Table of Contents  
REVIEW ARTICLE
Year : 2020  |  Volume : 32  |  Issue : 2  |  Page : 84-88

Use of carbohydrate antigen 19-9 in the management of bladder cancer


1 Department of Urology, North Devon Hospital NHS Trust, Barnstaple, UK
2 Princess Alexandra Hospital NHS Trust, Harlow, UK

Date of Submission19-Feb-2020
Date of Decision08-Mar-2020
Date of Acceptance03-Apr-2020
Date of Web Publication30-Nov-2020

Correspondence Address:
Muhammad Faisal Khan
North Devon Hospital NHS Trust, Raleigh Park, Barnstaple EX31, 4JB
UK
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/HUAJ.HUAJ_5_20

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  Abstract 


Over the years, a distant effort has been made to find new prognostic biomarkers in the assessment of accurate response to treatment and detection of recurrences of bladder cancer. Among them, the carbohydrate-rich glycoprotein, Carbohydrate Antigen (CA) 19-9 has shown some usefulness as it is linked with the tumour aggressiveness and the prognosis of disease. Aim of this study is to review available evidence about the role of CA 19-9 in diagnosis, staging and prognosis of bladder cancer. After careful review of the related articles, a total of 16 useful and valued studies were found on the database. These studies evaluated relation of CA 19-9 to various different aspects of bladder cancer. These aspects include use of CA 19-9 as a tool for detection of bladder cancer, its role in the assessment of the prognosis at diagnosis and also looked at the significance of the CA 19-9 in the response to treatment of bladder cancer. These studies indicate that CA19-9 sensitivity and specificity was 71.6 and 91.6 in high-grade tumour and sensitivity of 74% and 83% in Ta and T1 tumours. Serum levels of > 29 U/ml are associated with shorter survival time and carried a 2.54 higher risk of death. High levels in metastatic disease are associated with increase response to chemotherapy. Although these results are encouraging, but due to the limited evidence, there can be no strong recommendation for use of the biomarker CA 19-9 and further studies are needed to establish a useful link.

Keywords: Bladder cancer, carbohydrate antigen 19-9, systematic review


How to cite this article:
Khan MF, Tsampoukas G. Use of carbohydrate antigen 19-9 in the management of bladder cancer. Hellenic Urology 2020;32:84-8

How to cite this URL:
Khan MF, Tsampoukas G. Use of carbohydrate antigen 19-9 in the management of bladder cancer. Hellenic Urology [serial online] 2020 [cited 2021 Jan 28];32:84-8. Available from: http://www.hellenicurologyjournal.com/text.asp?2020/32/2/84/301822




  Introduction Top


Bladder cancer (BC) is the 11th most common cancer in the general population of Europe, with worldwide age-standardized mortality rate estimate of 3.2 for men and 0.9 for women, respectively.[1] Smoking tobacco, increased age, and industrial chemical exposure are all considered major risk factors for the development of this disease.[2] Among patients diagnosed with BC, approximately two-thirds present with non-invasive tumors (carcinoma in situ, state Ta-T1). The rest of patients present with T2-T4 tumors and are exposed to a higher risk of cancer-specific mortality.[3]

Radical cystectomy (RC) accompanied with neoadjuvant chemotherapy (NAC) is considered the best option for definitive treatment, although bladder-sparing approaches may also offer comparable results.[4] Ultimately, almost half of the patients after RC present with localized recurrences and distant metastases, impoverishing dramatically the prognosis of patients with BC.[3] In this regard, over the years, a distant effort by researchers has been made to provide new prognostic biomarkers in the assessment of accurate response to treatment and prompt detection of recurrences.

Among several markers, the carbohydrate-rich glycoprotein, carbohydrate antigen (CA) 19-9, has shown some usefulness as it is linked with the tumor aggressiveness and the prognosis of the disease.[5],[6] Moreover, other authors concluded that this marker might predict the effect of treatments in patients with advanced urothelial carcinoma.[7] In this study, we revisited the literature reviewing the possible role of CA 19-9 in the management of BC.


  Materials and Methods Top


The systematic review was performed according to the Cochrane reviews guidelines and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We searched PubMed, Embase, and Cochrane Library from inception to August 2019, and all English-language articles were included in the original search. The search terms included “Bladder cancer,” “Urothelial cancer,” “Carbohydrate antigen 19-9,” and “CA 19-9.” Boolean operators (AND, OR) were used with the above search terms to refine the search.

We included all studies of patients with BC, with CA 19-9 measurements. We also looked into available case series of nonurothelial malignancies such as colorectal malignancy and benign urological diseases where CA 19-9 was measured.


  Results Top


Literature search and included studies

After an initial search, 16 articles (2016 patients) met the inclusion criteria for the final review with the first paper published in 1996. We also reviewed twelve other studies including case series, to explain the established role of CA 19-9 in other conditions.

