Markers for Urological Malignancies
Table 1: Additional Investigational Biomarkers for Bladder Cancer Marker
Research Findings Lewis X antigen Survivin Cytokeratins (CK)
Immunocytological testing of urine yielded better sensibility than cytology, NMP-22 and BTA Stat for detection of both low- and high-grade BCa.
Urinary level outscored cytology and NMP22 for the diagnosis of BCa. A limitation is that a significant urinary amount is contributed by normal prostate. Promising accuracy reported for urinary fragment of CK19 (CYFRA 21-1 immunoassay).
Tumour expression of CK20 correlated with higher grade, recurrence and progression. Urinary CK20 mRNA detected cancer with high accuracy. CKs lack specificity.
Soluble Fas (sFas) and Circulating levels are an independent predictor of BCa recurrence and invasiveness in patients with a history 64,65
soluble Fas ligand (sFasL) of non-muscle-invasive BCa. Caspase 3 Bcl-2
P53
FGFR3 EGFR
CD44 BLCA-4 NMP52
E-cadherin Ki-67
DD23
Association between increased tumour expression and adverse pathological features and poor prognosis. Overexpressed in patients with muscle-invasive BCa, with disease recurrence or lower response rates to chemotherapy.
Mutations and accumulation in cell nuclei observed in tumour tissue and urine associated with tumour grade, stage, size, recurrence, progression and survival.
Lack of definitive evidence and low sensitivity of immunostaining of cells in voided urine. Urine FGFR3 mutation assay is a significant indicator of recurrence. Tumour expression predictive of progression and survival.
Immunopositivity in urine ThinPrep specimens correlated to disease stage. Frozen section immunostaining is required.
Elevated CD44v8-10- to -standard CD44 ratio in urinary exfoliated cells may serve as a novel prognostic predictor 76 and indicator of disease extent.
Urinary BLCA-4 indicated as a BCa-specific marker candidate for BCa screening, with better accuracy than NMP-22.
Urinary NMP-52 showed satisfying sensitivity and specificity for squamous cell carcinoma, transitional cell carcinoma and adenocarcinoma.
Decreased tissue and urinary level and increased serum level associated with recurrence and progression. Increased expression is related to tumour grade and stage, recurrence, progression and survival, and it is an independent prognostic indicator.
Urinary Ki-67 RNA distinguishes low-grade from high-grade tumours.
Immunocytological urinary assay advocated as an adjunct to enhance the sensitivity of urinary cytology. High sensibility for both low-grade and high-grade tumours, but low specificity.
83,84
BCa = bladder cancer; BLCA-4 = bladder-cancer-specific nuclear matrix protein; BTA = bladder tumor antigen; CK20 = cytokeratin 20; FGFR3 = fibroblast growth factor receptor 3; mRNA = messenger RNA; NMP-22 = nuclear matrix protein 22.
NMP-22 ELISA ranged from 47 to 100% and 60 to 80%, respectively.18,19 A 49.5% sensitivity and a 87.3% specificity have been reported for the detection of recurrent BCa with BladderChek.20
Although NMP-22
seems to be an easy-to-perform and quite inexpensive test of potential clinical relevance, especially when combined with cystoscopy,20 specificity issues arise when using the marker in the setting of patients without a diagnosis of previous BCa or with haematuria, urinary tract inflammations and other urological malignancies.21,22
Hyaluronic Acid and Hyaluronidase
Hyaluronic acid is a glycosaminoglycan involved in cellular adhesion, migration, replication and angiogenesis. BCa cells can induce the production of hyaluronic acid by fibroblasts.23
Increased hyaluronic acid
levels have been found in the urine of BCa patients, with higher positivity rates in low-grade than in high-grade tumours.24,25
Hyaluronic
The combination of hyaluronidases with hyaluronic acid would increase sensitivity while maintaining high specificity,28
although
some drawbacks are still to be resolved with further refinement of the assay technique and evaluation in larger clinical trials.29
EUROPEAN UROLOGICAL REVIEW
acid levels were correlated with invasive potential, and smaller angiogenetic fragments were present in higher-grade disease.24 Hyaluronidases are endoglycosidases that cleave hyaluronic acid, and their secretion by BCa cells correlates with invasive potential.26 Reportedly, the sensitivity and specificity of urinary concentration of hyaluronidase were high in high-grade disease (100 and 89%, respectively).27
Matrix Metalloproteinases
Matrix metalloproteinase 9 (MMP-9) is increased in the urine of patients with advanced BCa.30
Patients with non-muscle-invasive
and muscle-invasive BCa also had increased urinary levels of MMP-2 and MMP-9.31
By applying their novel non-invasive urine assay
(Clinical Intervention Determining Diagnostic [CIDD]) for MMP-9, Fernandez et al. correctly identified 42% of cases that were cystoscopy-negative with a 98% negative predictive value.32
MMP-9
tissue expression in BCa was also found to be associated with better prognosis.33
Thus, the assay may help in the follow-up of BCa patients, identifying those at higher risk of recurrence and needing cystoscopy.
Fibrin/Fibrinogen Degradation Products
Fibrin/fibrinogen degradation products (FDPs) are derived from the increased leakage of plasma proteins in tumour tissue where microvasculature permeability is increased. The ACCU-Dx® (Intracel, Inc., Rockville, Maryland) immunoassay for qualitative determination of FDPs demonstrated a sensitivity of 68 and a specificity of 86.2%.34
However, false-positive results are possible in
patients with haematuria. Growth Factors
Epidermal growth factor (EGF), a potent mitogen and tumour promoter, has been found at decreased levels in the urine of BCa patients and has been proposed as potential marker of tumour
37 29,77,78 79 80 81,82
66 67
68–70 71 72–75
References 54–56
57–59 60–63
Page 1 |
Page 2 |
Page 3 |
Page 4 |
Page 5 |
Page 6 |
Page 7 |
Page 8 |
Page 9 |
Page 10 |
Page 11 |
Page 12 |
Page 13 |
Page 14 |
Page 15 |
Page 16 |
Page 17 |
Page 18 |
Page 19 |
Page 20 |
Page 21 |
Page 22 |
Page 23 |
Page 24 |
Page 25 |
Page 26 |
Page 27 |
Page 28 |
Page 29 |
Page 30 |
Page 31 |
Page 32 |
Page 33 |
Page 34 |
Page 35 |
Page 36 |
Page 37 |
Page 38 |
Page 39 |
Page 40 |
Page 41 |
Page 42 |
Page 43 |
Page 44 |
Page 45 |
Page 46 |
Page 47 |
Page 48 |
Page 49 |
Page 50 |
Page 51 |
Page 52 |
Page 53 |
Page 54 |
Page 55 |
Page 56 |
Page 57 |
Page 58 |
Page 59 |
Page 60 |
Page 61 |
Page 62 |
Page 63 |
Page 64 |
Page 65 |
Page 66 |
Page 67 |
Page 68 |
Page 69 |
Page 70 |
Page 71 |
Page 72 |
Page 73 |
Page 74 |
Page 75 |
Page 76 |
Page 77 |
Page 78 |
Page 79 |
Page 80 |
Page 81 |
Page 82 |
Page 83 |
Page 84