Urology Introduction PDF

Lezione 1 UROLOGY INTRODUCTION General information about the course The professor starts the lesson by stating that he doesn’t want to teach us urology since probably no one of us will want to become a urologist, but he rather wants to transmit the passion for medici...

Lezione 1 UROLOGY INTRODUCTION General information about the course The professor starts the lesson by stating that he doesn’t want to teach us urology since probably no one of us will want to become a urologist, but he rather wants to transmit the passion for medicine and surgery. However, he states that the most amazing and complete specialty for him is urology and he will try to demonstrate that through his lessons. Textbook Regarding the textbooks he will provide a QR code in the slides. The recommended book is “Smith and Tanagho’s general urology”. He will also provide the Italian version in his slides which he recommends using especially for looking at the images, from radiologies to interoperative pictures. However, no extra information will be asked in the exam, which he claims to be “extremely easy” since only basic knowledge will be required. He also talks about the possibility of a pre-examination in itinere. Urology introduction and patient evaluation The professor gives then a general overview of urology stating that it is a specialty which has both medical and surgical implications in diseases of the urinary tract system and reproductive organs. Urology deals with many clinical conditions, such as urinary infections or incontinences for example, but there is also an important surgical component, ranging from open surgeries to the use of robotic platforms and even endoscopic instruments. Moreover, it is a specialty involving many organs such as the kidneys and the adrenal glands, the ureters, the bladder, the urethra in both females and male but it may also deal with the prostate and the uterus. Urology also comprehends the field of sexuality and sexual disorders. During the evaluation of an urologic patient, a physician needs to first evaluate the patient rather than the disease. The professor talks about understanding the level of comprehension of the patient based on social and intellectual levels and modulating the communication based on how much the patient can understand. The collection of data and history of the patient is a crucial step in the diagnostic process. For example, by considering a stone former, which is a patient with a very long history of urolithiasis, by simply collecting his past history we can assess his current situation. The focus of an urologist should also be on other possible co-morbidities. Afterwards we need to perform the physical examination, which can be crucial to avoid unnecessary invasive exams. The abdominal and rectal examination are the most important in this field. An accurate anamnesis and physical examinations can lead to a complete understanding of the situation of our patient and only after defining a possible diagnosis we can select the best optimal laboratory and radiological exam. For example sometimes there can be a patient with two different diseases but the exams may only show one of these, while through anamnesis we can understand possible symptoms related to the second condition. This is valid for all medical fields. There are many tools in managing the urologic patients and these are classified by the guidelines. In Italy we use the guidelines by the European association of urology (EAU) that can be found here: www.uroweb.org. The guidelines are a fantastic tool, not only for the treatment since identifying the correct therapeutic pathway is very complex, but also for diagnosis of urological conditions. However they need to be adapted to the different situations. Lezione 2 SYMPTOMS OF UROLOGY The use of guidelines When reviewing the guidelines on prostate cancer, we see that a patient may present with symptoms, or sometimes none at all. We can use certain parameters derived from anamnesis, physical examination, and laboratory or radiological tests to identify the specific characteristics of the prostate cancer. This allows us to choose among different treatment options: medical, radiotherapeutic, or surgical, each with varying outcomes. However, the natural history of the disease can be complex, as patients are often not fully aware of their condition. Therefore, it is necessary to carefully evaluate the symptoms reported by the patient, even when a clear diagnosis is not immediately available. We must identify the correct guidelines and the best diagnostic pathway to arrive at an accurate diagnosis, adapting our knowledge to daily clinical practice. For this reason, guidelines serve as a kind of "bible" for us, in particular the EAU guidelines on www.uroweb.org. It is important to begin with the analysis of urological symptoms, as at the patient's bedside, a well-defined diagnosis may not yet be clear. Symptoms in urology Lower urinary tract symptoms: o Hematuria o Urinary incontinence o Pain o Sexual dysfunction Lower urinary tract symptoms The most common urological symptoms reported by patients involve the lower urinary tract. We define these symptoms as those associated with the urinary bladder and its outlet. For example, a patient with prostate issues may present with symptoms related to voiding or storage dysfunction, or may report dysuria (painful urination). Such symptoms can be due to any combination of obstructive or irritative causes Lower urinary tract symptoms (LUTS) can be divided into two main categories: those related to bladder storage and those related to bladder emptying. There is also a third category, consisting of post-voiding symptoms. It is important to note that these symptoms can occur in both men and women, but in men, the incidence increases with age. In elderly patients, it is common to encounter a combination of these symptoms. Storage symptoms occur when the bladder struggles to retain urine. A typical example is increased urinary frequency, which may be caused by urinary infections or inflammation of the bladder walls. [irritative : increased frequency and urgency of passing urine (having a need to pass urine urgently), urge incontinence and needing to get up to pass urine at night] Voiding symptoms, on the other hand, are related to the inability to fully expel urine. For instance, an enlarged prostate may cause difficulty in completely emptying the bladder, leading to symptoms such as hesitancy (delay in initiating urination), intermittent stream (starting and stopping flow), and straining (sforzo nell’urinare), as well as "terminal dribbling," where a few drops of urine continue to exit after completing urination. There are also certain conditions that can induce similar symptoms, such as excessive consumption of caffeine, alcohol, or fluids. Post-voiding symptoms include the sensation of incomplete bladder emptying, which can significantly impact the patient's quality of life. The causes of these symptoms are not necessarily confined to lower urinary tract problems but may also include unusual circumstances. For instance, there are cases where foreign objects are found in the bladder, inserted for sexual purposes, such as a patient who inserted a pearl necklace into the urethra to enhance sexual satisfaction. In another case, a male patient inserted an electrical cable into his urethra for recreational purposes, but the cable became knotted, necessitating a surgical incision of the bladder for removal. Patients often deny how these foreign objects came to be in their bladder, attributing it to accidental causes. Urinary symptoms can be quantified using tools such as the International Prostate Symptom Score (IPSS) questionnaire, which assigns numerical values to the severity of symptoms. In patients unable to clearly articulate their condition, visual questionnaires may be employed. These kinds of questionnaires can be employed with neurological patients or patients with sexual disorders. In the advanced stages of lower urinary tract symptoms, patients may develop acute urinary retention, where they are unable to pass urine and require catheterization. In chronic cases, especially in those with long-standing prostate enlargement, there may be a gradual accumulation of urine in the bladder, potentially exceeding one liter. This can lead to overflow incontinence, where excessive urine leaks involuntarily due to bladder overdistension. Nocturia One of the most common urological symptoms (especially in male patients) is represented by nocturia. Nocturia is defined as the need for patients to get up at night (or during the main sleep period) to urinate for a relatively large number of times. The causes of nocturia vary and can range from cardiac problems to excessive fluid intake but also due to prostatic problem, and each of them requires careful evaluation to select the most appropriate treatment. This table explains how nocturia could also be due to inappropriate liquid intake, indicating that nocturia may sometimes have a psychological cause. [The slides also include the EAU Guidelines for the management of male and female lower urinary tract symptoms, which the professor did not explain]. Hematuria Finally, an important symptom to consider is hematuria, the presence of blood in the urine, which may be visible to the naked eye (gross hematuria) or detectable only microscopically (microscopic hematuria) or through a dipstick. Hematuria is particularly concerning, as it may signal a neoplastic disease of the urinary organs (in 25% of cases). There can also be cases of pseudo-hematuria, where the urine appears red due to dehydration or the presence of certain drugs or foods, and not due to the presence of red blood cells (RBCs) in the urine. Lezione 3 MAIN URINARY SYMPTOMS HEMATURIA Hematuria is defined as the presence of blood in urine. It is a quite concerning urological sign, as in about 1/4 of the patients complaining this symptom the cause is found to be a urologic cancer. For this reason, patients with hematuria need to be cautiously studied, considering also that it’s not uncommon for them to deny this symptom. Types of hematuria Hematuria is further divided in microscopic, when the presence of blood is not visible by naked eye, and macroscopic or gross, in which urine is visibly discolored by blood. Furthermore, the sole presence of red-colored urine is not always the result of blood: we talk about pseudo-hematuria, that can occur for example in patients under diuretic restriction, mimicked by the color of concentrated urine, or due to the intake of some drugs like Rifampicin. [also, some foods can cause it] Another important distinction to be made is between hematuria and urethral bleeding, or urethrorrhagia: in this case the bleeding is separated from the micturition, and it means that the source of the bleeding is below the sphincter. If the bleeding occurs together with micturition instead the source is most likely above the sphincter. A rapid tool to identify hematuria is the urine dipstick, although its results are not so certain; sometimes in fact this test is subject to false positives, and so for this reason it needs to be always confirmed by urinalysis. Microhematuria As soon as MH is detected on a sample, the first thing to evaluate is its persistence on a second analysis, because its positivity on two following samples can be indicative of cancer and thus needs to be carefully evaluated. Urinary tract cancers share a list of common risk factors, among which we find: - Smoking, which is the leading responsible for bladder