Nephrology & Urology - Urothelial Carcinoma PDF

Nephrology and Urology Paciotti - Urology - Lesson 14: Urothelial Carcinoma 07/11/2024 - Group #9 (Tommaso Caserta, Virginia Beghelli) Urothelial carcinoma is one of the most common urological malignancies. It can origi...

Nephrology and Urology Paciotti - Urology - Lesson 14: Urothelial Carcinoma 07/11/2024 - Group #9 (Tommaso Caserta, Virginia Beghelli) Urothelial carcinoma is one of the most common urological malignancies. It can originate from any district of the urinary tract, both upper (calyces and pelvis) and lower (ureters and bladder), but the bladder is the most common location. N.B. The Professor asked ten questions that were answered at various points in the lecture; these will be listed, together with the correct answers, at the end of the document. BLADDER CANCER (90-95%) Epidemiology Bladder cancer is the 7th most common cancer in the male population and 10th in the general population. It can also affect females, it has a higher mortality and lower incidence. Females tend to have a higher stage at diagnosis and a worse prognosis – this is probably due to the fact that the symptoms of bladder cancer are often mistaken for those of a urinary tract infection or cystitis, which are encountered frequently in women. Bladder cancer is common in Europe and the US, less common in east asia and africa (or less diagnosed). Mortality is relatively high overall. Risk factors - Tobacco smoke is the most important and established risk factor. - Family history seems to be less relevant, we haven’t yet discovered susceptibility genes for this tumor. - Occupational risk (aromatic amines, aromatic hydrocarbons, and other compounds encountered in factories) is the second most important risk factor. - Schistosomiasis (endemic in countries such as Egypt) - Environmental pollution - Previous medical interventions in the pelvis (secondary tumor due to radiation) also increase the chance of developing BC. Tobacco smoke is estimated to account for 50% of the tumors and current smokers have a 4 fold higher risk of developing BC compared to non-smokers. The first recommendation for patients while treating this tumor is to quit smoking: retrospective data indicate that the effect of environmental exposure to tobacco smoke is generally stronger in women and strongest in women who have never smoked. Tobacco smoke contains aromatic amines and other 1 substances known to cause BC, they are excreted through the urinary tract and could exert a carcinogenic effect in any of its parts. Occupational risk-related carcinogenic substances include mainly aromatic amines, which are estimated to account for 10% of all BC. The workers that are most at risk are those who handle dyes, paint, metals and petroleum products. This must be considered during diagnosis. Diet seems to have little impact on the development of BC. Products such as meat and supplementary vitamins have been found to be linked to BC by some studies, but this topic remains controversial. Histology The most common type of BC and upper urinary tract tumor is urothelial carcinoma aka transitional cell carcinoma (90% of cases). It can be pure or present in a number of histological variants. The cases that are not urothelial carcinoma that affect the urothelium are squamous cell carcinoma (presents with a meat-like appearance). Schistosomiasis is an important risk factor because squamous cell carcinoma is strongly linked to schistosomiasis infection. This kind of tumor is thus common in Egypt, where schistosomiasis is endemic. Tumors can also originate from cells that are not part of the urothelium, this is the case of the adenocarcinoma, small cell carcinoma, sarcomatoid carcinoma and other rare tumors. These account for about 1% of total cases. Diagnosis and Staging The most common symptom at presentation is haematuria, which may present alone (most commonly) or accompanied by lower urinary tract symptoms (especially irritative symptoms). This is relevant because LUTS are linked to a specific kind of tumor, the Carcinoma In Situ (CIS). Imaging is a bit controversial, in most cases we perform transabdominal US (first-line testing) because it’s cheap and non-invasive. US is not very accurate but it can detect renal and intraluminal bladder masses and hydronephrosis (a sign that can be secondary to occlusion in the ureters). Alternatively, we can skip US and go directly for CT urography. This technique requires a late-phase scan in order to allow contrast to be concentrated in urine and highlight lesions in the urinary tract. 