18. Рак мочевого пузыря и других уротелиальных областей

Уротелиальная карцинома мочевого пузыря

Введение

Мочевой пузырь является наиболее распространенной областью происхождения уротелиальной карциномы (urothelial cell carcinoma, UCC), хотя в других сайтах могут также возникать уротелиальные опухоли, включая простатическую уретру, почечную лоханку и мочеточник. Наиболее распространенной гистологией рака мочевого пузыря является UCC, ранее называемая переходно-клеточной карциномой, но другие гистологии также существуют как с обычными, так и с уникальными факторами риска. Исходная часть этой главы будет посвящена UCC мочевого пузыря, а другие гистологические варианты рака мочевого пузыря и других уротелиальных сайтов описаны ниже.

Заболеваемость и смертность

По оценкам Американского Онкологического Общества (American Cancer Society), в 2017 году в США будет диагностировано 79 030 новых случаев рака мочевого пузыря, и в этом же году приведет к и примерно 16 870 смертельных исходов, ассоциированных с этой болезнью [1]. Рак мочевого пузыря более чем в четыре раза чаще встречается у мужчин, чем у женщин, с показателями заболеваемости 35,3 и 8,6 случая на 100 000 человек в год, соответственно. Инцидент также увеличивается с возрастом, редко наблюдается до 40 лет и имеет средний возраст на момент диагностики 73 года. Неиспано белые подвергаются более высокому риску рака мочевого пузыря по сравнению с другими расовыми/этническими группами в США [2]. В дополнение к бремени болезни финансовое бремя также высокое; из всех злокачественных заболеваний рак мочевого пузыря имеет наивысшую стоимость на пациента [3].

Факторы риска и предотвращение

Множествые генетические и экологические факторы связаны с развитием UCC, главным из которых является табакокурение. Курение ответственно за 50% случаев у мужчин и 35% у женщин [4]. Курение сигарет увеличивает риск развития рака мочевого пузыря примерно в три раза, а бывшие курильщики, по-прежнему, подвергаются повышенному, хотя и более низкому риску. Наблюдается связь с дозой (количеством сигарет в день) и с продолжительностью (количество лет курения) [5]. Курильщики трубок и сигар также подвергаются риску, хотя и в меньшей степени, чем курильщики сигарет. Пассивное курение немного повышает риск [6, 7].

Многие профессиональные экспозиции также увеличивают риск UCC. В 1954 году Кейс (Case) и Хоскер (Hosker) продемонстрировали 20-кратное повышенние риска рака мочевого пузыря у рабочих, связанных с покраской и производством каучука [8], с тех пор были идентифицированы и другие профессии, включая задействованных в производстве кожи и алюминия рабочик, художников, водителей грузовиков и парикмахеров. Агенты, используемые в этих отраслях, такие как анилиновые красители, красители для волос и добываемое топливо, все подвергают рабочих экспозиции ариламинам.

Ариламины генерируют метаболиты, способные индуцировать ДНК мутации. Ряд генов, связанных с ДНК репарацией и детоксикацией, вовлечены в модификацией индивидуального риска, связанного с экспозицией ариламину. Наиболее изученными являются N-ацетилтрансфераза 2 (NAT2) и глутатион-S-трансфераза M1 (GSTM1), участвующие в детоксикации. NAT2 отвечает за N-ацетилирование ариламинов в печени, и этот ген проявляет полиморфизм, влияющий на активность. Снижение активности ассоциировано с замедлением клиренса ариламинов, и курильщики, экспрессирующие NAT2 с низкой скоростью ацетилирования, имеют повышенный риск развития UCC мочевого пузыря. Аналогично, GSTM1 играет роль в детоксикации, и в одном исследовании было показано, что около половины белого населения США не имеют обеих копий этого гена [9]. Нулевой фенотип GSTM1 ассоциируется с повышенным риском рака мочевого пузыря в некоторых исследованиях.

Воздействие мышьяка, преимущественно через питьевую воду, связано с раковыми заболеваниями мочевого пузыря, легких и кожи. На Тайване региональные различия в уровнях мышьяка воды коррелируют с частотой мочевого пузыря UCC. Риск явно увеличивается при уровнях выше 100 мкг/л. Недавние исследования предполагают повышение риска на более низких уровнях [10]. Частные скважины (well) в некоторых частях США содержат повышенные уровни, и, следовательно, некоторые группы населения подвержены риску [11]. Как и в случае с ариламинами, имеются данные о том, что генетическая восприимчивость играет роль в злокачественных новообразованиях, вызванных мышьяком. Некоторые препараты повышают риск развития рака мочевого пузыря, включая фенацетин и циклофосфамид.

More recently, pioglitazone has been associated with increased risk of bladder cancer, although in positive studies the excess risk appears to be small (20% higher) and increases with higher doses and with greater than 2 years of use [12].

As noted above, smoking is a major contributor to the burden of bladder cancer. Evidence suggests that smoking cessation decreases the risk of developing bladder cancer, particularly after 5 years, although the risk continues to remain elevated compared to never smokers [13]. Additionally, there is some evidence suggesting that smoking cessation following the diagnosis of bladder cancer is associated with decreased disease recurrence [14]. Non-steroidal anti-inflammatory use, aside from phenacetin, has been associated with decreased bladder cancer risk [15]. Total fluid intake has also been linked with a decreased risk of bladder cancer in some series, although the effect is not found uniformly across studies. The effect of dietary factors and vitamin supplementation on the development of UCC appears to be minimal [16].

Патология

UCC is the most common histology of bladder cancer in the US, accounting for over 90% of cases. Nonurothelial histologies include squamous cell carcinoma and adenocarcinoma; these rarer histologies will be discussed later in this chapter. Most urothelial tumors demonstrate a papillary growth pattern which is appreciable on cystoscopic examination. Some tumors, particularly high-grade tumors, may be sessile with a solid growth pattern, and carcinoma in situ (CIS) is flat with an erythematous or velvety appearance on cystoscopy. The most important pathologic tumor characteristics in UCC are tumor grade and depth of invasion. Invasion can be seen microscopically as nests, clusters, or single cells within the lamina propria or deeper, and often there is an associated desmoplastic or inflammatory response. Most tumors at initial presentation (75–80%) do not invade the detrusor muscle, and are referred to as nonmuscleinvasive bladder cancer (NMIBC). This distinction is important as treatment options change dramatically once the tumor invades the detrusor muscle. Invasion of detrusor muscle should be established by histologic evidence of tumor infiltrating thick bundles of smooth muscle, as opposed to involvement of the muscularis mucosa, a thin muscular layer present in the subepithelial connective tissue of some regions of the bladder.