and urinary cancer, including the kidney and of course other organs as well. - Male gender, - Age older than 35 years, - occupational or other exposure to chemicals or dyes (benzenes or aromatic amines), - Analgesic abuse, - History of gross hematuria, - History of urologic disorder or disease, - History of irritative voiding symptoms, - History of pelvic irradiation, - History of chronic urinary tract infection, - Exposure to known carcinogenic agents or chemotherapy such as alkylating agents, - History of chronic indwelling foreign body [from the slides, not mentioned] In the course of the patient visit it’s therefore important to not only consider the results of urinalysis, but also to collect a complete and proper patient’s history. On the slides he left a flowchart “for our curiosity” regarding the study of the symptoms and the search of a diagnosis. Gross hematuria The situation here likely becomes more complex, as the amount of blood is significantly more. As the picture shows there are different degrees of gross hematuria: in this case the first sample presents light hematuria, while the second it’s much more relevant, likely from an arterial bleeding. The third picture, presenting an almost brown discoloration of the sample, is usually associated to the presence of clots, for example in the bladder. It’s sometimes defined as “Coca Cola urine”. French urologists use a scale to classify hematuria based on the colors of different wines There are some situations in which an accurate and detailed data collection from the patient is extremely important to identify the cause and thus the diagnosis of the bleeding. This distinction can be easily made thanks to the “Three glasses test”: - Sometimes the hematuria is not complete, with the bleeding only occurring in the first part of the micturition and pseudo-normal urine towards the end. In this case the problem is most likely problem regarding the urethra, which gets flushed by the first stream of urine - Another situation is the one in which the entire micturition presents a red discoloration - The third and most strange possibility is the one in which only the last drops of urine are colored by blood. This is due to a particular situation in which the bleeding occurs due to a contraction of the detrusor muscle, and it’s typical of the presence of a neoplasm of the bladder wall, thus resulting the most worrisome case out of the three. In concomitance with hematuria, it is also important to analyze and ask the patient if there are other associated symptoms. For example, if the bleeding is associated to Lower Urinary Tract Symptoms [explained in the previous lecture, will be referred as LUTS from now on], especially with the irritative ones, this becomes the typical presentation of an infection: there is a bleeding resulting from the inflammation, while the presence of pathogens irritates the bladder’s mucosa, resulting in a hemorrhagic cystitis. Causes of hematuria - Prerenal: the cause can be an overdose of anticoagulants (especially occurring in the elderlies due to improper intake). [also hypertension and sickle cell anemia, from the slides] - Renal: the source of the problem might not only be nephrological, such as glomerulonephritis, but also the presence of a cancer or stones in the upper urinary tract, and vigorous exercise.  - Postrenal: the most likely cause is bladder cancer, although also bladder stones, prostate cancer and a traumatic catheter insertion might be responsible. In this group it is relevant to not forget the ureters, that are quite fragile structures. It is once again of crucial importance to have a proper history taking, that in this case also helps to distinguish between a nephrological and urological disease. [for example, if the patient has a history of glomerulonephritis, I will be brought to think that the bleeding is related to that and so the matter is nephrological] There are some cases in which the sequence and timing of symptoms appearance becomes highly relevant for the final diagnosis. Let’s take gross hematuria and flank pain as an example: - These symptoms may be the result of a large stone at the level of the ureter. The stone is first revealed by a great deal of pain in the flank, then, descending from the kidneys all the way down, it scratches the wall of the ureters, causing bleeding. - On the contrary, if a patient complains of continuous hematuria for three days and then a renal colic onsets, the cause of the situation might be a neoplasm at the level of the ureter: the mass is first causing bleeding, and then as the blood clots in the ureters it obstructs the channel, evocating the colic in the kidney. Nutcracker syndrome In this case the bleeding during micturition is caused by an rare anatomical abnormality: normally the renal vein passes normally between the superior mesenteric artery and the abdominal aorta, however in this alteration the artery partially occludes the renal vein by squeezing it. The result is an increase of the venous pressure into the kidney, (which can cause hematuria by chatgpt) Of course this technique is only diagnosed through imaging such as AngioCT. “Summary scheme of the things you need to know about hematuria” Keep in mind that, more often than not, hematuria is a sign of neoplasm in the system, therefore it always needs to be paid careful attention. URINARY INCONTINENCE It’s defined as the involuntary loss of urine. One of the causes of the condition is the so-called stress incontinence, in which the passage of urine is caused by an increase of the intra-abdominal pressure when laughing, coughing or doing strong physical exercise. Stress incontinence is also encountered in women after birthgiving, because the delivery might determine strong injuries and stretches to the pelvic floor muscles and the supporting structures of the bladder and the uterus, especially in case of macrosomia of the child. Another type of situation is more associated to infection, especially in concomitance with irritative LUTS. In this case the patient experiences urge incontinence, feeling the urgency of passing urine; the causes include cancer, which continuously irritates and thus stimulates the bladder wall, and bladder stones for the same reason. Other causes included idiopathic cases and neurogenic bladder (due to the neurological alteration resulting from a trauma or cerebral ischemic events.). The third kind of incontinence is defined as overflow, that is typical of males with an enlarged prostate. In this case there is a progressive increase of the urine volume inside the bladder, deriving from the inability of emptying it completely. The result is an overstretching of the wall’s fibers, with the bladder that can reach a volume of 5, 10 up to 15L, and a possible continuous dripping of urine from the sphincter due to the increased pressure. Also in this case the patient’s history comes in hand: if a patient underwent prostatectomy due to cancer, he might be complaining of stress incontinence due to an alteration of the physiological mechanism for continence. As we’ll see later, nowadays there are robotic techniques that allow to remove the prostate with a very low risk of post-operative incontinence. Neuropathic bladder is instead a very complex situation because it may be due to the neurological alteration resulting from a trauma or cerebral ischemic events. Overactive bladder [definition from slides: presence of urinary urgency, with or without incontinence, usually accompanied by increased frequency and nocturia. Etiology: genitourinary syndrome, obesity] This condition causes a great deal of discomfort in the patient, as they always need to figure out where the nearest restroom is in public, causing a negative social impact. Also, some factors like cold might increase the occurrence of the episodes. This situation might actually be more dramatic than stress incontinence, as in such case the patient knows which are the “events” that might lead to involuntary loss and avoid it. The slides also described Enuresis, which is incontinence during sleep, but he did not mention it. PAIN The first example of pain in urology must be colic pain, in which the location can really help pinpoint the cause. For example, if the patient presents pain in the flank, a likely diagnosis would be a stone in the calices of the pelvis, and thus a renal pain, while if the pain extends anteriorly to the inguinal zone chances are that the stone is passing through the ureters, causing ureteric pain. Colic pain can be elicited by manual palpation of the flank, or by using the Giordano maneuver and simply hitting the costovertebral angle with the hand. The great amount of pain derives from the distension of the upper urinary tract following the obstruction. Ureteric pain sometimes displays a less usual manifestation, that occurs when a stone presents in the last portion of the ureter: here it is able to stimulate the sensitive fibers of the bladder and mimic the symptoms of a cystitis, including LUTS and urgency. A different kind of pain results from a stone obstructing the neck of the bladder: this is vesical pain, that affects the suprapubic region and is accompanied by acute urinary retention. In order to elicit vesical pain, similar maneuvers are utilized between males and females. In women a double-hand manipulation is performed, in order to compress the bladder between the fingers inside the vagina and the hand in the suprapubic region, while in males a digital rectal examination is performed while compressing the same area. A similar evaluation is needed in males in case of prostatic pain, caused for example by an acute infection. Scrotal pain Another possible site of pain is the scrotum: the structure of the testicles is rather complex, as they descend in a channel from the abdomen into the scrotum and carry a layer of muscles, which forms the cremasteric muscle, and of peritoneum, that forms the tunica albuginea. Scrotal pain is therefore an indicator of different possible diseases: a common cause of sudden and severe pain is a testicular torsion, in which the rotation of the testicle determines a twisting of the artery and a temporary ischemia of the organ. This situation usually comes with associated symptoms that are abdominal pain and possible vomiting; also, the event might be hinted by finding a testicle in a higher position or a different angle with respect to the other, as a result of the twisting. This is a urological emergency, because the physician needs to manually or surgically derotate the testicle in order to restore a normal perfusion; this needs to occur within the first 10-12h so that necrosis can be avoided, case in which the removal becomes necessary. Specific awareness programs in schools are being done by the wonderful Urology department in order to avoid spontaneous torsions in youngsters. There are some specific exams that are put in place in order to diagnose the condition. Urinalysis is useful as it demonstrates the absence of leukocyturia; in fact, the scrotal pain comes in differential diagnosis with an acute infection, called orchiepididymitis, in which the WBC count would be very high. There are however more specific tests, especially imaging: the best tool is an echo Doppler, that enables to demonstrate the absence of blood flow at the level of the testicular parenchyma. The image on the left presents sustained blood flow, like in the case of an infection, while on the right the absence of flow suggests ongoing ischemic damage from the torsion. A quite less common situation with a similar presentation is constituted