2 The image below depicts what transabdominal US can show us when visualizing a bladder with a papillary lesion or similar intraluminal lesions. However, US cannot exclude the presence of upper tract tumors or rule out all potential causes of haematuria. In the CT urography image on the right, the bladder is filled with contrast, and we can see a suspicious lesion on the right lateral wall of the bladder. CT urography is the gold standard to diagnose muscle-invasive tumors of the bladder and to diagnose upper urinary tract carcinoma. Intravenous urography is an X-ray imaging technique that involves injection of contrast media in veins. It can be as accurate as CT urography according to some studies, but since the advent of CT urography it fell into disuse, and it has been largely substituted by transabdominal US as a first-line imaging technique to detect upper urinary tract obstruction (similar accuracy). However, it can still be an option in cases in which CT is unavailable. Also, CT gives us information about nodes and distant metastases, while IVU does not. MRI is widely used for the diagnosis of prostate and breast cancer (evaluation tools such as PIRADS are employed), and this technique can be useful for local (primary tumor) staging of bladder cancer, but its role in this context is still under evaluation. CIS cannot be diagnosed with MRI because it is a flat lesion. Urinary cytology is an additional modality that can be used for diagnosis. The pathologist examines voided urine or bladder-washing specimens, looking for cells or aggregates of cells with suspicious morphology. Cytology can be very accurate in the detection of high-grade tumors, but it is not as sensitive for low-grade tumors1. The sensitivity of urinary cytology 1 Sensitivity is the ratio between the number of detections and the number of patients tested that actually have the condition, so basically the probability of detecting a disease in a patient that has it. Specificity is the ratio between the number of true negative results and the total number of negatives, so it represents the capability of a technique of testing positive ONLY if the pathology is present. 3 is generally low because the samples analyzed might not contain cancer cells, even if a cancer is present. For this reason, the test is usually repeated multiple times (in Italy, thrice) on different samples. If the test results are positive, it is extremely likely that a tumor is present somewhere in the urinary tract. Whenever other conditions are affecting the urinary tract, specificity decreases because of possible findings relative to other diseases in the samples. [Urine molecular tests are currently under evaluation, but their use is limited to investigation and none of them has been accepted for diagnosis or follow-up in routine practice or clinical guidelines.] Cystoscopy is extremely important for the diagnosis of BC. The bladder is visualized with a camera that is inserted through the urethra. This technique allows easy detection of papillary tumors, while identification of flat lesions can be challenging. The procedure is often performed with a flexible instrument, which makes it suited to an outpatient setting (it can also be done with bigger and rigid instruments, but it is more painful for the patient and complex for the physician). Cystoscopy is often performed before the CT scan (the order is usually transabdominal US → Cystoscopy/cytology → CT), but in some cases CT may precede cystoscopy. To sum up, it is important to always take the patient's history (to account for realistic risk factors) and then utilize US, CT urography, cystoscopy and cytology (which may reveal evidence of flat lesions missed by cystoscopy) to diagnose bladder cancer. In order to improve detection of flat tumors (CIS) we can use enhanced methods of visualization such as Narrow-band imaging and Photodynamic diagnosis. These improve the accuracy of cystoscopy in detecting flat lesions, but specificity decreases because lesions that are hypervascularized but are not tumors (e.g. deriving from non-cancer-related inflammation or recent TURB) are marked as suspicious as well. The idea is to administer markers that bind to different targets and then use light at various frequencies to highlight the tumor. NBI darkens hypervascularized lesions and helps us in their detection. Therapeutic Approaches to Non-Muscle-Invasive Bladder Cancer (NMIBC) Transurethral resection of bladder tumors (TURBT) is the standard first approach to BC and is both a diagnostic and a therapeutic step: it is diagnostic because it is used to collect specimens for histological confirmation of the tumor, local staging (how deep the tumor goes into the bladder wall) and grading; it is therapeutic because a complete resection can improve prognosis. In TURBT, the cystoscopy is performed with rigid instruments and that’s why it is carried out in the operating room under anesthesia. A ‘resection loop’ is used to resect the lesion which is then analyzed by the pathologist. Both flat and papillary lesions can be removed. It is helpful in differentiating between Muscle-invasive bladder cancer (MIBC) from the non muscle-invasive type (NMIBC). 