Patient characteristics

There were 2016 patients with a median age of 69 years. All patients had a diagnosis of BC and CA 19-9 level reported [Table 1].
Table 1: Patients Characteristics in studies analyzed for systematic review

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Established clinical role of carbohydrate antigen 19-9

CA 19-9 is a monosialoganglioside attached to sialylated Lewis A blood group antigen and circulates in serum with a half-life of approximately 14 h. This glycoprotein is produced by pancreatic and biliary epithelium and secreted by gastric, colonic, endometrial, and salivary epithelia.[8] Since the marker is considered tumor-associated rather than tumor-specific, increased blood levels of CA 19-9 should be interpreted wisely. Cholangitis and other benign diseases such as cholestasis may also increase the blood levels of the marker and makes it difficult to differentiate between malignant and benign conditions. This is important for gastroenterology cases as only those patients with a suspicious pancreatic mass and increased blood levels of CA 19-9 should be considered as having a pancreatic adenocarcinoma and treated so.[8] In case where a diagnosis of pancreatic carcinomas has been established, preoperative CA 19-9 levels can add useful information regarding staging and prognosis, whereas normalization or a decline of serum CA 19-9 after treatment is linked with better response and improved survival.[9] As far as the urinary tract is concerned, cancer cells of conventional transitional cell carcinoma or mixed with other infrequent subtypes have been reported as a bed for expression of CA 19-9 in their surface.[10],[11],[12],[13] Therefore, several studies have been conducted searching for the possible role of the biomarker in the diagnosis and the assessment of the severity of the disease.

Use of carbohydrate antigen 19-9 as a tool for the detection of bladder cancer

About three decades ago, Tizzani et al. investigated the diagnostic role of three tumor markers, including CA 19-9, by measuring their urinary levels in patients with BC.[14] The authors observed that CA 19-9 urinary levels were high in patients with urothelial cancer. The other important observation was that the levels were higher in high-grade tumors as compared to low-grade tumors. In general, the marker offered adequate sensitivity and specificity of 71.6% and 91.6%, respectively.[14] Similarly, Casetta et al. have reported that the combination of CA 19-9 with tissue polypeptide antigen demonstrated a sensitivity of 74% and 83% in Ta and T1 tumors, respectively, and 62% in well-differentiated tumors.[6] In another study, Vestergaard et al. observed that urinary levels of CA 19-9 were significantly higher in patients with BC than healthy individuals, whereas the highest levels were observed in cases of concomitant dysplasia of the urothelium. However, the authors raised the concern about the complexity of the synthesis of CA 19-9 and pointed out those results may vary according to genetic differences among individuals.[15] Nagao et al. observed that urinary levels of the biomarker CA19-9 achieved a similar detection rate of high-grade bladder tumors when compared to urinary cytology. The Marker also showed some encouraging results in detecting low-grade bladder cancers.[16] The latter capacity of the marker was also highlighted from Pal et al., who observed that urinary CA 19-9 levels could predict low-grade tumors more efficiently than urinary cytology and was not affected by the presence of hemoglobin.[17] Likewise, Roy et al. reported that increased urinary levels of the biomarkers indicated the presence of the low-grade carcinoma of the bladder, drawing attention to the superiority of CA 19-9 in comparison to urinary cytology in the same patients.[18] Finally, in a delicate, experimental study, Escorcia et al. used a CA19.9-specific antibody-based construct for positron emission tomography for the detection of urothelial cancer in the bladder of mice and reported remarkably promising results.[19]

Role of carbohydrate antigen 19-9 in the assessment of the prognosis at diagnosis

Commonly reported by most studies, the level of the CA 19-9 is associated with the advanced stage and bulkiness of the tumor, which proportionally is associated with the prognosis of the condition. Sashide et al. concluded that CA 19-9 was strongly associated with the high stage, tumor bulk, poor prognosis, and reduced survival at the time of the diagnosis.[5] Furthermore, Casetta et al. reported that pre-operative, urinary levels of CA 19-9 >300 U/ml in patients with infiltrating disease were strongly associated with poor prognosis.[6] Furthermore, Margel et al. observed that patients with clinically organ confined disease (cT2 or less N0) and high precystectomy levels of CA 19-9 had poor prognosis, highlighting the role of the biomarker as a possible independent predictor of disease specific mortality.[20] For the aforementioned, the same authors included CA 19-9 as an individual parameter in a nomogram for the prediction of nonconfined disease before cystectomy, in an effort to achieve a more accurate estimation of pathologic stage.[21] Furthermore, in another prospective study, the role of CA 19-9 as an independent prognostic factor of mortality in patients with BC was highlighted by the authors; patients with known BC and increased serum levels (>29 U/ml) experienced significantly shorter survival time and carried a 2.54 higher risk of death.[22]