UCC is now graded on a two-tiered system and reported as low grade and high grade per the World Health Organization (WHO). Differences between the two are based on architectural and cytologic changes when compared to normal urothelium. Low-grade urothelial tumors are characterized by ordered cell layers with minimal loss of polarity, and the cells have slight variation in size and shape with occasional mitoses. Low-grade tumors are almost uniformly non-invasive, with invasion only reported rarely into the superficial lamina propria. In contrast, high-grade cancers demonstrate disordered cell layers with frequent loss of polarity, marked cellular pleomorphism, prominent nucleoli and frequent mitoses (Figure 18.1). High-grade tumors are responsible for the majority of muscle-invasive tumors, and thus this finding increases the risk of disease progression. An additional WHO category, papillary urothelial neoplasm of low malignant potential (PUNLMP), has an appearance between normal urothelium and low-grade carcinoma and is by definition noninvasive [17].

Рисунок 18.1. Карцинома in situ.

An additional pathologic finding important in characterizing invasive urothelial tumors is lymphovascular invasion (LVI). Although not included in bladder cancer staging, LVI is predictive of outcomes in patients with urothelial carcinoma. LVI can be seen in both transurethral resection (TUR) and cystectomy specimens, although there is some interobserver variability in recognizing as well as reporting this finding. In prior studies, LVI is reported in 10–28% of TUR specimens for T1 UCC, and is seen in 30–50% of radical cystectomy specimens [18]. A number of investigators have found that LVI is predictive of pathologic lymph node involvement, disease recurrence, and progression following cystectomy and nephroureterectomy for UCC of the bladder and upper urinary tract, respectively. In patients with clinical stage T1 bladder UCC, LVI independently predicts disease progression and metastases [18]. Thus, LVI may not only help with prognostication, but help identify candidates for neoadjuvant or adjuvant chemotherapy, as well as consideration for early cystectomy.

Some variant histologies of UCC have prognostic and therapeutic implications. These generally represent about 7% of bladder tumors obtained by TUR, although arecent multi-institutional cystectomy database found variant histology in 24.6% of specimens [19]. This disparity is because tumors with variant histology generally present with more advanced stage, warranting more aggressive surgical therapy. UCC with squamous or glandular differentiation is the most common variant histology (Figure 18.2), particularly in those with muscle-invasive bladder carcinoma (MIBC). Thought to be chemoresistant, reanalysis of a Southwest Oncology Group neoadjuvant MVAC (methotrexate, vinblastine, doxorubicin and cisplatin) trial found that UCC with squamous or glandular differentiation were more responsive to MVAC and in fact may be an indication for neoadjuvant chemotherapy [20]. In other aspects as well, these histologies are treated similarly to conventional UCC.

Micropapillary bladder cancer is another histologic variant of UCC, found in about 1% of bladder tumors, although its incidence may be underreported (Figure 18.3). As with many variant histologies, these tumors present more often in advanced stage and evidence suggests worse outcomes following treatment. In a series of 100 patients with micropapillary bladder tumors, Kamat et al. found that only 44 had NMIBC at presentation, and 67% of the 27 who attempted bladder preservation with intravesical therapy following TUR developed disease progression [21]. They also noted a high incidence of pathologic upstaging in those undergoing immediate cystectomy (75%) and neoadjuvant chemotherapy did not appear to have any benefit in this series. Despite this aggressive course, outcomes by stage appear similar to conventional UCC [22], and more recent studies demonstrated a good pathologic response to neoadjuvant chemotherapy, with 13/29 (45%) found to be pT0 at cystectomy [23].

Рисунок 18.2. Высокозлокачественная, мышечноинвазивная уротелиальная карцинома с железистой дифференцировкой

Рисунок 18.3. Микропапиллярный вариант высокозлокачественной уротелиальной карциномы.

Sarcomatoid carcinoma of the bladder, also known as carcinosarcoma, is another rare histologic variant (<1%) of bladder UCC. Similar to sarcomatoid carcinomas of other organs, it contains elements with mesenchymal-appearing morphology in addition to the epithelial (urothelial) elements. The mesenchymal portion can appear as undifferentiated spindle cells, or have other histologic components such as bone, muscle, or cartilage. Molecular studies suggest these cancers are of monoclonal origin, and the component with mesenchymal differentiation is derived from the epithelial component. In comparison with conventional UCC, these tumors present with more advanced stage and have poorer survival even when controlling for stage. Although limited numbers have been reported, these tumors appear to be responsive to similar chemotherapeutic regimens as UCC. Numerous other histologic variants of UCC have been identified [24], some with variations in their management relative to conventional UCC [25], but their description is beyond the scope of this chapter.

Стадийность

As with any cancer, appropriate staging assists in determining the next step in treatment. The TNM staging system of the American Joint Committee on Cancer and the Union for International Cancer Control for bladder cancer is shown in Table 18.1 [26]. Ta, Tis, and T1 constitute NMIBC, and encompass 70–80% of bladder cancer at diagnosis, with the remainder being T2–T4. It should be noted that prostatic involvement as part of T4 specifically means bladder tumor which has grown to the point where it invades the prostatic stroma, as opposed to an independent prostatic urothelial cancer which would be staged separately. Nodal regions within the true pelvis include the external iliac, obturator, hypogastric, and presacral areas. It should also be noted that involvement of the common iliac nodes is considered N3 disease, and nodal spread beyond this is considered metastatic disease (M1). The M1 category has been divided into M1a (metastasis to nodes beyond the common iliac nodes) and M1b (nonlymph node distant metastases).

Pathologic staging occurs after radical cystectomy, and the specimen allows for more accurate staging and assessment of the risk of recurrence and progression. Clinical staging occurs through the combined findings of transurethral resection of the bladder tumor (TURBT), bimanual examination under anesthesia and cross-sectional imaging (computed tomography (CT) or magnetic resonance imaging (MRI)). The TURBT specimen obtained is evaluated by a pathologist to determine grade and stage, including evidence of invasion. As the resected tumor is obtained in pieces and may contain cautery artifact, depth of tumor invasion in various layers can be difficult to determine. Examination under anesthesia is typically performed before and after TURBT, mainly to determine if the mass is palpable, and if so, if it is still palpable after resection. Masses which are palpable prior to resection are considered at least T2b, and those which are still palpable after resection or are fixed are considered to be locally advanced, T3b–T4 disease. CT or MRI can be used to evaluate the primary tumor as well as to detect evidence of lymphadenopathy or metastatic disease. CT is more commonly used, and can determine tumors with extension into perivesical fat, with sensitivity and specificity ranging from 60 to 96% in various series [27, 28]. MRI appears to have similar results [27], although technological advances in MRI have led to improving capabilities in determining muscle invasion, extravesical extension, and lymph node involvement [29]. In addition to CT and MRI, positron emission tomography (PET)/CT has been demonstrated to improve nodal and metastatic staging [30].

Таблица 18.1. TNM стадийная система Американскиого объединенного комитета по раку (American Joint Committee on Cancer, AJCC) для рака мочевого пузыря.