4 Staging is the degree of extension of the primary tumor. In this case it is important to distinguish MIBC from NMIBC. TIS is a synonym for CIS, this category constitutes a separate chapter so for convenience we can consider the possible stages to be Ta (non-invasive, limited to mucosa), T1 (invades submucosa) T2 (invades the detrusor muscle), T3 (reaches outside of the bladder either macroscopically or microscopically) and T4 (invades other organs or the pelvic wall). This is not the complete picture but it is sufficient to understand what we are talking about. Ta and T1 are called superficial tumors, while T2 or higher is a muscle-invasive tumor. Approximately 75% of bladder cancers classify as NMIBC, but 15-20% of these progress to become Muscle-invasive. Staging also includes categories that highlight the presence of distant metastases and lymph node involvement – MIBC gives rise to metastases more often than NMIBC. → T1 sub-staging depends on the extent of invasion into the lamina propria and has been demonstrated to be of prognostic value in retrospective cohort studies. T1 tumors progress quite frequently and require aggressive treatment. Additionally, there are two grading systems for bladder tumors that can be used concomitantly. One grading system goes from G1 to G3, the other distinguishes low (LG) and high grade (HG) tumors. G1 would be equivalent to low grade, while G2 and G3 are high grade tumors. CIS (TIS) is by definition limited to the mucosa and high grade, it has potential to progress and can be quite aggressive. It is often multifocal and it is difficult to resecate because it is a flat lesion. De novo CIS constitutes less than 3% of all urothelial neoplasms, it can be found alone or associated with papillary lesions, or as a recurrence after the removal of a papillary lesion. Second resection or re-TURBT is usually done within 2-6 weeks after the first resection if for any reason the first resection was not macroscopically complete. A second resection can also be performed to confirm the staging of the tumor and reduce the risk of under-staging (which may occur if the muscle is not sampled correctly or in the right place) or in the case in which the specimen does not contain any detrusor muscle (unless the tumor is Ta Low-grade or primary CIS). If the tumor is sufficiently small (less than 3 cm in diameter) we can perform an en-bloc resection (the tumor is removed as a whole starting from the root); this allows to reduce cell scattering and diffusion of the tumor, ameliorating prognosis. Some studies suggest that saline solution washing of the bladder in the 24 hours following the surgery improves the outcome of the procedure because it might wash out remaining cancer cells. Bladder cancer may potentially involve the entirety of the urothelium 5 of the urinary tract because cancer cells can spread easily through urine, however this is often not the case. After removal of the primary tumor, we stratify patients based on the risk of recurrence and progression. The main factors in predicting these are the age of the patient, the number of tumors, their size, prior recurrence rate, staging, presence of concurrent CIS and grade. The risk groups indicated by European guidelines are Low, Intermediate, High and Very High risk, and the disease management pathway changes according to the risk group. After TURBT, we should counsel the patient to cease smoking and determine the following therapeutic steps based on the risk group classification of the patient: - Low Risk Group - “patients with tumors presumed to be at low risk and in those with small papillary recurrences (presumably Ta LG/G1) detected more than one year after previous TURB” should receive one immediate single chemotherapy instillation within one day from surgery to reduce the probability of recurrence. In case of a small, recurrent low grade Ta tumor specifically, office fulguration and active surveillance might be considered. - Repeated instillations of chemotherapy (mitomycin, gemcitabine or pharmorubicin) can be offered to patients that belong to the Intermediate Risk Group. Alternatively, Bacillus Calmette-Guérin (BCG) treatment can be used to activate the patient’s immune system against the tumor. - The indication for the High Risk Group is BCG. Furthermore, immediate radical cystectomy may also be discussed with the patient if the tumor is high grade, even if not muscle-invasive. - For patients with Very High Risk tumors, immediate RC is recommended in addition to BCG. In this case, the likelihood of the tumor progressing is so high that radical cystectomy, albeit a significant procedure as for what concerns the patient’s quality of life, is fully justified. - CIS cannot be cured only by resection, we must also use BCG treatment. To sum up, the therapeutic pathway for NMIBC is TURBT (which also allows histological diagnosis), adjuvant intravesical instillations (one shot or repeated) and radical cystectomy. Fulguration and active surveillance are reserved for selected cases and are seldom employed. Therapeutic Approaches to Muscle-Invasive Bladder Cancer Muscle-invasive BC by definition reaches into the detrusor muscle of the bladder. This tumor requires staging of nodes and metastases, which is performed with contrast-enhanced CT (which is however unable to differentiate between stages Ta and T3a). Instead, MRI was reported to be more accurate in staging of the primary tumor. TURBT does not provide 6 information about