by the torsion of the Hydatid of Morgagni, which is essentially the appendix of the testis. This is a benign situation with a presentation mimicking a testicular torsion, while at surgical exploration it is demonstrated that only this tiny portion is twisted. SEXUAL DYSFUNCTION A very common condition in this field is erectile dysfunction, which is experienced by more than 50% of men over 40yo. The causes include vasculogenic and neurogenic matters, although the most common reason is represented by psychological discomfort in the life. What is done in this situation is try to identify the real cause of the condition and then design the proper therapeutic approach. Treatment for erectile dysfunction is not limited to drugs like Viagra or Alprostadil, but also tools like Vacuum devices or some specific prostheses that can be inserted in the penis to mimic the erection. Other sexual dysfunction symptoms include the loss of libido, that may be due to hormonal alteration: in particular, of estrogen in females and androgens in males. Premature ejaculation is also a very frequent symptoms in males, and occurs when the ejaculation happens in less than one minute [(if lifelong) or 3 minutes (if acquired) and must be associated with inability to delay ejaculation and with negative personal consequence]. The condition affects about 1/3 of males, with significant secondary effects on the patient’s sexual life. The most common factor is again a psychological disorder or an emotional situation, although also a prostatic infection might cause it. Failure to ejaculate (dry ejaculation, anejaculation) it can be due to some drugs, but it’ll be better addressed later on. Hematospermia indicates the presence of blood in the ejaculate and it’s generally a symptom of an inflammation, not only at the level of the testes but also in the prostate and the seminal vesicles. Another cause is anticoagulant overuse, just like prerenal hematuria. What must be done, anyway, is utilize imaging and lab testing in order to exclude the association of the bleeding to cancer. —-- Anorgasmia is the absence of orgasm that can be due to psychogenic causes, but also due to the use of strong medications [used to treat psychiatric ailments]. Urethral discharge it’s classically caused by an infection, like a urethritis, and is a common symptom of STDs. [Patients should be screened for high-risk sexual behavior. Bloody discharge may be concerning for urethral carcinoma] Induratio penis plastica is the condition in which there is an excessive curvature of the penis, that sometimes prevents the normal intercourse as it can reach above 90° of curvature. It can be due to trauma or metabolic situations. These patients are treated by reassessing the geometry of the organ, creating artificial curves to reduce the excessive inclination. Notice also the esthetic value of the urology department, with the aim of providing sexual comfort to the urologic patients. Digression about urology is not popular in Italy because we are bigots and this also impacts the awareness about sexual matters and cancer prevention. Lezione 4 BENIGN PROSTATIC HYPERPLASIA (BPH) Prostate The prostate is an exocrine gland situated inferior to the bladder and anterior to the rectum. It typically weighs approximately 20 grams and tends to increase in size with advancing age, potentially leading to clinical complications. The urethra traverses the central zone of the prostate, which is also penetrated by the ejaculatory ducts originating from the seminal vesicles. These ducts terminate at the prostatic urethra, which terminate into the external urethral sphincter. Recognizing these anatomical landmarks is crucial for surgical interventions, as damage to the sphincter can result in urinary incontinence. The prostate receives its blood supply from branches of the internal iliac artery, specifically the inferior vesical artery. Venous drainage is facilitated by the periprostatic venous plexus, also known as the Santorini plexus, which is connected to the dorsal vein of the penis. Such vessels must be carefully managed during surgery to prevent significant hemorrhage. Anatomically, the prostate is divided into five lobes: the anterior lobe, posterior lobe, median lobe (often associated with benign prostatic hyperplasia and enlargement with age), right lateral lobe, and left lateral lobe, which is continuous with the anterior lobe. This anatomical structure serves as a landmark during surgical procedures, as its proximity to the rectum poses a risk of rectal injury during prostatectomy. The urethra within the prostate is not linear but follows a curved path, which is crucial to consider in the context of urinary incontinence. The anterior aspect of the prostate is anchored to the pubic symphysis, while the bladder is secured to the anterior abdominal wall. This curvature facilitates the closure of the urethra during increases in intra-abdominal pressure, aided by the support of the pubic bone. Consequently, during prostatectomy, it is essential to reconstruct this anatomical configuration to prevent postoperative incontinence by ensuring the functional integrity of the urethral sphincter mechanism. Histology The prostate is composed of epithelial glands embedded within a stroma of fibromuscular and connective tissue, which includes collagen fibers and smooth muscle (SM) fibers. The presence of smooth muscle fibers is particularly significant when considering the pharmacological effects of certain medications, as these fibers play a crucial role in the contractile function of the prostate. Embryology The development of the prostate is a complex process that originates from the Müllerian tubercle. The prostate arises from the urethral epithelium, which is associated with the mesonephric (Wolffian) duct. This developmental relationship establishes a significant anatomical and functional correlation between the prostate and the upper urinary tract components. This connection underscores the potential for infections, as bacteria can migrate from the rectum to the urinary tract. Additionally, due to anatomical differences, females are at a higher risk of urinary tract infections (UTIs) compared to males. Endocrinology The prostate gland is under endocrine control, primarily regulated by testosterone. In male dogs, as in humans, the prostate enlarges with age due to the hormonal influence of testosterone. This growth is not observed in castrated dogs, which remain smaller overall. Testosterone plays a crucial role in the development of secondary accessory organs and sexual behavior. It can also increase mortality and the risk of certain diseases due to its involvement in maintaining the immune system. Testosterone has been linked to addictive behaviors, as its influence on the brain’s reward system can lead to dependency on substances or activities that increase its levels. Behaviorally, testosterone is associated with increased aggressiveness. It is important to note that males also produce estrogens, which are balanced with androgens. Testosterone supports growth and development, while estrogens contribute to the fibro-stromal tissue component. Testosterone itself is not active but requires metabolic conversion by the enzyme 5-alpha-reductase to become dihydrotestosterone (DHT), its active form. Certain drugs can modulate the activity of this enzyme, thereby regulating the levels of active testosterone. This modulation can have a progressive castration effect on the prostate. Benign Prostatic Hyperplasia (BPH) An enlargement of the prostate gland can lead to Benign Prostatic Obstruction (BPO), mechanically obstructing the urethra and causing urinary retention. Obstruction can also occur in benign conditions, such as Benign Prostatic Enlargement (BPE) where the bladder neck closes despite a normal-sized prostate. Patients may present with similar lower urinary tract symptoms (LUTS), such as frequency, urgency, nocturia, and weak stream. Neurological causes can also produce similar symptoms. It is important to note that prostate enlargement can result in a wide range of symptoms, from severe to none. Typically, prostate enlargement progresses slowly over decades. During this time, the bladder compensates by increasing its muscular activity to maintain urine flow. Eventually, the bladder’s compensatory mechanisms fail, leading to a reduced urine stream and ultimately, urinary retention. The hyperplastic process and gland hypertrophy begin in adolescence and are influenced by sex hormones. LUTS usually manifest much later, often 15-20 years after the onset of gland hyperplasia. Thus, young patients with significant gland hyperplasia may not exhibit symptoms immediately. Prostate growth often follows a nodular pattern, with progressive stretching of the peripheral zone, creating a pseudo capsule around the gland. Enlargement typically originates from the transition zone near the bladder neck, causing a mechanical obstruction. There is also a dynamic component to the obstruction due to the high density of smooth muscle fibers in the prostate, which contains alpha-adrenergic receptors. These receptors regulate the tone of the urethra, causing it to constrict under stress or strong stimulation. Under stress, increased sympathetic activity can exacerbate urethral closure, leading to acute urinary retention. Long-term obstruction affects bladder muscle contraction, leading to muscle hypertrophy and thickening of the bladder wall, which can increase from the usual 0.5 cm to 2-4 cm. Additionally, bladder capacity may be reduced. Chronic obstruction can cause the formation of diverticula, which are herniations of the bladder mucosa due to high intravesical pressure. Other effects include progressive bladder dilation, upper urinary tract dilation such as J-hooking of the ureters, hydronephrosis, and ultimately renal function impairment. Residual effects can include the formation of bladder stones, which can be large and manifest with LUTS, hematuria, and urine retention. Additionally, there is an increased risk of urinary tract infections (UTIs) and sepsis. Medical History A comprehensive medical history, conducted following established guidelines, is essential for these patients. Utilizing standardized questionnaires, such as the “EUA Guidelines of Non-Neurogenic Male Lower Urinary Tract Symptoms (LUTS), including Benign Prostatic Obstruction (BPO)”, can objectively identify symptoms. These assessments should include detailed inquiries about the duration, frequency, and onset of micturition, among other factors, to obtain a complete clinical picture. Physical Examination Referring to the digital rectal examination (DRE) of the rectum, a thorough visual inspection and palpation of the abdomen is performed initially to evaluate for signs of bladder distension, indicative of chronic urinary retention. The examination is conducted using the index finger, as it is the most sensitive. During the DRE, the size, consistency, and symmetry of the prostate are assessed, along with the temperature to identify potential infections such as prostatitis. Additionally, the presence of neoplasms or other abnormalities is evaluated. Other Diagnosis Methods Urinalysis: Demonstrates secondary effects of UTIs, like obstruction. Renal Function Measurement: In case of large dilation of the upper UT, there might be a progressive impairment in renal function, secondary to chronic retention of the urine. Prostatic Specific Antigen (PSA): A prostate cancer marker. Uroflowmetry: a simple device that describes the quantity of urine passed in a certain period. The information is collected to form a graph, where the flow usually peaks at the beginning of the micturition  (Qmax). In pathological situations, the graph changes and there is a decrease in the Qmax and prolonged urination, which happens in BPH. Ultrasonography: easily performed in the clinic, and cheap to use, that allows one to get an anatomical picture of the situation. In this case, we can notice a larger median lobe. In this enlargement example, the impact and risk of obstruction are very high. It could also be used to assess the upper urinary tract, for example, to look at a dilation. CT Scan: also used to better assess dilation, and fluid detection, like in the case of urosepsis, that could be lethal if not detected and treated. Differential Diagnosis 1. Urethral Stricture Definition ○ A narrowing of the urethra due to scarring, results in a loss of urethral elasticity. Cause ○ Trauma from accidents, radiation therapy, or a complex sexually transmitted infection (STI) leads to scar formation. Symptoms ○ Elongated micturition (prolonged time to urinate). ○ Seen in uroflowmetry as a lack of a peak, showing a plateau on the graph. Treatment ○ Endoscopic surgical intervention to open the urethra. ○ High risk of recurrence. ○ In case of recurrence, a substitution of the stenotic part of the urethra with a portion of buccal mucosa may be performed due to its high vascularization, which promotes quick revascularization of the urethra. 