotic prophylaxis to avoid any generalisation of possible inflammation of the prostate gland or haematogenous spread of bacteria from the rectum leading to generalized urosepsis and fatal case is also possible (Desmond et al. 1993, Aus et al. 1996, Gilad et al. 1999, Aron et al. 2000, Lindert et al. 2000).
The urodynamic investigation measures physiological changes in bladder and urethral sphincter function when the patient is experiencing his usual symptoms of disturbed micturition (Blaivas 1984). The urinary flow rate can be measured with a uroflowmeter, and cystometry is a method for measuring the pressure-volume relantioship in the bladder, but these investigations alone cannot give a definite diagnosis of disordered micturition, and synchronous methods (pressure-flow study) are needed (von Garrelts 1956).
Pelvic pain and voiding difficulties are symptoms commonly attributed to CP/CPPS, and incidental observations of intraprostatic reflux in voiding cystourethrography may have a causal relationship with increased urethral pressure in patients with CP/CPPS (Hellstrom et al. 1987, Theodorou et al. 1999). Indeed, many patients are misdiagnosed and treated empirically for CP/CPPS with useless antibiotic courses when they have in fact functional bladder outlet obstruction (BOO) defined by urodynamic examination (Kaplan et al. 1994, Kaplan et al. 1997, Liao et al. 1999, Theodorou et al. 1999). It has been stated that the most important part of the urodynamic examination in the case of CP/CPPS patients is the urethral sphincter profilometry (Liao et al. 1999, Theodorou et al. 1999), because behavioural changes in the external urethral sphincter include spasms and instability (Hellstrom et al. 1987, Liao et al. 1999).
Inflammatory signs may also be present in cases of obstruction caused by benign prostatic enlargement, and CP/CPPS patients can clinically have lower urinary tract symptoms (LUTS) (Kohnen & Drach 1979, de la Rosette et al. 1992b, Tammela & Kontturi 1993, Mayo et al. 1998, Nickel et al. 1999a).
There is no need for routine cystoscopy of patients with symptoms of CP/CPPS, but it must be born in mind that suprapubic pain with voiding complaints may be a sign of interstitial cystitis or in situ carcinoma of the bladder, and biopsies taken from several parts of the bladder must be considered in suspicious cases (Miller et al. 1995, Schellhammer et al. 1995, Solsona et al. 1996, Montie et al. 1997, Berger et al. 1998, Luzzi & Cranston 2000).