the invasion of perivesical fat, so T3b staging can only be achieved using CT or MRI. There is currently no evidence supporting the use of PET scans in clinical practice. Micro-US can be used to visualize the tumor and the degree of invasion of the bladder wall (differentiate between MIBC and NMIBC), but in routine practice radical cystectomy requires histological confirmation. This technique is more easily performed in females because of the absence of the prostate gland. The gold standard for treating MIBC is radical cystectomy with extended bilateral pelvic lymph node dissection. Radical cystectomy also involves removal of the prostate or uterus and ovaries. If the patient is fit for cisplatin-based chemotherapy and if their tumor is T2-T4a, cN02 M0, we should offer neoadjuvant chemotherapy. Neoadjuvant chemotherapy (NAC) is the one that is performed before surgery, whereas adjuvant is administered after surgery.After cystectomy, in some cases, adjuvant chemotherapy could be appropriate. Even if the cancer is non muscle-invasive, if it is aggressive and very likely to progress a radical cystectomy should be offered. For MIBC, radical cystectomy is the standard procedure, but other bladder-sparing approaches can be discussed with selected patients. 2 The letter “c” before the N means that the staging is clinical, since no lymphadenectomy has yet been carried out. 7 For what concerns lymphadenectomy, obturator, external iliac, internal iliac and common iliac lymph nodes are generally removed, but different templates may be followed: After RC, we need to surgically divert the flow of urine. This can be achieved through procedures that render the patient incontinent (unilateral/bilateral ureterostomy, ileal conduit) or that preserve continence (ureterosigmoidostomy, heterotopic or orthotopic neobladder). INCONTINENT DIVERSIONS which is then connected to a stoma in the skin. - Patients that undergo CONTINENT DIVERSIONS ureterocutaneostomy/ureterostomy, which may be uni- or bilateral, (direct - Following radical cystectomy, an connection of ureters to a stoma in the orthotopic (Studer or Paduan) skin) need to always have a catheter neobladder can be shaped starting inserted in the stoma to avoid possible from a portion of the ileum, which is strictures. then positioned in the pelvis and - In an ileal conduit procedure, an anastomosed to the urethra. Ureters anastomosis is created between the are then connected to the bowel, ureters and the last part of the ileum, allowing flow of urine into the neobladder. Bladder-sparing treatment consists of a trimodal therapy (chemotherapy, maximal transurethral resection and radiotherapy) and can be used as a further alternative in selected patients. In metastatic bladder cancer, the surgery is generally performed for salvage or palliative reasons, but otherwise the treatment normally involves chemotherapy, immunotherapy and potentially new clinical trials. 8 UPPER URINARY TRACT TUMORS (5-10%) Epidemiology Tumors of the upper urinary tract include all tumors that develop in the ureters and in the pelvis and calyces of the kidneys (only in urothelium, not in the parenchyma). Bladder cancers constitute the vast majority of urothelial carcinomas (90-95%), whereas only 5-10% involve the upper urinary tract. Tumors of pelvis and calyces are twice as common as those of the ureters. In 17% of cases, concurrent bladder cancer is present, especially in the trigone. This is why upper urinary tract imaging is often performed in the follow-up of BC patients. The peak incidence is in the eighth decade of life, both for BC and UTUC. Some cases of UTUC are linked to hereditary nonpolyposis colorectal carcinoma (HNPCC), also known as Lynch syndrome. Risk factors Risk factors coincide with those of BC, tobacco and occupational exposure (aromatic amines) are the main ones. Patients presenting with haematuria should always be asked what their job is and if they are smokers. Tobacco smoking alone increases the relative risk of UTUC from 2.5 to 7. Histology More than 95% of Urinary tract cancers are derived from the urothelium, although sarcomas deriving from the ureter have also been described. Some studies suggest that the biology of UTUC is slightly different from that of BC, however most of the indications for treatment of UTUC derive from studies performed on BC, which is much more common. UTUCs can be non-invasive papillary tumors, flat lesions (CIS) or muscle-invasive carcinomas. UTUCs are more likely to present as invasive at the time of diagnosis compared to BC, this is due to the fact that the wall of the ureter is much thinner than that of the bladder and also because UTUCs tend to be even more aggressive than BC. 7% of patients have metastatic disease at presentation. Staging of UTUC is essentially the same as that of BC. Symptoms and diagnosis The diagnosis of UTUC can be incidental due to detection of hydronephrosis through imaging. The most common symptom is gross or microscopic haematuria (70-80%), flank pain occurs in 20-40% of cases and a lumbar mass is present in 10-20% (both secondary to hydronephrosis). Haematuria and positive cytology in a patient that presents the most important risk factors for urothelial carcinoma should prompt study of the upper urinary tract with CT urography, even if the US, cystoscopy and urinary cytology are negative. If suspicion is extremely high ureteroscopy can be performed instead. 