Первичная опухоль (T)
TX Первичная опухоль не может быть оценена
T0 Нет свидетельства первичной опухоли
Ta Неинвазивная папиллярная карцинома
Tis Карцинома in situ
T1 Опухоль инвазирует субэпителиальную соединительную ткань
T2 Опухоль инвазирует собственную пластинку мышцы
pT2a Опухоль инвазирует поверхностную собственную пластинку мышцы (внутренняя половина)
pT2b Опухоль инвазирует глубокую собственную пластинку мышцы (внешняя половина)
T3 Опухоль инвазирует перивезикальную ткань
pT3a Опухоль инвазирует перивезикальную ткань микроскопически
pT3b Опухоль инвазирует перивезикальную ткань макроскопически
T4 Опухоль инвазирует окружающие органы/стенку тела
T4a Опухоль инвазирует строму простаты, матку, влагалище
T4b Опухоль инвазирует стенку таза, абдоминальную стенку
Региональные лимфатические узлы (N)
NX Лимфатические узлы не могут быть оценены
N0 Нет метастазов в лимфатические узлы
N1 Метастаз в один региональный лимфатический узел в истинном тазу
N2 Множественные метастазы в региональные лимфоузлы в истинном тазу
N3 Метастаз в типичные подвздошные лимфатические узлы
Отдаленный метастаз (M)
M0 Нет отдаленных метастазов
M1 Отдаленный метастаз
M1a Distant metastasis limited to lymph nodes beyond the common iliacs
M1b Non-lymph node distant metastasis
Когда T есть… И N есть… И M есть… Тогда стадийная группа есть
Ta N0 M0 0a
Tis N0 M0 0is
T1 N0 M0 I
T2a N0 M0 II
T2b N0 M0 II
T3a, T3b, T4a N0 M0 IIIA
T1–T4a N1 M0 IIIA
T1–T4a N2, N3 M0 IIIB
T4b N0 M0 IVA
Любой T Любой N M1a IVA
Любой T Любой N M1b IVB

Диагноз

Рак мочевого пузыря представлен обычно безболезненной макрогематурией или микрогематурией. Among patients with gross hematuria, about 15% will have bladder cancer found on subsequent evaluation, while in those with microscopic hematuria, bladder cancer is found in about 4% [31]. Other symptoms suggestive of UCC include irritative voiding symptoms such as urinary urgency and frequency, which may be caused by CIS. More advanced disease may present with pelvic, hip, or low back pain, renal insufficiency from obstruction, or symptomatic metastases.

Those who present with hematuria undergo an evaluation which includes cystoscopy, upper urinary tract imaging and voided urine cytology. CT with intravenous contrast including delayed images to evaluate the renal pelvis and ureters (CT urogram) has supplanted excretory urography as the method of upper urinary tract imaging most commonly used for the evaluation of hematuria. This provides evaluation of other potential causes of hematuria, such as kidney stones or renal cell carcinoma, as well as an evaluation of the renal pelvis and ureters for filling defects suggestive of upper urinary tract UCC. Some larger bladder tumors can also be visualized on CT. However, complete hematuria evaluation also requires cystoscopy for bladder evaluation due to sensitivity of 79% for tumors ≤1 cm and 58% when ≤5 mm [32].

Cystoscopy is the gold standard for the detection of bladder tumors, and typically bladder tumors are seen as a papillary or sessile mass within the bladder, or flat erythematous or velvety areas in the case of CIS. A common problem in bladder cancer is recurrence, and while some of this is due to de novo formation of new tumors, there is also evidence that some tumors already present are incompletely detected and treated. In recent years some adjunctive technologies have been studied to improve the visualization of tumors and provide better endoscopic treatment. Hexaminolevulinate (HAL) cystoscopy or photodynamic diagnosis is one method shown to improve bladder tumor detection. HAL is an ester of 5-aminolevulinic acid, and when instilled into the bladder it causes protoporphyrin accumulation which can be visualized pink under blue light (around 400 nm). This accumulation occurs preferentially in tumors, and a recent meta-analysis of multiple studies confirms higher detection rates of Ta and Tis tumors when compared with standard white light cystoscopy [33]. Additionally, recurrence rates following TURBT assisted by HAL cystoscopy were lower at 12 months than standard cystoscopy (34.5% vs 45.4%) [33]. More recently narrow-band imaging has been utilized increasingly and shows promise in improving bladder tumor detection. This technology again takes advantage of the higher blood flow within tumor tissues, and uses two light wavelengths (415 and 540 nm) which are absorbed by hemoglobin. It allows better differentiation between surface capillaries and tumors. Tumors continue to appear red against a background of green. Many studies have found improved tumor detection rates with this technology, and two prospective, randomized trials have been able to demonstrate decreased recurrence rates following narrow-band imagingbased tumor resection as well [34, 35].

Urinary cytology is also typically performed as part of the workup of hematuria and in monitoring patients with a history of UCC. The results are reported at most institutions as negative, atypical, suspicious, or positive. Voided urine is typically collected for this test, although some use bladder barbotage at the same time as cystoscopy in an attempt to improve sensitivity. This is because cytology has poor sensitivity for UCC, particularly for low-grade tumors. Reported sensitivity rates for cytology range from 20 to 70%, but typically for highgrade tumors and CIS the sensitivity is 40–60% [36]. The main benefit of cytology is its specificity, which is 90–100% in most series, thus making it useful to identify patients in need of biopsy to look for CIS in the absence of abnormalities on cystoscopy. A number of other urinary markers have been developed and still more are in the investigational stage, mainly in the interest of foregoing cystoscopy in bladder cancer diagnosis or follow-up, or in an attempt to replace urine cytology. The NMP22 BladderChek, Urovysion (FISH), ImmunoCyt and BTA test are Food and Drug Administration approved tests for use in the US. While many have improved sensitivity relative to cytology, as yet none has proven sufficient to supplant cystoscopy [37]. For this reason, the American Urologic Association, National Comprehensive Cancer Network, and European Urologic Association guidelines do not have recommended use of these markers in the diagnosis and treatment of bladder cancer at this time. There are special circumstances where some of these tests may be valuable [38–40], and this was the subject of a recent review [41].

Once a bladder tumor is diagnosed on cystoscopy, the next step in diagnosis and first step in treatment is a TURBT. This is an endoscopic procedure performed under regional or general anesthesia, and the tumor is removed in a piecemeal fashion with the use of monopolar or bipolar electrocautery. Once the tumor is completely resected, an additional specimen of the tumor base is usually obtained to ensure accurate staging in case of invasion. Any additional areas of abnormality should also be biopsied or resected. A final step which can be considered following TURBT is perioperative instillation of mitomycin C (MMC). Immediate or early (within 24 h) administration of intravescial chemotherapy following TURBT has been evaluated in a number of trials, with MMC being the most common agent used for this purpose. A large meta-analysis of various perioperative chemotherapy agents demonstrated decreased recurrence in those who received a single dose of intravesical chemotherapy (odds ratio 0.61) [42]. The benefit is more definitive in those with single, low-grade bladder tumors, with uncertain benefit in the setting of multiple tumors or high-grade disease. MMC is cytotoxic, and if there is any evidence of bladder perforation from the TURBT then MMC should be withheld.