2. Marion’s Disease Definition ○ Congenital disease is the first identified condition affecting the bladder neck, leading to urinary obstruction. Cause ○ Contraction of the bladder neck, resulting in difficulties with micturition. Symptoms ○ Similar to prostate enlargement, particularly obstruction to urine flow. Treatment ○ An electric incision at the bladder neck to create an opening at the urethra and restore normal urine flow. ○ Risk of retrograde ejaculation, where ejaculatory fluid flows back into the bladder instead of the urethra, which can affect fertility. 3. Bladder Neck Contracture Definition ○ A rare condition where scar tissue forms at the bladder neck, narrowing the passage and obstructing urine flow, typically after prostate surgery or treatment. Cause ○ Formation of scar tissue following prostate surgery or radiation therapy. Symptoms ○ Weak or interrupted urine stream. ○ Frequent urination. ○ Straining to urinate. ○ Incomplete bladder emptying.  ○ Urinary retention. ○ Pain or discomfort. ○ Potential for urinary tract infections due to incomplete bladder emptying Treatment ○ Use of catheters or dilators to widen the urethra. ○ Surgical removal of scar tissue to restore normal urinary function. Prognosis Key predictors of the clinical progression of benign prostatic obstruction include: Elevated PSA levels: While PSA is not a disease-specific marker, it is indicative of prostatic tissue. Larger prostates produce higher PSA levels. Increased prostate volume. Higher baseline post-void residual (PVR). (the amount of urine retained in the bladder after micturition) Elevated markers indicate a poorer prognosis and an increased likelihood of requiring medical intervention. Male lower urinary tract symptoms (LUTS) can result from various etiologies, necessitating a thorough collection of patient information to accurately identify the underlying cause. The overall complexity of the patient’s condition must also be considered. This flowchart aims to outline the steps for managing male LUTS. It is essential to consider patient-specific scenarios, such as a patient experiencing nocturia who is unable to return to sleep, significantly impacting their quality of life. Treatment Therapy in the Past Historically, many surgical interventions were performed to address prostate-related issues, with some of the earliest procedures focused on removing bladder stones. Evidence suggests that patients were placed in the lithotomy position (derived from the Greek "lithos," meaning stone), and surgeons made incisions in the peritoneum to access and remove the stones and use vegetables or bamboo as catheters. One remarkable case is that of Jan de Doot, who famously performed bladder stone surgery on himself with a kitchen knife and survived. Therapy As a first-line treatment, behavioral and dietary modifications are recommended. For instance, patients experiencing nocturia are advised to reduce fluid intake in the evening to limit nocturnal urine production. Additionally, distraction techniques can be employed to alleviate irritative symptoms. Medical guidelines emphasize the importance of these conservative approaches before progressing to pharmacological interventions. These behavioral modifications are often combined with medical therapies, such as the administration of pharmacological agents or placebo treatments, and, if necessary, surgical interventions. The second line of treatment typically includes: 1. Phytotherapy Definition ○ Treatment using plant extract-based drugs, such as Prostamol, aimed at reducing symptoms like nocturia (frequent nighttime urination). Target ○ Reduces prostate inflammation, though the specific mechanism isn't fully detailed. Effects ○ May help alleviate mild symptoms of prostate inflammation, particularly nocturia. However, its effectiveness is often questioned. Side Effects ○ No specific side effects are mentioned, though skepticism about its limited effectiveness exists. 2. Alpha-Blockers Definition ○ Medications that relieve obstruction by relaxing muscle fibers in the bladder neck and prostate. Target ○ Muscles under adrenergic control, particularly at the bladder neck, and prostate, to improve urine flow and prevent acute urinary retention. Effects ○ Improves the urine stream by relaxing fibers, alleviates symptoms of obstruction, and prevents acute urinary retention. Side Effects ○ Increased risk of vascular-related events due to systemic vasodilation (affects more than just prostate receptors). ○ Hypotension (low blood pressure), postural hypotension (dizziness upon standing), tachycardia (rapid heart rate). ○ Retrograde ejaculation (bladder neck remains open, causing ejaculation to flow into the bladder), is more common in younger patients and reversible after discontinuing the treatment. 3. 5-Alpha-Reductase Inhibitors Definition ○ Medications that reduce prostate size by inhibiting the enzyme responsible for converting testosterone into dihydrotestosterone, the active form of testosterone. Target  ○ The enzyme 5-alpha-reductase, which converts testosterone into dihydrotestosterone. Effects ○ Slows prostate growth, leading to a 20% reduction in prostate volume (progressive castration) and reducing symptoms over a long-term period (6 to 12 months). Side Effects ○ Sexual side effects include impotence, reduced libido, and decreased ejaculatory volume. Counseling is necessary before starting therapy. Surgical Therapy If lifestyle changes and medical therapies prove insufficient or inappropriate, surgical interventions may be required to address prostate-related obstructions. Several advanced techniques are available today: 1. Transurethral Resection of the Prostate (TURP): This is the oldest technique, where a resectoscope (an electric loop) is inserted through the external meatus to reach the prostate. It scrapes away the internal portion of the gland, enlarging the urethra and solving the obstruction. It's a quick procedure, but care must be taken to avoid cutting the external urethral sphincter, which could lead to incontinence. Rarely, complications like bladder explosion due to excessive gas can occur, requiring surgical repair. 2. Laser Resection | Enucleation or Vaporization: Like TURP, this technique uses a laser to remove the internal portion of the prostate. It allows precise control of bleeding and tissue removal. After the procedure, a device is used to aspirate the remaining material. The outcome is comparable to TURP, though the professor notes that high energy from the laser may cause irritative symptoms, which can be problematic. 3. UroLift: A minimally invasive option where small implants are used to lift and hold enlarged prostate tissue  away from the urethra, avoiding incisions or tissue removal. This procedure improves urine flow without the risk of retrograde ejaculation, making it a good option for younger patients. 4. AquaBeam | REZUM: REZUM uses water vapor therapy, where steam is injected into the prostate through a needle to shrink the gland. Over time, this leads to necrosis and an improved urine stream. It preserves normal ejaculation and is often recommended for patients seeking to avoid sexual side effects. However, there is a risk of tissue regrowth, potentially requiring further intervention later. 5. Simple Prostatectomy: For extremely large prostates (200-300g, contrary to physiological 20g), open surgery through the abdominal wall can be performed to remove the internal portion of the prostate. Though robotic and less invasive techniques have made this approach largely obsolete, it remains an option. For elderly or frail patients, placing a catheter may be a more practical solution, helping to maintain kidney function without the risks of surgery. (NoS: https://www.youtube.com/watch?v=K1yLUyfgjpI) Catheter | Suprapubic Tube The most straightforward and cost-effective intervention for patients presenting with symptoms such as urinary retention or severe lower urinary tract symptoms (LUTS) is catheterization. The procedure involves the insertion of a catheter into the bladder, followed by the inflation of a balloon to secure the catheter in place. This method provides an efficient and economical means of facilitating urinary drainage and preventing retention, particularly in elderly patients or those with comorbidities who are unsuitable candidates for surgical intervention.  Alternatively, catheterization can be performed via a suprapubic approach, wherein the catheter is inserted through the abdominal wall directly into the bladder. Although this method can sometimes be more uncomfortable for the patient compared to traditional transurethral catheterization, it remains a viable option. However, the use of catheterization as a long-term solution is generally limited to specific clinical scenarios. Lezione 5 Prostate Cancer Introduction about Prostate Cancer Before starting the lecture November is recognized internationally as Men's Health Month, with particular attention given to prostate cancer. The symbol for this campaign is specific to prostate cancer, as is the case for each type of cancer. When discussing prostate cancer, it is important to consider the gland's anatomical location and its relationship to surrounding organs, such as the rectum, blood vessels, and muscles. The management of prostate cancer is quite complex. However, understanding every detail is not required at this stage. What is essential is a clear grasp of the key messages, along with a few specific details. Prostate Cancer Epidemiology  fig1 Prostate cancer is the most common non-cutaneous cancer diagnosed in males, particularly in Western countries. A comparison between incidence and mortality rates (fig1) shows that the incidence of prostate cancer is far higher than its mortality rate. This discrepancy is due to several factors, including an understanding of the natural history of the disease and the treatment options available today. This diagram compares the impact of prostate cancer with other cancers. Around 300,000 men die from prostate cancer annually. Therefore, while it is not the deadliest form of cancer, it still presents a significant global health