Biological Markers in the Diagnosis of Recurrent Bladder Cancer

Abstract and Introduction

Over the last years, many biological markers emerged that act as an adjunct for the detection of early bladder cancer recurrence. Some of these markers had a proven better sensitivity and specificity for cancer detection than urine cytology. Nevertheless, the majority of these biological makers are still in advanced stages of clinical trials and are not used for routine clinical purposes. In this article, we give an overview on the biological markers that can play a role in early bladder cancer detection and can perhaps subsequently reduce the need for frequent cystoscopies.

Bladder cancer is the second most common genitourinary malignancy after prostate cancer. It is the fourth most prevalent cancer in males and the eighth most prevalent cancer in females, accounting for 6 and 2% of the newly diagnosed malignancies in males and females, respectively.^[1]

Bladder cancer is usually stratified into two broad categories: papillary superficial and solid invasive tumors. Superficial tumors are the most frequent of all newly diagnosed bladder cancers, comprising 75%. This type is often diagnosed in an early and noninvasive stage (stage Ta), with mild forms of cellular dysplasia (low grade). Progression to muscle-invasive disease occurs in less than 5% of patients with Ta and up to 50% of patients with T1 bladder cancer.^[2]

Solid tumors are often of high grade and usually diagnosed in an invasive stage (T1 or worse). In more than half of the cases, muscle invasion is diagnosed upon presentation (stage T2 or worse). They are believed to arise from flat, highly dysplastic but noninvasive lesions called carcinoma in situ (CIS; stage Tis). However, CIS is associated with minimal symptoms and consequently it is seldom diagnosed as the primary lesion (only 10% of cases). Concomitant CIS is more common, and may be found in up to 40% of stage T1 cancers and in 50% of the muscle invasive stages. The 5-year survival of patients is less than 50% for muscle-invasive disease and 10% for metastatic disease.^[3]

In the WHO 2004 classification, urothelial lesions are described as the following ^[4]:

Normal urothelium
Hyperplasia
- Flat hyperplasia
- Papillary hyperplasia
Flat lesions with atypia
- Reactive (inflammatory) atypia
- Dysplasia
- CIS
Papillary neoplasms
- Papilloma
- Papillary urothelial neoplasms of low malignant potential
- Papillary carcinoma (low grade)
- Papillary carcinoma (high grade)

Bladder cancers are histologically graded into ^[5]:

Grade I: Well-differentiated tumors
Grade II: Moderately differentiated tumor
Grade III: Poorly differentiated tumors

Occupational exposure to certain chemicals (β-naphthylamines, xenylamine, 4-nirtobiphenyl and benzidine) that are found in the textile, leather and rubber industry and smoking are among the most common risk factors for bladder cancer. Other risk factors include pelvic irradiation, chronic cystitis (including biharziasis) and cyclophosphamide therapy.^[6]

Genetic factors may play a role in the pathogenesis of bladder cancer. Superficial bladder cancer has at least two discrete pathways for development and progression, which may explain the differences in the invasive and metastatic potential of the disease. Constitutive activation of the receptor tyrosine kinase (RTK)–Ras pathway and deletion of chromosome 9 are mainly responsible for early development of papillary Ta superficial bladder cancer. The former category includes mutation of fibroblast growth factor receptor-3 (FGFR3), found in 60–70%, and HRAS, in 30–40% of the disease.^[3]

The main clinical presentation of bladder cancer is hematuria (>80% of patients). It is usually macroscopic and painless. It could occasionally present as asymptomatic microscopic hematuria or lower urinary tract symptoms (such as frequency, urgency and dysuria). In less than 10% of cases, the disease is diagnosed incidentally on routine radiological examination.^[6] The mainstay of diagnosis is the identification malignant cells in urine specimens and direct visualization of the bladder mucosa with cystoscopy and resection of the tumor if identified.

Bladder cancer is characterized by the high rates of recurrence (50–80%). The 3-year recurrence-free survival rate is higher in Ta disease than in T1 disease (50 vs 30%). The rates are also affected by tumor grade, with 50% in G1 disease, 40% in G2, and 20% in G3. The pathological stage affects the progression rate of disease to the muscle layer. In Ta disease, the 3-year progression-free survival rate is 96%, whereas survival decreased to 70% in T1 disease. The rate of G3 disease (55%) is different from that of G1 (100%) and G2 (89%) disease. Thus, the pathological stage and grade are factors predictive of recurrence and progression in short- or intermediate-term follow-up of superficial bladder cancer. Tumor size, multiplicity, CIS and tumor stage and grade are listed as clinical and pathological factors affecting recurrence and progression of the disease.^[7]

Strict surveillance of patients with bladder cancer is essential to detect early recurrence. Surveillance is usually by urine cytology and cystoscopy. The frequency of check cystoscopies vary according to the stage and grade of the tumor.^[8] Patients with low-risk cancers (TaG1) should have their first cystoscopy at 3 months. If negative, then the next cystoscopy is advised at 9 months and yearly afterwards for 5 years. High-risk patients should have a check cystoscopy every 3 months for the first 2 years, then every 4 months in the third year. Later on, they are checked every 6 months for the following 2 years, and yearly afterwards. Yearly imaging using intravenous urogram or computed tomography scan is recommended.^[9]

This vigilant surveillance makes bladder cancer the most expensive in terms of terms of follow-up and treatment of complications. Annual direct costs of treating bladder cancer in the USA alone are estimated at approximately $4 billion, and the cost from diagnosis with bladder cancer to death is estimated to be $96000–187000 per patient.^[10,11]

Urine cytology is regarded as the gold standard noninvasive method for diagnosing bladder cancer. It has been used either as a voided or bladder-washout specimen as an adjunct to bladder cancer surveillance. Urine cytology is a sensitive test for the detection of recurrence of high-grade, superficial and muscle-invasive bladder cancer. However, it has low sensitivity (30%) for low-grade tumors. It also requires an experienced cytopathologists for interpretion of the results. Therefore, it is of limited use as a reliable means of diagnosing low-grade bladder cancer recurrence. In addition, false-positive results could be produced in patients receiving intravesical chemotherapy.^[12]

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