Those with a positive cytology but no evidence of bladder tumor also require an endoscopic procedure to localize the source of the positive cytology. In these cases, random bladder biopsies are performed as well as a prostatic urethral biopsy in males, and upper urinary tract washings are also obtained for cytology. The pathologic results of the TURBT or biopsies, as well as findings on CT and examination under anesthesia, allow for appropriate pathologic staging of the patient with newly diagnosed bladder cancer and assist in decisions regarding the next stage in treatment.

Лечение

Лечение рака мочевого пузыря зависит преимущественно от патологической стадии и степени злокачественности. Как указано выше, существует значительный порог на уровне инвазии в мышцу, который полностью изменяет алгоритм лечения, равно как и развитие метастатического заболевания. Поэтому мы рассмотрим лечение NMIBC (Ta, Tis и T1), MIBC (T2-4, N1-3, M0) и метастатического рака мочевого пузыря отдельно.

NMIBC

This group represents roughly 70–80% of bladder cancer cases at diagnosis. The first step in treatment is that already mentioned – TURBT with or without perioperative instillation of intravesical chemotherapy. The next step depends on a number of factors which all relate to the risk of tumor recurrence and progression. Established risk factors include tumor grade, presence of invasion (T1), presence of concomitant CIS, tumor size ≥3 cm, number of tumors and, in those with a history of bladder tumors, frequency of recurrence [43]. Among those with NMIBC, about 70% are low grade and noninvasive (PUNLMP or low-grade Ta). For most of these patients, no further treatment is required, but surveillance is needed to monitor for recurrence (see Follow-Up). A caveat to this generalization applies to patients with multiple and/or recurrent low-grade Ta tumors, in whom further intravesical therapy may be considered to slow the rate of recurrence.

Repeat TURBT about 6 weeks following initial resection is indicated in those who did not undergo complete tumor resection at initial TURBT, as well as those with invasive disease (T1) found at TURBT. The risk of residual disease and pathologic understaging in those with T1 tumors has been studied by a number of groups. In a large series of suspected T1 tumors, 48% had residual NMIBC (Ta, Tis, or T1) on repeat TURBT, and 30% upstaged to T2 disease [44]. The rate of upstaging on repeat TURBT is higher in those without detrusor muscle present in the initial specimen. Additionally, upstaging at cystectomy for clinical T1 disease has been reported to be as high at 50%, and a randomized controlled trial demonstrated decreased risk of recurrence and progression following repeat TURBT for those with T1 disease on initial resection [45]. Thus, those with T1 disease require repeat resection, and some would argue those with high-grade Ta disease should also undergo repeat TUR, as recurrence rates are lower in retrospective series [46]. The American Urologic Association and European Association of Urology guidelines recommend repeat resection for those with T1 disease.

Patients with NMIBC can be divided into three risk groups – low, intermediate, and high – based on tumor size, number, level of invasion, presence or absence of CIS, and recurrence history. Sylvester et al. [43] have developed a mathematical model for prediction of the risk of recurrence and progression using data from a large group of patients who had previously been treated on several clinical trials. These models are represented in the form of tables available in an electronic and paper format that allow for easy calculation of risk of recurrence and progression. The one issue with this prediction model is that most of the patients were treated with intravesical chemotherapy, not immunotherapy such as bacillus Calmette– Guйrin (BCG), and hence any advantage that immunotherapy holds over chemotherapy may not be considered. Stratification in this manner can help identify patients who may benefit from further treatment, such as intravesical therapy or early cystectomy, or closer surveillance, as discussed under Follow-Up.

Intravesical therapy is administered in a variety of situations, some of which have been outlined. A variety of agents are used for this purpose, most commonly chemotherapeutic agents such as MMC, gemcitabine, epirubicin, doxorubicin, valrubicin, and thiotepa. The side effects of these agents are mainly due to local toxicity, with the exception of thiotepa, which can cause myelosuppression. Immunotherapeutic agents have also been administered intravesically, such as BCG and interferon. BCG, as an attenuated mycobacterium, can result in systemic side effects including disseminated infection. The two most studied and utilized intravesical agents are MMC and BCG. Postoperative instillation of intravesical chemotherapy, as discussed above, is one common use of intravesical agents, although immunotherapy is not used for this purpose. Intravesical agents are also typically given as an induction course about 2–6 weeks following complete TURBT, and in some cases with an additional maintenance schedule for up to 3 years. The induction course is typically delivered intravesically once per week for 6 weeks. Indications for an induction course of intravesical therapy include multiple, large, or recurrent low-grade Ta tumors, or those with high-grade tumors (Ta, T1, or Tis). For those with extensive or recurrent lowgrade disease, in whom the risk of recurrence is high but the risk of progression is low, BCG or MMC can be used to prevent recurrence. There is some evidence that BCG, particularly with maintenance therapy, is more effective in preventing recurrence although at the cost of increased urinary adverse effects [47]. For those with high-grade disease, BCG should be used unless contraindicated, and evidence suggests that maintenance therapy results in greater reduction in disease progression compared to induction alone [48].

For some patients with high-grade NMIBC, radical cystectomy is indicated due to the high risk of occult progression and death from disease. Those with high-grade T1 tumors are particularly at risk for occult muscle invasive disease due to the potential for clinical understaging. In a multicenter study of 1136 patients who underwent cystectomy for high-grade T1 bladder UCC, 50% were = T2 on final pathology and 16% had nodal metastases [49]. For those who initially undergo intravesical BCG instillation following TURBT, approximately 35% of those with high-grade T1 will progress to T2 disease, and this is despite optimized initial staging with repeat TURBT [50]. Additionally, those who present with NMIBC and undergo cystectomy at progression to T2 fare worse than those who present initially with T2 disease with a 3-year cancer-specific survival of 37% versus 67% [51]. Thus, as many will progress and risk poor outcomes with deferring of definitive local therapy, early cystectomy should be considered in some NMIBC patients at high risk of progression. Early cystectomy should be offered to those with high-grade T1 disease and risk factors for recurrence and progression including multifocal disease, difficult resection site hindering complete resection, LVI, tumor within a diverticulum or prostatic urethra, or associated CIS. Another population with NMIBC who should strongly consider cystectomy is patients with high-grade recurrence (including CIS) following BCG, termed BCG failures. Treatment alternatives in this group include repeat BCG induction with or without interferon, intravesical chemotherapy with gemcitabine or other agents, or cystectomy. Response rates for repeat induction BCG with or without interferon are worse than those without prior treatment (15–35%), although this depends on time from initial BCG to recurrence [52]. Gemcitabine has improved activity compared to repeat BCG induction in this population [53], although the progression rate in this small study was similar between the two treatments at around 35%. Thus, for those with early recurrence after induction BCG, termed BCG-refractory, cystectomy should be offered for the increased risk of occult disease progression, similar to those with high-grade T1.