burden. fig2 When stratifying the incidence of prostate cancer geographically (fig2), certain regions, such as Asia, exhibit notably lower rates compared to others. This geographic variance raises questions about risk factors, particularly genetic predispositions. Other factors to consider include the quality of life, dietary habits, and environmental influences. Prostate cancer is highly heterogeneous, with an incidence ranging from 6.3 to more than 80 per 100,000 people. This wide range underscores the variability of the disease. Further analysis of incidence and mortality across different countries reveals a significant gap between the two rates. This difference is uncommon in oncology, where high incidence typically correlates with high mortality. It suggests that novel techniques and technologies may be playing a role in improving treatment outcomes for prostate cancer. There was a notable increase in prostate cancer incidence starting around 1990. This spike can be attributed to the discovery of prostate-specific antigen (PSA, covered in later part of lecture) in 1986. PSA is a biomarker for prostate neoplasms that allows for the early detection of cancer. The widespread use of PSA testing led to a temporary surge in diagnoses. However, after the initial spike, the incidence has not continued to rise significantly. The question arises as to why there was no sustained increase in diagnoses over subsequent years, which will be addressed in the next slides. Prostate Cancer in Italy fig3 In the specific context of Italy, the probability of surviving one year after a prostate cancer diagnosis is very high, at 97%. An interesting aspect of this is seen in the diagram (fig3), where it is shown that for a patient diagnosed with prostate cancer at the age of 58, considering a median life expectancy of 84 years, the cancer could reduce life expectancy by up to 7 years. On the other hand, for a patient diagnosed at 70 years old, the impact on life expectancy is negligible. This finding is quite significant when considering the different ages at diagnosis and the overall impact of prostate cancer on survival. It is also important to consider the treatment options for elderly patients. These factors must be kept in mind when discussing different types of therapy for prostate cancer. The Italian situation is notably heterogeneous, with life expectancy being significantly higher in the northern regions compared to the southern regions. This disparity is not due to ethnic differences but is likely related to access to adequate healthcare and disease management. Other risk factors for prostate cancer (Ethnicity, age, family history, genes, obesity)  fig4 fig5 Ethnic background also plays a role in prostate cancer incidence (fig4), with non-Hispanic black men showing the highest rates. Interestingly, when Asian descent migrate to Western countries (United States), and adopt western dietary habits, their risk of developing prostate cancer increases. This suggests that environmental factors, particularly diet, have a significant impact on cancer incidence, beyond genetic or ethnic predisposition. When evaluating the incidence rates across different age groups, there is a clear upward trend (fig5). Prostate cancer is primarily a disease of men aged 50 and older, with incidence peaking after age 70. The likelihood of developing prostate cancer in men is younger than 40 or 50 is extremely low = Approximately 1 in 10,000. Aged 40 to 60 = Approximately 1 in 100 Aged 60 to 80 = Approximately 1 in 8 This is a concerning statistic and highlights the importance of recognizing the social and medical impact of prostate cancer. fig6 For other risk factors for prostate cancer Age is the primary factor, with the disease predominantly affecting men in the later stages of life. Ethnicity is another significant factor, with African and black men generally having higher incidence rates. Family history also plays a crucial role, as prostate cancer tends to occur more frequently in families with a history of the disease.  Presence of specific genes, such as BRCA1 and BRCA2. These genes are well-known due to public figures like Angelina Jolie, who, upon discovering her BRCA positivity, opted for prophylactic surgery to lower her risk of breast cancer. Similarly, the presence of these genes increases the risk of developing prostate cancer. Obesity is another factor strongly linked to the rising incidence of prostate cancer. When evaluating the impact of obesity on various types of cancer, the geographic distribution of obesity shows a notable similarity to the map of prostate cancer incidence. This observation suggests a strong role of obesity in the development of prostate cancer. Specifically, excessive total fat intake, particularly from animal fats and red meat, is associated with a higher incidence of the disease. Conversely, certain dietary elements, such as lycopene, selenium, and fish, may have a protective effect by reducing the risk of prostate cancer. Histology of prostate cancer Regarding histology, 95% of prostate cancers are adenocarcinomas. This is significant because, despite the high incidence of prostate cancer, the histological uniformity allows for a consistent understanding of the disease’s natural progression. This uniformity is crucial, as it enables predictions about the evolution of the disease based on the stage at diagnosis. fig7 Most prostate cancers arise from the peripheral zone of the prostate (60~70% cases) (fig7), which has implications for surgical treatment. For example, in cases of benign prostatic hyperplasia (BPH), surgical removal of the inner portion of the prostate, such as through transurethral resection, does not reduce the risk of prostate cancer. This is because prostate cancer tends to develop in the peripheral zone, which is usually left untouched during such procedures. Prostate Cancer Classification fig8 The Gleason score (fig8) is a grading system used to assess the aggressiveness of prostate cancer. It is based on two components: the primary Gleason pattern, which reflects the most common cell differentiation pattern in the tumor, and the secondary Gleason pattern, representing the second most common pattern. The pathologist assigns grades to these patterns, and the combination of the two gives the Gleason score, which helps determine the tumor’s aggressiveness. More recently, the Gleason score has been replaced by the ISUP grading system, which categorizes prostate cancer into five distinct groups based on cellular differentiation. The level of differentiation is directly related to the cancer’s aggressiveness and prognosis. For example, patients in ISUP grade 1 generally have a very favorable prognosis, while those in ISUP grade 5 are at high risk of developing metastases or experiencing rapid local progression. Identifying the grade of the tumor during a biopsy, such as a preoperative biopsy, is critical for estimating prognosis and selecting the most appropriate treatment for the patient. Prostate Cancer Symptoms In terms of symptoms, many older men (aged 60 to 70 years) often experience urinary symptoms related to benign prostatic hyperplasia rather than prostate cancer itself. These symptoms are not typically a direct result of the malignancy. It is extremely rare for prostate cancer to present with symptoms due to the infiltration of the bladder wall or the ureter. In most cases, prostate cancer is completely asymptomatic. Occasionally, there may be a single episode of hematuria (blood in the urine) or bone pain, but these symptoms typically occur only in advanced cases when the cancer has spread to the bones. The majority of prostate cancer patients, however, are asymptomatic. Diagnosis of Prostate Cancer Diagnosing prostate cancer relies heavily on collecting comprehensive medical history, especially data regarding family history. It is well known that the BRCA1 and BRCA2 genes are associated with a higher incidence of prostate cancer in males and breast cancer in females. Recognizing a genetic predisposition to prostate cancer is crucial because it allows for earlier initiation of screening programs. In cases of early diagnosis, radical treatments can be offered, as heritable forms of prostate cancer are often more aggressive and require early intervention. After gathering the patient's medical history, the next step in the diagnostic process is a physical examination, specifically a digital rectal examination (DRE). This involves the use of a finger to palpate the prostate gland. Although some may perceive this technique as outdated, it remains highly effective in assessing not only the size of the prostate but also the presence of induration or nodularity, which may indicate malignancy. While a DRE can be uncomfortable for the patient, it is essential to inform the patient that it is a fundamental step in evaluating prostate health and is critical for initial cancer detection. Following or concurrent with the DRE, the prostate-specific antigen (PSA) test is often performed to evaluate the risk of prostate cancer. PSA and Prostate Cancer Diagnosis PSA is a protease produced exclusively by the prostate, but it is important to emphasize that PSA is prostate-specific, not prostate cancer-specific. There are many conditions that can cause elevated PSA levels, including urinary tract infections, prostatitis, and even activities like recent prostate stimulation or bicycling, which can elevate PSA. Certain medications can also influence PSA levels. The typical PSA threshold is set at 4 ng/mL, but this value may be adjusted based on the patient’s age. For instance, a PSA level of 3.5 ng/mL in a younger patient may be cause for concern, while a PSA level of 4.5 ng/mL in an older patient with an enlarged prostate may not be as alarming. Among 100 patients with elevated PSA levels, only about 3% of these patients will have a prostate cancer diagnosis. However, it is also important to note that approximately 2% of prostate cancer cases occur without an elevated PSA, underscoring the importance of considering multiple diagnostic tools beyond just PSA levels. PSA test upside and downsides are Upside o Helps early diagnosis of prostate cancer, allowing less side effects by less aggressive treatment (urinary incontinence or erectile dysfunction) Downside o PSA screening led to more diagnosis of prostate caner, but it did not necessarily led to higher survival from prostate cancer. o Patients were often over-treated, although their cancers were indolent or slow-growing. (According to their Gleason score or ISUP classification, these patients may have experienced a completely uneventful course of the disease had they not been treated.) Most of regions in Italy are not conducting massive PSA screening excepting the region of Lombardia. The European guidelines suggest that healthcare providers engage in informed discussions with patients about the option of PSA testing. These discussions should include both the potential benefits and risks. The guidelines recommend that the decision to undergo PSA screening should be made collaboratively between the healthcare provider and the patient, considering the patient’s preferences and values. There are certain strong indications for performing early PSA testing. These indications include, Men over 50 years old, or men over 45 years old with a family history of prostate cancer or a history of related cancers (Breast cancer, which can suggest the presence of BRCA1 or BRCA2 mutations) Ethnicity (African descent) High BMI, since obesity is a significant risk factor. In patients with a negative