9  We should keep in mind that the sensitivity of urinary cytology for detection of UTUC is lower compared to BC, but it is still quite high for high-grade tumors. The sensitivity of CT in detection of UTUC is less than 70%, while specificity is higher than 90%. Imaging can be extremely inaccurate for the clinical staging of this kind of tumor. MRI urography is an alternative for patients that are unfit for iodinated contrast media (e.g. high creatininemia, which is not uncommon in this setting). On the right is an extreme example of a tumor in the distal part of the ureter as seen in MRI, while the image on the left displays a lesion in the renal pelvis. Diagnosis of UTUC can be achieved through all the tools we have mentioned: CT urography, MRI, cystoscopy, urine cytology, as well as diagnostic ureteroscopy - the latter permits tissue sampling through a flexible ureteroscope, which also allows for biopsy and laser ablation of the lesion if it is small enough. Local staging of this kind of tumor is difficult because it is almost impossible to sample the muscle layer since it is so thin. This makes the process of risk stratification more challenging, as it is difficult to determine whether the tumor is muscle-invasive or not. In general, if the tumor is less than 2 cm in diameter, low-grade and no sign of invasiveness on imaging it is considered a low-risk tumor, otherwise it is classified as high-risk. Treatment For low-risk tumors, kidney-sparing approaches such as segmental ureterectomy and anastomosis might be considered, where you essentially only remove a piece of the ureter and then stitch the remaining segments back together. Alternatively, laser ablation of the tumor in the context of ureteroscopy may also be performed. In most cases, however, a radical nephroureterectomy is performed. This procedure involves removal of the entire kidney and ureter, including the part of the ureter that 10 enters the wall of the bladder. This is done to avoid recurrence in the wall of the bladder, which would be hard to treat because of the closure of the ureter that would follow the surgery. The indications for lymphadenectomy are less clear, but this procedure can improve the outcome for the patient. Depending on where the tumor is located, different lymph nodes are removed. Patients with low-risk tumors can be offered conservative treatment. If the patient has only one kidney it is imperative to perform a kidney-sparing surgery whenever possible, because otherwise the need for dialysis would worsen the quality of life so much that it would arguably render the procedure inappropriate, making palliative care a better option. As explained, conservative management options include ureteroscopy with laser ablation, segmental resection and adjuvant topic agents (intravesical chemotherapy). Systemic therapy can be helpful in improving the prognosis in aggressive and poor-outcome tumors. CLINICAL CASE Question 1 Haematuria can be caused by: - Bladder cancer - Kidney cancer - Kidney stones - Cystitis - All the answers are correct Question 2 What is the most important risk factor for Bladder cancer? - Dietary habits - Occupational exposure to aromatic amines - tobacco smoking - family history - schistosomiasis Question 3 What first line diagnostic test would you use in the case of Mr. R. ? - Cystoscopy - Transabdominal US - Transrectal US - Abdominal MRI - Urinary cytology Question 4 What is the gold standard for the diagnosis of Bladder cancer? - CT urography - Transabdominal US - Cystoscopy - Abdominal MRI - Transrectal US 11 Question 5 Which diagnostic test is indicated in addition to cystoscopy to detect high-grade tumor? - Urine culture - Transrectal US - Urinary molecular marker tests - Urine analysis - Urine cytology Regarding the clinical case: Question 6 What is the following step? - immediate BCG instillation 12  - Transurethral resection - Follow-up at 3 months with urinary cytology - radical cystectomy - office-based fulguration Question 7 What next? - Second TURBT (re-TURBT) - induction course with intravesical BCG - radical cystectomy - induction course with mitomycin - induction course with gemcitabine Question 8 Which therapy would you suggest to Mr. R. ? - BCG induction course (6 weekly instillations) - radical cystectomy - intravesical chemotherapy - systemic chemotherapy - neoadjuvant chemotherapy (if possible) + radical cystectomy Question 9 Which of these syndromes is associated with hereditary UTUC? - Li Fraumeni syndrome - MEN 1 - Lynch syndrome - Cowden syndrome - Von Hippel Lindau syndrome 13 Question 10 Which imaging technique has the highest diagnostic accuracy for UTUC? - CT urography - transabdominal US - MRI - PET-CT with Ga-68-PSMA - PET-CT with 18F-FDG 14