MIBC

Approximately 20% of patients will present with muscleinvasive disease, and others with NMIBC will progress to muscle-invasive disease. Radical cystectomy is the gold standard for obtaining local control in this setting. Prior to consideration for cystectomy, staging is needed in these patients to confirm that there is no evidence of metastatic disease, as this would dramatically alter management. Typically, this involves CT of the abdomen and pelvis including delayed images to examine for upper urinary tract disease, chest X-ray or CT, and bone scan for those with bone pain or elevated alkaline phosphatase. FDG-PET has also been shown to have a potential role in finding nodal or visceral metastases (which can alter management) before cystectomy [54]. Candidates for radical cystectomy also require a thorough preoperative evaluation, as short-term complication rates are reported as high as 60% and perioperative death rates around 2%. Once radical cystectomy is indicated, timely evaluation and treatment are needed as evidence suggests worse outcomes in those with delays greater than 12 weeks from diagnosis [55].

Radical cystectomy in males includes removal of the bladder, prostate, seminal vesicles, and distal ureters. For men interested in orthotopic urinary diversion, the bladder neck and prostatic urethra should be free from tumor, and a frozen section of the urethral margin should confirm this. Nerve-sparing techniques are also performed in select patients to attempt to maintain erectile function, with variable results published to date. Radical cystectomy in females classically involves the removal of the bladder, uterus, adjacent anterior vaginal wall, urethra, and distal ureters. For those concerned with sexual function, the anterior vaginal wall and/or uterus may be spared in cases without extensive posterior wall involvement with invasion of these structures. Additionally, in women interested in orthotopic diversion, the urethra may be spared in the absence of bladder neck and urethral UCC similar to men. While classically radical cystectomy is an open procedure, robot-assisted laparoscopic radical cystectomy is gaining popularity in recent years. While the technique is performed to mimic the open procedure, the results of ongoing clinical trials will help determine the safety and oncologic efficacy of this approach.

Pelvic lymph node dissection is included as a standard part of the surgery, and the nodes include those of the external iliac, obturator, internal iliac, and common iliac vessels. Extent of lymphadenectomy has been associated with increased likelihood of finding positive lymph nodes, as well as a potential therapeutic benefit in lymph node positive and negative patients [56–59]. While attempts have been made to standardize a lymph node count sufficient for prognostic and therapeutic benefit, many patient, surgeon, and pathologist variables have been demonstrated to affect lymph node counts. The template of dissection is likely more important than any actual number [60], and ongoing clinical trials are examining the extent of dissection (standard described above compared to extended dissection up to the inferior mesenteric artery) as it relates to cancer-specific survival.

Таблица 18.2. Сообщенная 5-летняя выживаемость без рецедива (RFS) после радикальной цистэктомии по поводу уротелиальной карциномы мочевого пузыря [61, 103].

Патологическая стадия 5-летняя RFS (%)
≤pT1 81–88
pT2 70–81
pT3 44–68
pT4 16–44
N+ 29–35

Outcomes following radical cystectomy vary based on pathologic stage. Reported 5-year recurrence-free survival rates as related to pathologic stage are listed in Table 18.2. Patients with nonorgan confined disease and positive lymph nodes have worse outcomes overall. In a cohort of 1,054 patients undergoing cystectomy, 558 (53%) had= T3 disease and/or positive lymph nodes at the time of cystectomy, suggesting many patients undergoing cystectomy are at high risk of disease recurrence and death [61]. A recent series of 447 recurrences postcystectomy reveal that most patients (65%) recur at distant sites exclusively, and another 16% recur concomitantly at local and distant sites [62]. Thus, improving outcomes in these patients at high risk of recurrence requires systemic therapy. Neoadjuvant and adjuvant chemotherapy address this need in MIBC, although some controversy exists regarding the optimal timing of delivery of such chemotherapy.

Neoadjuvant chemotherapy for bladder cancer currently consists of cisplatin-based combination therapy, most commonly gemcitabine and cisplatin (GC). A meta-analysis of 11 randomized trials including 3,005 patients demonstrated a 5% improvement in 5-year overall survival (OS) and 9% improvement in 5-year disease-free survival (DFS) with neoadjuvant cisplatin-based combination chemotherapy [63]. Based on phase 2 data and the Southwest Oncology Group trial, a combination of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) was initially the most common regimen used, although toxicity limited its utility in the elderly and those with excessive comorbidity. A trial comparing MVAC with GC in the setting of metastatic disease demonstrated relatively equivalent efficacy with reduced toxicity in the latter [64], and this has been extrapolated to the neoadjuvant setting in the absence of level 1 evidence. This is an important point as the GC regimen is better tolerated, potentially allowing better functional status at the time of the subsequent cystectomy. One problem with cisplatinbased regimens is the requirement for adequate renal function and good functional status, which preclude delivery in as many as 40% of patients with MIBC [65]. Alternatives in these patients include carboplatin-based regimens, which have less activity in UCC. Additionally, up to 40% of UCC is resistant to cisplatinbased combinations, thus in many patients the time allotted for chemotherapy is only a delay and chance for disease progression. This is compounded by inaccuracies in clinical staging, which, assuming only those with nonorgan-confined disease benefit from chemotherapy, means overtreatment if all patients with MIBC are given neoadjuvant chemotherapy. This has led to use of adjuvant chemotherapy in selected patients based on their cystectomy pathology (pT3–4 or node-positive disease). Unfortunately, there is less robust data to support the use of adjuvant chemotherapy in MIBC. A meta-analysis of six adjuvant trials with 491 patients demonstrated a 25% reduction in risk of death with adjuvant chemotherapy, although the authors concluded that there was insufficient numbers to make this evidence strong enough toguide clinical practice [66]. Unfortunately, no well-designed trials compare adjuvant and neoadjuvant chemotherapy at this time, and, despite level 1 evidence demonstrating the efficacy of neoadjuvant chemotherapy, it currently has a low level of acceptance. Future studies on molecular markers of treatment susceptibility and improvements in clinical staging may help determine patients appropriate for neoadjuvant therapy and improve usage of this modality.