medical history, a normal digital rectal examination (DRE), and a PSA level of less than 2 ng/mL up to age 60, it is recommended to repeat the PSA test every 8 years, since the risk of developing prostate cancer under these conditions is very low. There is also the option of measuring both total PSA and the ratio of free to total PSA. Normally, PSA exists in two forms in the blood, and this ratio can be a helpful diagnostic tool. Cancer tends to bind PSA, so in cases of neoplasm, the percentage of free PSA (relative to total PSA) decreases. The threshold for this ratio is generally 16%. In the accompanying diagram, the area under the curve (AUC) from receiver operating characteristic (ROC) curves demonstrates that the free-to-total PSA ratio provides more significant information than the total PSA alone. For instance, in patients with abnormal PSA levels between 4 and 10 ng/mL, evaluating the ratio of free-to-total PSA can provide additional valuable information in determining whether cancer is present. A patient with a total PSA of 5 ng/mL but a free-to-total ratio greater than 20% or 30% has a lower risk of prostate cancer compared to a patient with the same total PSA but a ratio lower than 16%. This means that, in contrast to most markers, where higher values increase suspicion, with the free-to-total PSA ratio, a lower value increases the likelihood of cancer. This method helps reduce unnecessary further investigations. This synoptic scheme is useful for understanding that different PSA levels correlate with varying probabilities of prostate cancer. For example, a patient with a total PSA of 100 ng/mL has a significantly higher probability of cancer than a patient with a total PSA of 4.1 ng/mL. Additional tests for Prostate Cancer Ultrasonography is generally not useful for diagnosing prostate cancer because the ultrasonographic pattern of the cancer appears similar to that of the normal prostate gland. Therefore, specific nodules cannot be detected through ultrasonographic evaluation alone. fig9 The investigation with the highest sensitivity and specificity for prostate cancer is the multi-parametric magnetic resonance imaging (mpMRI) (fig9). It is MRI with multiple imaging parameters to assess the specific characteristics of prostate tissue. For example, a neoplastic area of the prostate may show an increased uptake of contrast, and this enhancement could indicate a more aggressive cancer. In addition, evaluating the water concentration in certain areas can help detect neoplastic lesions. Based on these findings, different zones of the prostate can be evaluated for cancer risk. Nuclear medicine doctors classify the risk levels using the PI-RADS (Prostate Imaging Reporting and Data System) scoring system, which has five levels of suspicion. PI-RADS 1 & 2 = Indicate zones that are likely normal and have no significant suspicion of an aggressive neoplasm PI-RADS 3 = Intermediate risk, where no definite lesion is observed, but some abnormalities suggest the potential for malignancy. PI-RADS 4 & 5 = Associated with a high or very high suspicion of cancer. After performing a multi-parametric MRI, a detailed map of the prostate gland can be generated, identifying specific areas of suspicion. Biopsies can then be taken from these targeted zones to improve diagnostic accuracy. A transrectal ultrasound (TRUS) guide is often used to collect biopsy samples, and it is also possible to fuse the MRI images with live ultrasonographic images for enhanced precision in targeting suspicious areas during the biopsy.  fig 10 Regarding biopsy techniques, two classical approaches are available Transrectal approach = Inserting a transrectal ultrasound probe to guide the biopsy needle through the rectal wall and into the prostate to collect samples. Transperineal approach = The same transrectal ultrasound probe can be used for guidance, but the biopsy needle is inserted through a small incision made under the testicles, at the level of the perineum. This approach avoids penetrating the rectal wall. The latest guidelines now recommend the transperineal approach over the transrectal approach due to its lower complication rates. (Reduces the risk of urinary infections due to contamination from the rectal wall) Lezione 6 PROSTATE CANCER PART 2 Diagnosis Continuation: Biopsy A biopsy, utilizing the tru-cut technique, involves the insertion of small needles to collect not only cells but also a tissue fragment. This procedure is essential for accurately assigning the Gleason grade, as the pathologist must evaluate not only individual cells but also the architectural patterns to better assess the neoplasm's aggressiveness. Side Effects: 1. Hematuria or light hematuria 2. Fever 3. Urinary retention 4. Edema Particularly when the prostate is enlarged, the stimulation and edema caused by the biopsy may lead to a further increase in prostate volume, potentially exacerbating lower urinary tract symptoms (LUTS) and, in some cases, resulting in urinary retention. It has been demonstrated that it is essential not only to collect samples from suspected areas identified by multi-parametric magnetic resonance imaging (MRI) but also to perform a standard biopsy to create a comprehensive and detailed map of the prostate. This approach allows for improved management of the neoplasm by identifying its precise distribution. Additionally, there are instances where normal samples may be obtained from the suspected areas indicated by MRI, while a neoplasm might be present in other regions of the prostate that exhibit a normal pattern on MRI evaluation. STAGING TNM Classification: The TNM classification describes both the local and distant status of a neoplasm: T represents the local extension of the neoplasm, N represent the involvement of the lymph nodes, M represents the presence or not of distant metastases. T1A and T1B: These subcategories belong to the incidental diagnosis of prostate cancer discovered during interventions for benign prostate enlargement. For instance, a transurethral resection of the prostate (TURP) may be performed on a patient with normal PSA levels who presents with lower urinary tract symptoms (LUTS) that cannot be managed with medication. During histopathological evaluation of the resected prostate tissue, the pathologist may identify the presence of cancer. The staging is then determined based on the percentage of cancer found in the resected tissue, with distinctions made for less than 5% (T1A) or more than 5% (T1B) involvement. This percentage significantly influences subsequent patient management and treatment decisions. T1C: The third subcategory of T1, known as T1C, refers to prostate cancer that is detected exclusively through biopsy. This occurs in cases where an elevated PSA level is observed, but both the digital rectal examination and imaging results are normal, leading to the decision to perform a biopsy, which subsequently confirms the presence of a neoplasm. In contrast, when the tumor is palpable during a digital rectal examination, either unilaterally or bilaterally, or when there is evidence of extension to surrounding organs, the classification and clinical scenario differ significantly. Various classifications exist to assess nodal involvement and the presence or absence of metastatic lesions. For this reason, accurate staging is essential. Techniques such as bone scans are traditionally used to identify widespread skeletal metastases. However, advancements now allow for more precise radiological evaluations. PET Scan A PET scan, for instance, is highly effective in detecting even small or very small lesions by identifying cellular hyperactivity in localized areas, including small bone segments or abdominal organs. This technique enhances the ability to stage cancer more accurately and detect metastases at an earlier stage. PET PSMA Specific markers, such as PSMA (Prostate-Specific Membrane Antigen), can be utilized in PET scans. PSMA is a receptor found on the surface of prostate cells, and its use in imaging is highly sensitive in detecting prostate cells not only within the prostate itself but also in surrounding or distant organs. This marker enhances the ability to identify the spread of prostate cancer with greater accuracy, providing critical information for the staging and management of the disease. PET MRI It has been demonstrated that an evaluation combining PET with MRI can significantly enhance the predictive accuracy for identifying distant metastases and lesions. This integrated approach improves the detection capabilities by leveraging the strengths of both imaging modalities, leading to a more precise assessment of cancer spread. (NoP: From the slides: PET/MRI seems to have applications in the following: 1- The diagnosis of primary tumor 2- Facilitating biopsy targeting 3- Predicting or monitoring tumor aggressiveness (especially during the active surveillance) 4- Early detection of recurrent PCa 5- Guiding targeted therapies ) Student Question: Is a PET scan routinely performed to look for metastasis in every patient diagnosed with prostate cancer, or only after screening? Answer: This is an excellent question. According to current guidelines, there is significant benefit in conducting this type of investigation after a prostate cancer diagnosis and before treatment. It helps in determining whether a patient is suitable for a specific local treatment or requires a different approach. However, challenges arise due to the high costs and limited availability of PET scan machines. For example, in the region surrounding Padua, there are only two centers (one in Castelfranco at the IOV and another near Verona) that offer this service. Therefore, PET scans are generally reserved for patients where the results would directly influence the management and treatment plan. Primary Prevention In terms of primary prevention of prostate cancer, lifestyle modifications play a crucial role. Key preventive measures include increasing physical activity and improving dietary quality. These adjustments can contribute to reducing the risk of developing prostate cancer by promoting overall health and mitigating factors that may influence cancer development. The emphasis on smoking is warranted, as it represents the most significant risk factor for bladder cancer, even more so than for lung cancer. Additionally, smoking can have detrimental effects on small blood vessels, leading to early erectile dysfunction in males due to vascular occlusion. For females, smoking also poses risks, particularly concerning the small vessels in the pelvic floor, potentially resulting in organ prolapse. Such consequences underscore the importance of avoiding tobacco use for overall health. Risk Stratification The treatment approach for a patient diagnosed with prostate cancer is dependent upon several factors, with the first being the patient's overall health status. It is essential to evaluate and quantify the patient's level of frailty. For instance, in the case of a 90-year-old patient with multiple comorbidities who is unable to walk, considering radical treatment for low-grade prostate cancer may not be advisable. Therefore, treatment decisions must be balanced against the patient's life expectancy. This highlights the importance of a thorough and accurate assessment of both the patient's general condition and the characteristics of the neoplasm. Such evaluations guide the selection of the most appropriate treatment strategy tailored to individual patient needs. This explains the categorization outlined in the EAU Guidelines, established by the European Association of Urology, which are followed in Italy. Patients can be classified into three broad categories based on risk: Low Risk: The first category consists of lower-risk patients, characterized by a very small neoplasm confined to the gland and a PSA level of less than 10ng/ml. In such cases, the risk of distant metastasis is exceedingly low, and the disease exhibits low aggressiveness. Intermediate risk High Risk: In contrast, the approach for high-risk patients, who may present with larger neoplasms, possible infiltration of surrounding organs, positive nodal involvement, or elevated PSA levels, is markedly different. High-risk patients may also be classified according to the ISUP grading system. This differentiation is crucial, as the velocity of tumor progression varies across these classifications, necessitating tailored treatment strategies based on individual risk profiles. These broad categories can be further subdivided, with the very low-grade, low-risk patient characterized by a slow tumor progression. The rate of progression can vary significantly among patients, making it essential to utilize classification systems such as the ISUP grading to assess aggressiveness accurately. Treatment It is crucial to evaluate and communicate the patient's actual situation to facilitate informed discussions regarding the selection of the most suitable management strategies. While treating the neoplasm is paramount in oncology, it is equally important to consider the potential impacts of treatment on urinary continence and sexual function. These factors significantly affect the patient's quality of life, presenting a genuine dilemma that must be addressed. Active Surveillance In cases of low-risk neoplasms, where the prognosis is favourable, active surveillance can be recommended as a viable option. This approach allows for close monitoring of the cancer without immediate intervention, thus minimizing treatment-related side effects while still ensuring the patient receives appropriate care. By balancing the necessity of oncological treatment with the preservation of quality of life, a tailored management plan can be established in collaboration with the patient. This strategy ensures that patients are protected from unnecessary harm while allowing for timely intervention should the cancer exhibit signs of progression. Watchful Waiting Another approach is known as watchful waiting, which involves conservative management for patients who are deemed unsuitable for active treatment. This strategy is often considered for individuals whose age or presence of other comorbidities indicates that the risk of mortality from prostate cancer is significantly lower than the risk of death from other health issues. For instance, in the case of an elderly patient, such as a 90-year-old, aggressive treatment may be deemed unnecessary due to the potential complications, such as anesthetic risks or the possibility of overtreatment. Watchful waiting allows for careful monitoring of the patient’s condition without subjecting them to the burdens of treatment that may not confer a meaningful benefit to their overall health or longevity. The guidelines suggest that active surveillance should be offered to patients with a life expectancy of more than 10 years who have a low-risk neoplasm. In contrast, watchful waiting is recommended for elderly patients whose overall health status may not warrant aggressive treatment. It's important to note that various countries may have differing protocols regarding these management strategies, reflecting variations in clinical practice and healthcare systems. PRIAS Protocol One widely utilized protocol is the PRIAS protocol, which outlines a structured approach for the first 5 to 7 years of active surveillance. This protocol includes specific planned visits that involve testing PSA levels and evaluating the need for repeat biopsies. For instance, a biopsy may be repeated after four years and again after seven years to monitor for any signs of upgrading or upstaging of the neoplasm. During these follow-up biopsies, it may be confirmed that the lesion remains small, with only a few positive biopsy samples indicative of low-grade disease. However, this monitoring process also allows for the identification of any increases in tumor size, an increase in the number of positive biopsy samples, or a change in the grading system, such as an increase from ISUP grade 1 to ISUP grade 2. Upon confirming any such progression, the patient can then be considered for treatment in a safe manner, minimizing the risk of cancer dissemination. This structured approach ensures timely intervention while maintaining a low risk of complications related to the disease's progression. This represents an international protocol, with various options available; however, all active surveillance protocols indicate that the risk of distant metastasis, which could significantly impact life expectancy, is effectively zero. This zero percent risk signifies that patients adhering strictly to active surveillance protocols, whether treated or untreated, do not experience a reduction in life expectancy and do not develop distant metastases. It is crucial to communicate to patients that active surveillance is a safe management approach. This information can help alleviate or mitigate anxiety related to their cancer diagnosis while allowing for the avoidance of unnecessary treatment. By emphasizing the effectiveness and safety of this protocol, patients can make informed decisions about their management options without undue concern about their prognosis. In Italy, a concerning trend has emerged where the majority of patients transitioning from active surveillance to therapeutic protocols for low-grade, low-risk neoplasms do so primarily due to anxiety about their cancer diagnosis, rather than evidence of actual disease progression or upstaging. This reflects a significant shortcoming in the healthcare system's ability to effectively communicate the nature and characteristics of active surveillance protocols to patients. Long-term follow-up data, spanning approximately ten years, indicate that only 50% of patients suitable for active surveillance underwent aggressive treatment. The remaining half successfully followed the surveillance protocols without any intervention or associated side effects. The final results of the PRIAS protocol for active surveillance demonstrate that, when evaluating prostate cancer-specific survival, there are no reported cases of metastatic disease or reductions in life expectancy among patients adhering to this protocol. In contrast, the approach of watchful waiting involves a different clinical scenario. In this group, patients may have more aggressive neoplasms; however, treatment is deferred because mortality risks are more closely associated with comorbidities rather than the prostate cance-r itself. Radical Prostatectomy The first procedure involves the removal of the prostate, known as a radical prostatectomy. Initially, this surgery was performed using an open approach, which presented certain challenges due to the complex vascularization of the prostate. This complexity increases the risk of significant bleeding during the operation, especially if a major artery or one of the large veins is severed. In some cases, this risk can be severe and difficult to manage intraoperatively, potentially leading to critical complications, including, in rare instances, the possibility of intraoperative patient death. Another problem related to the anatomy of the prostate is that the presence of the so-called erigentes nerves, that are related to the mechanism of erection. If the prostate is removed without careful consideration of the surrounding structures, it can result in complete erectile dysfunction. This risk is one of the key reasons why, in the past, alternative treatments were explored to avoid the physical removal of the prostate. The introduction of advanced technologies, particularly minimally invasive techniques like laparoscopy and robotic surgery, has significantly improved surgical outcomes. These innovations not only enhance the effectiveness of oncologic treatments but also help preserve important functions, such as erectile function and urinary continence. For example, figure A is the prostate and the seminal vesicles. In this case, two distinct features of the lateral margins can be observed. On one side, there is a significant amount of tissue surrounding the prostate, including nerves, while on the other side, there is no tissue on the prostate. This difference arises from an analysis/mapping based on MRI imaging and the distribution of positive biopsy samples. The presence of cancer in this lobe, extending close to the external pseudo-capsule, indicated a higher risk of extracapsular spread involving the neurovascular bundles, complex structures of nerves and vessels surrounding the prostate. As a result, the neurovascular bundles on that side were removed to mitigate the cancer risk, while the nerves and vessels were preserved on the other side to maintain the patient's functional outcomes. It is crucial to have a detailed and precise map of the gland to determine whether to preserve or remove surrounding structures, ensuring complete removal of the neoplasm. This approach is essential because the oncologic outcome remains the top priority. Over time, there has been a significant shift in radical prostatectomy techniques. The open retropubic approach has declined, while minimally invasive treatments (like laparoscopy and robotic surgery) have seen a considerable increase. Lymph Node Dissection Before discussing minimally invasive options, it's important to note that, in some cases, removing not only the prostate but also the surrounding lymph nodes and pelvic vessels is necessary, often through lymph node dissection. A pelvic lymph node dissection targeting specific areas can be crucial for removing affected nodes and ensuring accurate staging if neoplastic cells have migrated to the lymph nodes. However, removing the lymph nodes is not considered a therapeutic action, as it has minimal impact on the progression of the neoplasm. This is why lymph node removal is typically only performed in cases of confirmed significant positivity on a preoperative PET scan. Additionally, lymph node dissection carries a high risk of complications, such as the formation of a lymphocele or lymphorrhea, where excess lymph fluid cannot be reabsorbed by the surrounding tissues. This accumulation can lead to the formation of a large fluid mass, potentially compressing pelvic veins, which may result in deep vein thrombosis (DVT). In severe cases, this can lead to thromboembolism, which, though rare, can be life-threatening for the patient. The Pleat Technique At Padua, the concept was developed to create two openings in the peritoneum along the midline of the prostate, leaving two lateral "windows." This technique allows lymphatic fluid to drain from the pelvis into the abdomen, significantly reducing the occurrence of post-operative lymphoceles and related complications. It’s a simple maneuver, but highly effective in minimizing such risks. This approach highlights the need for continuous adaptation in surgical techniques to reduce potential post-operative issues. The impact of surgical prostate removal on life expectancy depends largely on the stage of the cancer. In cases of locally advanced neoplasms, the risk of recurrence or distant metastasis is significantly higher compared to cases involving low- or intermediate-risk tumors. Therefore, the final stage of the cancer plays a critical role in determining the long-term outcomes of the surgery. Radiotherapy Radiotherapy is one of the most effective treatments for prostate cancer due to the high radiosensitivity of prostate cells. It can be applied in two distinct ways: External Beam Radiotherapy Another therapeutic option is external beam radiotherapy, where the tumor is treated with external radiation. While effective for oncologic control, it can lead to significant side effects due to radiation exposure to surrounding structures like the bladder and rectum. To mitigate this, a pioneering technique was developed, placing a biodegradable balloon between the prostate and rectum. By inflating the balloon, the distance between these organs increases, significantly reducing rectal irradiation and lowering the risk of side effects such as proctitis, rectal fistulas, or other complications from radiotherapy.  