Radical cystectomy and urinary diversion is an extensive procedure, with a high risk of complications as well as resultant changes in lifestyle from the urinary diversion. Some patients are not candidates for cystectomy due to frailty or extensive comorbidity, and others simply refuse the procedure. Thus, bladder sparing options are available for these patients who have reasonable outcomes with appropriate selection. TURBT alone is capable of completely treating some MIBC, as evidenced by a pT0 rate of about 16% at cystectomy in the absence of neoadjuvant chemotherapy. Selection criteria include T2 disease based on clinical evaluation including examination under anesthesia and imaging, size =3 cm and no CIS. Patients considering this treatment need repeat TURBT with no residual tumor on the second resection. Safety of this approach has been verified in small series, with only 18% dying of disease at >10 years of follow-up if no tumor was found at the repeat resection [67]. Partial cystectomy can be offered to a similar patient population with the added benefit of better staging of the local tumor as well as the lymph nodes. One caveat is that the tumor must be in a location amenable to partial cystectomy, such as at the dome or in a diverticulum, and away from the ureteral orifices. Similar outcomes can be found in these patients, and some have used this in patients with a good response to neoadjuvant therapy to ensure complete pathologic response. Lastly, combinations of TURBT, chemotherapy, and radiation have been used in select patients with MIBC who are medically unfit or refuse cystectomy. Best responses are seen in those with solitary cT2–T3a tumors amenable to complete TURBT, no hydronephrosis, no CIS, and adequate renal function for chemotherapy. Five-year survival rates in various trials are around 50%, which is similar to those found in neoadjuvant chemotherapy and cystectomy trials, although no trials directly compare the two modalities in this highly selected patient population. Of note, in one large series about 30% required cystectomy due to incomplete response to therapy or recurrent invasive tumor on follow-up [68], thus close surveillance is required as some patients will fail early or late with persistent or recurrent disease.

Метастатический рак мочевого пузыря

Patients who have developed metastatic bladder cancer carry a poor prognosis overall. Despite reported response rates to firstline chemotherapy as high as 70% in some series, median overall survival in these trials is in the range of 10–15 months. Prognostic indicators in these patients were analyzed in a large group who received MVAC at Memorial Sloan-Kettering Cancer Center [69]. Karnofsky performance score <80% and presence of visceral metastases were predictors of poorer survival in this population. Patients with neither of these risk factors had a median survival of 33 months, while those with one or two of these factors had a median survival of 13.4 and 9.3 months, respectively.

First-line chemotherapy in these patients is similar to that used in the neoadjuvant setting, with GC and MVAC used most commonly in those with adequate renal function and performance status. In the randomized trial of GC versus MVAC, median OS was 14.8 months for MVAC and 13.8 months for GC (P = 0.746) [66]. Response rates were 46% and 49% for MVAC and GC, respectively, with similar complete response rates at 12%. Cisplatin is replaced with carboplatin in some patients with poor renal function or in elderly/frail patients, although response rates for carboplatin are lower. Until recently, second-line therapies for those that failed prior platinum-based regimens included gemcitabine and taxanes either alone or in combination, with a reported median OS in this setting of 7–10 months. While not approved in the US, vinflunine was approved in Europe in 2009 based on a phase 3 randomized trial demonstrating a 2.6 month OS benefit in the population which met all eligibility criteria (6.9 vs 4.3 months, P = 0.040), although the intent-to-treat population which included 13 ineligible patients did not reach statistical significance [70]. In May 2016, the Food and Drug Administration approved atezolizumab, a PD-L1 antibody, in those with disease progression following platinumbased chemotherapy based on a single arm, phase 2 trial in 310 patients. Among all patients, 15% had an objective response and in those with higher PD-L1 expression the response rate was higher (26%) [71]. These responses appear durable, as 84% of responders continued to respond at median follow-up of 11.7 months. Since atezolizumab, other PD-L1 inhibitors (durvalumab, avelumab) as well as PD-1 inhibitors (nivolumab, pembrolizumab) have been FDA approved for use in those with locally advanced and metastatic urothelial carcinoma. Future directions include targeted molecular therapies, which are currently in clinical trials.

Наблюдение

Follow-up for patients with NMIBC at some institutions is similar for all patients, without stratification based on risk. Typical follow-up schedules would involve cystoscopy and urinary cytology every 3 months for 2 years, then every 6 months for 2 years and then annually. This presumes no bladder recurrence, but should the patient recur the process starts again. The risk of upper urinary tract cancer in general is low, so upper tract imaging is repeated every 2 years. This does take into account the fact that recurrences are more common in the first 2 years and then recedes thereafter, but it assumes the risk is approximately the same in all patients with NMIBC.

Others have adopted a stratified approach based on the risk of recurrence in certain subgroups. Those with PUNLMP have a 25–50% risk of recurrence and very low risk of progression. For those with low-grade Ta lesions, the risk of recurrence is approximately 50–70% and the risk of progression is approximately 5%. Additionally, the risk of upper tract recurrence is less than 1% in this population. The EAU has adopted surveillance programs based on risk, and this is increasingly being accepted in the US. In these patients, cystoscopy and cytology can be performed at 3 months and, if negative, repeated at 9 months and then annually. Upper tract surveillance is not routinely performed in this group, but rather based on symptoms. The intensity of this regimen increases in those with intermediate risk disease (multifocal, large, or recurrent low-grade Ta UCC), and is further intensified in those at high risk (high-grade disease). Those with high-risk disease are recommended to have cystoscopy and cytology every 3 months for 2 years, then every 6 months until 5 years, then annually. Additionally, due to an up to 20–25% risk in upper tract recurrence, annual or at least biennial upper tract imaging is recommended.

Follow-up after cystectomy is also based on the risk of recurrence at most institutions, although there is debate on the utility of various components. The risks of recurrence include local or distant recurrent disease, as well as risk of upper tract recurrence and urethral recurrence for those with the urethra left in situ. General guidelines include routine chest X-ray and crosssectional imaging of the abdomen and pelvis to examine for local, nodal, and visceral metastases as well as upper urinary tract disease. Urine cytology is also usually performed to examine for upper tract recurrence as well. Urethral surveillance with washings or voided cytology in those with an orthotopic diversion is debated, as some have shown similar outcomes in patients with recurrence detected via surveillance as those with symptomatic presentation (i.e., blood per urethra). This can be stratified based on risk of recurrence determined by pathologic stage, and with decreasing intensity as most local and distant recurrences occur in the first 2–3 years following cystectomy [72].

Уротелиальная карцинома верхних мочевыводящих путей

UCC of the renal pelvis makes up around 10% of all renal tumors and 5% of all urothelial tumors. Upper urinary tract urothelial carcinoma (UUT-UCC) is much less common than UCC of the bladder, thought to be due to decreased exposure times to the same carcinogens. Exceptions with a higher incidence of UUTUCC than bladder are in cases of Balkan nephropathy and phenacetin abuse. Balkan nephropathy is a chronic tubulointerstitial disease associated with a high frequency of urothelial atypia. In these cases the tumors are mainly in the upper tract, low grade and often bilateral [73]. Lynch syndrome II of hereditary nonpolyposis colorectal cancers is associated with extracolonic cancer sites, especially UUT-UCC, and in these cases tumors are usually bilateral as well. Aristolochic acid, often ingested in herbal medicines, is a risk factor for UUT-UCC, and is also a potent nephrotoxin. Other risk factors for UUT-UCC are male gender, white race, history of bladder UCC, arsenic exposure, and cigarette smoking.