Brachytherapy In another approach, small radioactive seeds are implanted directly into the prostate, providing localized treatment from within, as opposed to external radiation. This method helps minimize radiation exposure to surrounding organs, as the emission distance is limited. However, achieving full treatment requires the insertion of many seeds. One significant drawback is that the seeds can cause strong tissue adhesion and fibrosis making future surgical removal of the prostate nearly impossible, as the prostate can fuse with the rectum and bladder. Due to this complication, some, including the professor, prefer to avoid brachytherapy, as the seeds remain in place. Focal Therapy Another option is focal therapy which encompasses various techniques, including limited cryotherapy, high-intensity focused ultrasound (HIFU), interstitial laser therapy, and other methods. Focal therapy targets only a small lesion or area of the prostate based on findings from multiparametric magnetic resonance imaging. While this approach may help minimize side effects by avoiding treatment of the entire prostate, it has significant limitations. Techniques such as cryotherapy or laser therapy may not effectively eradicate all neoplastic cells, as prostate cancer often involves multiple lesions distributed throughout different areas of the prostate. Therefore, treating only a portion of the prostate may not adequately address the oncologic issues associated with this cancer. This diagram illustrates the characteristics and potential consequences of focal therapy, but it is not a favored approach. Hormonal Treatment Another potential treatment option is hormonal therapy, which works by reducing the activity of neoplastic cells through androgen deprivation. As testosterone has a direct effect on prostate cells, specific classes of drugs, such as LHRH agonists or antagonists, can be utilized to block the hormonal cascade from the hypothalamus to the pituitary gland, ultimately inhibiting testosterone production in the testes and adrenal glands. This technique is effective; the researcher who pioneered this approach was awarded the Nobel Prize for his contributions. Hormonal therapy is typically indicated in specific situations, particularly for treating metastatic disease when local treatments are insufficient. As a systemic treatment, it can also target metastatic lesions. In some cases, additional medications may be required to maintain castration levels, meaning testosterone levels should be kept below 50 nanograms per deciliter. It is often necessary to combine an anti-androgen with an LHRH agonist. When evaluating treatment options, it is important to consider various scenarios as seen in Figure B. For instance, there are four situations to take into account: 1. Low-Risk Neoplasm 2. Intermediate-Risk Neoplasm 3. High-Risk Neoplasm 4. Metastatic Disease In the case of patients with metastatic disease, particularly those over the age of 70, androgen deprivation therapy is often recommended. Conversely, for younger patients with very low-risk disease, surgical intervention may be a suitable option. Alternatively, active surveillance can be employed, allowing for effective monitoring and management of the neoplasm without significant side effects, which is particularly important for younger individuals. This diagram (Figure C) discusses the potential for medical treatment across various stages of neoplasm progression. Referring to the diagram illustrating PSA levels, the natural history of a neoplasm can be traced, beginning with a hormone-sensitive tumor that is asymptomatic. Typically, treatment is initiated when PSA levels exceed a certain threshold, allowing for early diagnosis of the neoplasm. In many cases, this early intervention leads to successful resolution of the condition. However, if a radical treatment is not performed, or if the neoplasm is managed solely with medical therapy, the neoplastic cells may progressively transform from hormone-sensitive to castration-resistant neoplasm. Despite administering an LHRH agonist or antagonist, cancer cells may develop resistance to these treatments within five to ten years, resulting in a rise in PSA levels, indicating tumor growth. At this stage, alternative medications can be employed to address castration-resistant non-metastatic neoplasms. However, if the disease progresses, distant metastasis may develop, accompanied by further increases in PSA levels. This progression can lead to a castration-resistant neoplasm with metastasis, where standard treatments may no longer be effective in fully controlling cancer cell growth. In such cases, specific chemotherapy agents can be utilized to achieve partial control over the neoplasm. As the PSA levels rise again, this indicates a continuous growth of the cancer cells. At this point, using specific medications known as Androgen Receptor Targeted Agents (ARTA) can be considered, which are effective for treating castration-resistant neoplasms. However, patients may begin to experience symptoms, possibly due to complications such as bone metastases. In such cases, it becomes necessary to address these metastases, often through targeted radiotherapy focused on the affected bone areas. Unfortunately, the neoplasm continues to progress, ultimately leading to the patient’s death. It is important to note that interventions can be implemented at various stages of this natural progression to alter the course of the disease. Clearly, the management strategies differ greatly depending on the findings, with implications for potential side effects, benefits, and the overall natural history of the neoplasm. Decisions should not rely solely on traditional standard tools; instead, utilizing advanced imaging techniques can help restage the patient and provide a clearer understanding of their situation. Today, numerous drugs and treatment protocols are being explored to identify effective therapies tailored to specific stages of neoplasm progression. Lezione 7 BLADDER CANCER The bladder is a large organ located in a complicated position due to the many surrounding organs in both males (figure “a”) and females (figure “b”), as seen in the accompanying illustrations. A cystectomy, that is, the surgical removal of the bladder, is a very delicate and complex surgery due to the danger of injuring the surrounding organs or the rectum. a. b. Epidemiology Bladder cancer is the 9th most common type of cancer in the world, and its incidence is in more industrialized countries (being more frequent in Belgium, Lebanon, Malta, Turkey, Denmark, Hungary, Spain, Norway, Germany, and Egypt). Men are 4x more likely to develop this form of cancer than women. Its epidemiology is similar to prostate cancer and other urological cancers. It’s important to notice a strong correlation between the environment and the risk of developing urological cancer. Bladder cancer has an overall 78% 5-year relative survival rate, being generally more aggressive than prostate or kidney cancer, with a high risk of recurrence. Risk Factors Among the risk factors, tobacco smoking, in many different forms as cancer, such as lung cancer, strikes as one of the highest contributors, accounting for approximately 50% of bladder cancer cases (65% in men and 30% in women). Occupational exposure, especially for male workers in the chemical, dye, rubber, petroleum, leather, and printing industries is also at increased risk of developing it. It has also been reported that artificial sweeteners (such as the ones used in Coca-Cola Zero and other “sugar-free” drinks) increase the risk of not only bladder cancer, but also pancreatic cancer, obesity, and other diseases. Other risk factors include patients who have received cyclophosphamide (Cytoxan) for managing various malignant diseases. Areas with a higher incidence of Schistosomiasis correlate to a higher incidence of squamous cell carcinoma of the urinary bladder. This is due to schistosomes causing chronic granulomatous cystitis leading to squamous hyperplasia of the epithelium. Symptoms The most important symptom, present in 90% of cases, is represented by hematuria, either gross or microhematuria. There’s an important problem related to disinformation, especially regarding awareness of such symptoms. 75% of adults do not always check their urine, 14.5% rarely check, and 7.5% never check. Since gross hematuria is an early symptom, not being aware of such symptoms contributes to a late diagnosis, and consequently worse prognosis. So, the European Association of Urology (EAU), promotes campaigns especially in schools to inform about the importance of noticing symptoms and about the possible risk factors. Other LUTS (Lower urinary tract symptoms) indicate vesical irritability such as frequency, urgency, and sometimes dysuria. Irritative symptoms are more common when the cancer is invading at the level of the muscles, that is, (not??) carcinoma in situ (CIS), therefore causing direct mechanical irritation of the nerves of the bladder wall. Hematuria is often excluded as an oncological symptom by patients and attributed to dietary reasons. In the case of cancer evolving into a large mass in the bladder, as shown in the CT scans, secondary symptoms may include enlargement of local lymph nodes, chronic enlargement of kidneys, and obstruction of the upper left urinary tract, resulting in fever and colic pain. Pathology 95% of bladder cancers are transitional cell carcinoma. Knowing the natural evolution of the disease allows choosing the best therapeutic strategy according to the stage. However, there are also some aberrant cases related to such neoplasm that are observed in biopsies, as seen in the table below. Diagnosis Every diagnosis starts with a detailed medical history, with special attention to hematuria (gross or micro), smoking habits, and the patient's occupation to evaluate possible risk factors. The presence of hematuria can be evaluated in the office with a simple reactive dipstick that detects blood in the urine. In a patient with a suspected large mass in the bladder, a digital rectal examination and palpation of the abdomen can be performed to identify a mass. Another possible diagnostic tool is urinary cytology. It allows to identification of cancer cells in the urine through a Pap test or the insertion of a catheter and washing the content of the bladder to promote epithelial exfoliation, the cells are then analyzed. However, it’s not an ideal test, since high sensitivity only occurs in G3 urothelial carcinoma, which is rare. The information it can give is: No adequate diagnosis possible (No Diagnosis) Negative for urothelial carcinoma (Negative) A