While most UUT-UCC occur in the renal pelvis, when it occurs in the ureter it is typically in the distal portion. With high-grade UUT-UCC, the disease is often multifocal and associated with CIS. Bladder UCC patients have a low lifetime risk (2–4%) of UUT-TCC. However, UUT-UCC patients have a 25–75% risk of developing a bladder cancer [74] and bladder surveillance is needed in these patients. Most UUT tumors are identified on investigation for sources of hematuria, and larger, obstructing tumors may present with hydronephrosis and renal failure. Staging of UUT-UCC is similar to bladder UCC.

Treatment decisions can be complicated in UUT-UCC for a variety of reasons. Clinical staging is difficult – imaging studies can help although biopsies are usually too small to determine invasion adequately, unlike TURBT. Tumor grade has been shown to correlate directly with tumor stage. Thus, tumor grade often dictates the aggressiveness of therapy, and overall renal function also contributes to treatment decisions. The gold standard in the treatment of UUT-UCC is radical nephroureterectomy, which provides effective local tumor control and is the treatment of choice for high-grade, potentially invasive tumors except in patients with significant morbidity and renal impairment. Nephron-sparing procedures include partial ureterectomy in those with disease confined to the distal ureter and endoscopic management. Endoscopic procedures are performed either through a percutaneous approach or retrograde via the ureter, and can provide local control for lower stage and grade tumors, although it has higher rate of recurrence (up to 25–44%) when compared to extirpative surgeries [75]. Although some high-grade, Ta tumors would likely respond to endoscopic treatment, clinical staging is inaccurate thus depth of invasion is often unknown. This difficulty in clinical staging translates into difficulties in determining appropriate use of nephron-sparing surgery, as well as lymphadenectomy and neoadjuvant chemotherapy. Although there is some data on landing sites for nodal disease based on location of tumor [76], there are mixed results in retrospective studies on the potential therapeutic impact of lymph node dissection. The use of adjuvant chemotherapy is also debatable as there are no randomized trials and the results of retrospective studies are mixed [77, 78]. Another obstacle to the use of adjuvant therapy in UUT-UCC is that the regimens are usually cisplatin-based and contraindicated in those with renal insufficiency that can occur following nephroureterectomy. This makes neoadjuvant delivery an attractive option. However, there are no randomized trials specific to UUT-UCC and there are the same issues with clinical staging and determination of benefit as discussed in bladder UCC. Metastatic disease is treated in a fashion similar to metastatic bladder UCC.

Уротелиальная карцинома простаты

Urothelial carcinoma of the prostate can result from direct extension or indirect seeding from bladder UCC, and can also develop from the urothelium of the prostatic urethra. The incidence of primary prostatic UCC is estimated to be 1–4% of all prostate malignancies, whereas the incidence of involvement of the prostate with primary bladder UCC ranges from 12 to 48%. Risk factors for prostatic involvement include CIS of the bladder, multifocal disease, high-stage bladder cancer, lesions located in the trigone or bladder neck, and multiple courses of intravesical therapy. The staging system for primary prostatic UCC is different than staging of bladder UCC with prostatic extension (pT4a). This distinction is important as it correlates with the prognosis. Rather than pT4a and thus poor prognosis, a primary prostate lesion has a prognosis dependent on the depth of invasion of this lesion. Stromal invasion is classified as pT2, with similar implications as muscle involvement regarding need for cystoprostatectomy.

Identification of prostate involvement is crucial but challenging. Lesions may be easily be missed during cystoscopy. In one study 26.5% of patients with NMIBC without known prostatic involvement were found to have UCC in the prostate on biopsy, and 18% of them had CIS [79]. Different methods for the detection of prostate involvement have been examined, and TUR biopsies have better accuracy than prostate needle biopsy and fine needle aspiration. Treatment options for prostatic urothelial tumors depend on the depth of invasion. Superficial lesions can be treated with TUR and BCG with good results. Ductal involvement is still not an absolute indication for radical cystoprostatectomy, whereas stromal invasion is an indication as it is associated with a high nodal metastasis rate and poorer prognosis.

Неуротелиальные опухоли мочевого пузыря

Аденокарцинома

Primary adenocarcinoma accounts for 0.5–2% of primary bladder malignancies [80, 81]. It can be classified into urachal and nonurachal adenocarcinoma, where the former is much less common, accounting for 0.35–0.7% of all bladder malignancies [82]. For the sake of simplicity, primary adenocarcinoma of the bladder usually refers to the malignant neoplasm derived from urothelium (the non-urachal subtype). By definition, bladder adenocarcinoma has purely glandular differentiation and should be distinguished from mixed histology with UCC. Secondary adenocarcinoma of the bladder can result from direct extension or metastatic spread. The most frequent origins of secondary adenocarcinoma are colon, prostate, breast, endometrium, and lung [80, 83]. In addition to excluding secondary sources, the diagnosis of primary adenocarcinoma requires the exclusion of benign lesions of the bladder that have glandular histology such as cystitis cystica, cystitis glandularis, von Brunn nests, nephrogenic adenoma (nephrogenic metaplasia), and urachal remnant.

This tumor occurs more commonly in males and people in their sixth decade. Predisposing factors include bladder extrophy, where 90% of tumors arising there are adenocarcinoma, vesical schistosomiasis [81], chronic irritation, infection, and cystitis glandularis [84]. Nonurachal adenocarcinomas are most commonly found in the trigone or posterior bladder wall, and unlike UCC they are often solitary lesions [83]. The most common presentations are hematuria and irritative voiding symptoms.

Due to its rarity and poor prognosis, treatment data is limited to mainly small retrospective studies. Bladder adenocarcinoma generally is very aggressive, with metastatic disease reported in up to 40% of patients at the time of diagnosis and with a reported 5-year DFS rate of 55% (95% CI 50.3–59.3) [81]. The most important prognostic factor is tumor stage, and outcomes are similar to UCC when compared by stage. As most are at an advanced stage at diagnosis, radical cystectomy is the primary option for therapy [85]. Adjuvant radiation or chemotherapy may be considered in some cases. Several studies looked at the effect of 5-fluorouracil as an adjuvant or palliative treatment with good response in some subjects [86].

Urachal adenocarcinoma arises most often at the junction of the urachal ligament and bladder dome. It is believed that these tumors originate either from enteric rests during embryological development or from metaplasia of the urachal ligament [87]. There are still no clear diagnostic criteria for urachal adenocarcinoma, but some suggest that any adenocarcinoma arising at the dome of the bladder should be considered urachal until proven otherwise, often with a sharp demarcation between the tumor and surface epithelium. As with bladder adenocarcinoma, a separate primary adenocarcinoma needs to be excluded [88]. Sheldon et al. proposed a staging system that was followed by most reported case series [89], and others utilize the Mayo staging system (Table 18.3). Urachal adenocarcinoma affects younger people when compared with other bladder cancers, and many patients present with locally advanced disease that is not reliably cured with surgery. Treatment for clinically localized disease is partial cystectomy with a 5-year DFS of 44% [87]. There was no benefit of radical versus partial cystectomy in retrospective series. As the majority of survivors had the urachal ligament resected at surgery, it is recommended to remove the urachal ligament via en bloc resection of the bladder dome, urachal ligament, posterior rectus fascia, and umbilicus. There appears to be no role for adjuvant therapy at present, although salvage surgery for local recurrence has demonstrated good results [88].

Плоскоклеточная карцинома

The worldwide prevalence of bladder squamous cell carcinoma (SCC) varies by region from 1 to 75% of bladder cancers, and in the US it is about 3–7%. The incidence of this tumor is highest in areas of the Middle East and East Africa where bilharziasis is endemic. In these areas, SCC is the most common tumor of the bladder, and SCC of the bladder is the most common cancer in male patients [90]. Patients at risk for SCC of the bladder include smokers, those with occupational exposures to aromatic amines, Schistosoma haematobium (bilharzial) infections, and with long-standing cystitis[91].Chronic bladder infection and inflammation are believed to cause squamous metaplasia and leukoplakia of the urothelium, which are considered precancerous lesions [92]. The presence of a chronic urinary catheter as well as recurrent infections poses risk of this tumor in neuropathic bladder patients, especially in those with spinal cord injury, where the risk goes up to 2.5–10% after 10 years or more although more recent studies suggest a risk of 0.38% [82]. Patients being treated with cyclophosphamide for various malignancies have a 1.8% risk of developing SCC. This risk correlates well with the presence of hemorrhagic cystitis which develops usually after a year of treatment. Other possible risk factors are pelvic irradiation and immunosuppression in transplant patients [90]. There is no notable gender predilection in SCC, unlike urothelial carcinoma [91]. Most US patients with squamous cell carcinoma present in their sixth or seventh decade of life while patients with bilharzial SCC present earlier [93]. Some studies have reported an increased risk of SCC in patients treated with intravesical BCG in the presence of squamous dysplasia [89]. The role of high risk human papillomavirus is unknown [92].

Таблица 18.3. Стадийные системы карциномы мочевого протока (урахальной) [89, 90].

Stage Sheldon staging system Mayo staging system
I Confined to urachal mucosa Confined to urachus and/or bladder
II Invasion confined to urachus Extension beyond muscular layer of urachus or bladder
III A Extension to bladder Regional lymph node invasion
III B Extension to abdominal wall
III C Extension to peritoneum
III D Extension to viscera other than bladder
IV A Metastatic to lymph nodes Metastatic to nonregional lymph nodes or other distant sites
IV B Distant metastases

Bilharzial SCC is usually a well-differentiated tumor with exophytic, nodular, fungating lesions and a relatively low prevalence of nodal and distant metastases. Patients with nonbilharzial squamous cell carcinomas usually have advanced stage disease at presentation. The cancer is usually diffusely spread with muscle invasion in more than 80%. Metastases are identified in at least 10% of cases at the time of diagnosis [95] and are associated with a poor prognosis. Common sites for metastases include regional lymph nodes, bone, lung, and bowel.

The clinical presentation is hematuria with or without lower urinary tract symptoms. Diagnosis is usually with cystoscopy and biopsies. SCC is by definition made up entirely of squamous cells with intracellular bridges, pearls and keratohyalin granules, and should be distinguished from urothelial cancer with squamous differentiation [90].

Treatment of SCC mainly depends on the stage of disease at presentation. Superficial cancers are treated like UCC, with endoscopic resection. For muscle invasion, radical cystectomy remains the most effective treatment option where the 5-year survival rate ranges between 23 and 48% [96]. The lower survival rate for SCC as compared to UCC may be contributed to by the fact that patients usually present in advanced stages. Some recommend routine urethrectomy along with radical cystectomy, as urethral recurrence rates are reported to be as high as 40%. Radiotherapy failed to be effective as sole therapy with a reported 5-year survival rate of 5–18%. As for chemotherapy, some studies

showed promising results with the adjuvant use of agents such as epirubicin, with a 50–60% response rate being observed in patients with locally advanced and metastatic disease [90]. In cases of advanced disease with nodal or distant metastases, palliative chemotherapy or radiation therapy is used.

Мелкоклеточная карцинома

Small cell carcinoma (SmCC) is a neuroendocrine tumor, with an estimated incidence of 0.3–1% of all primary bladder cancers [97]. Most affected patients are in the fifth and sixth decade of life, and males are three times more likely to be affected than females [93]. SmCC of the bladder is associated with smoking in about 70% of cases [98] Other risk factors include recurrent or long-standing cystitis, bladder calculi, and augmented cystoplasty. Cases have also been related to pelvic irradiation and occupational chemical exposure [99].

The typical presentation is gross hematuria. Some patients will have symptoms of paraneoplastic syndromes including hypophosphatemia, elevated corticotrophin, and sensory neuropathy similar to pulmonary SmCC. Nephrotic syndrome due to secondary systemic amyloidosis, hypercalcemia, and elevated serum alpha-fetoprotein (AFP) have been also reported with bladder SmCC [97].

When compared to stage-matched bladder UCC, SmCC is more aggressive. SmCC has a tendency to invade adjacent organs, including the ureter, prostate, and ovaries. Bladder SmCC is associated with a high frequency of distant metastases and poor survival. Most patients (94%) with bladder SmCC present with muscle invasion, and approximately 67% of patients develop systemic metastases during the disease course. Metastases most commonly involve the liver, brain, lung, bone, and lymph nodes [100].

Due to the low incidence and the late presentation of the disease, only small retrospective studies are available. Transurethral resection of the bladder tumor as the sole treatment modality is not favored because the tumor is usually muscle invasive with poor 3–6 month survival rates [100]. Cystectomy alone is also usually not curative because of the high rate of systemic recurrence. This prompted the use of neoadjuvant chemotherapy or chemoradiotherapy with bladder-sparing protocols [101]. The most commonly used regimens are cisplatin and etoposide, carboplatin and etoposide, and cyclophosphamide, doxorubicin, and vincristine [97]. Bladder SmCC responds to the same chemotherapy regimens used in pulmonary SmCC, and some patients have durable complete remissions. The overall 5-year survival ranges from 8–40%[100].

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