Significance of the carbohydrate antigen 19-9 in the response of therapy

CA 19-9 may carry a significant role in making an accurate assessment to check the response of treatment. The normalization of serum levels of the biomarker is associated with success of treatment, whereas the fluctuation of serum levels of CA 19-9 indicates recurrence.[23] In a notable, recent study, Bazargani et al. reported that patients who had the biomarker normalized after NAC enjoyed a significant longer time to recurrence or progression and overall longer survival, whereas at the same time, the pathological stage did not differ between responders and non-responders.[24] In the framework of advanced disease, persistence or elevation of the marker indicated poor response in patients who either received NAC or chemotherapy due to metastatic disease of BC.[25] Moreover, in terms of advanced BC, CA 19-9 has also been used as part of a panel of biomarkers for the response in chemotherapy and data by Cook et al. showed that clinical response was accompanied with a response of at least one marker. If tumour markers show response to chemotherapy, it occurs very quickly in first eight weeks of treatment.[26] Finally, Yaegashi et al. reported that increased levels of serum CA 19-9 in patients with metastatic BC are associated with better response in chemotherapy, implicating that serum levels of the biomarker may act as markers of chemosensitivity.[7]


  Discussion Top


The pursuit of reliable biomarkers in the management of BC is justified due to some reasons. First of all, in the setting of the diagnostic process and follow-up of non-muscle invasive tumors, cytology remains the only recommended marker, especially for the detection of high-grade tumors, but some limitations apply. The interpretation is user dependent, it is susceptible to false-positive results, and it lacks sensitivity in low-grade tumors.[1]

On the other hand, urinary levels of CA 19-9 seem to carry some significance for the detection of low-grade tumors in comparison to cytology and the modality looks promising.[17],[18] However, it should be kept in mind that urinary levels of the biomarker may be elevated in urinary tract obstruction, which could limit its role in some patients.[27] Furthermore, what really matters in patients with non-muscle invasive tumors is the grade, as this is the factor that dictates prognosis.[3]

If the modality should be combined with cytology in order to substitute or assist or avoid unnecessary cystoscopies for the diagnosis or follow-up of BC, it could be a matter of future, prospective studies. However, no evidence exists yet that the use of the marker can be recommended. Second, another common problem in BC is clinical under staging or over staging, which is addressed to low accuracy of staging modalities (bimanual examination, computed tomography, or magnetic resonance imaging).[3]

In previous studies, Margel et al. have demonstrated that increased serum levels of CA 19-9 in patients who underwent cystectomy for localized disease (T2N0M0) were at high risk of extravesical and nodal positive disease; the patients in that setting had inevitably reduced survival.[28] Although the patients in those cohorts did not receive NAC, data implicate that the biomarkers such as CA 19-9 might bridge the gap between clinical and pathological staging, avoiding unnecessary interventions and alternate management toward the most feasible outcome. Similarly, in an aforementioned study, patients who received NAC and had their biomarkers normalized enjoyed significantly longer overall survival and lower recurrence, although the pathological stage did not differ between responders and non-responders.[24] These results should be considered significant, as far as the biomarker might provide a way to unmask patients at highest risk and alternate the management of the condition for the benefit of these patients.

Under these circumstances, CA 19-9 could play a role in BC similar to that in pancreatic carcinoma; having a limited role in diagnosis and should the diagnosis of the urothelial carcinoma has been set, serum levels can be a measure of tumor aggressiveness and help in the monitoring of the disease.[29] However, pitfalls may occur as far as tumors poorly differentiated may not express CA 19-9, indicating an unpredictably high malignant potential.[30]


  Conclusions and Main Points Top


To sum up:

  • Results from studies are encouraging, but due to the limited evidence, there can be no strong recommendation for the use of the biomarker CA 19-9 as a tool in the diagnosis and follow-up of non-muscle invasive BC
  • CA19-9 sensitivity and specificity were 71.6 and 91.6 in high-grade tumor and sensitivity of 74% and 83% in Ta and T1 tumors
  • Serum levels of >29 U/ml are associated with shorter survival time and carried a 2.54 higher risk of death
  • High levels in metastatic disease are associated with increase response to chemotherapy.


Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
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Yaegashi H, Izumi K, Kadomoto S, Naito R, Makino T, Iwamoto H, et al. High Serum CA19-9 Concentration Indicates High Chemosensitivity and Better Survival in Advanced Urothelial Carcinoma. Anticancer Res 2019;39:375-80.  Back to cited text no. 7
    
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Tsen A, Barbara M, Rosenkranz L. Dilemma of elevated CA 19-9 in biliary pathology. Pancreatology 2018;18:862-7.  Back to cited text no. 8
    
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Ballehaninna UK, Chamberlain RS. The clinical utility of serum CA 19-9 in the diagnosis, prognosis and management of pancreatic adenocarcinoma: An evidence based appraisal. J Gastrointest Oncol 2012;3:105-19.  Back to cited text no. 9
    
10.
Kuroda N, Hayashi Y, Nishida Y, Itoh H. Combined small and transitional cell carcinoma of the urinary bladder with CA19-9 production. Pathol Int 1999;49:462-7.  Back to cited text no. 10
    
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Kikuno N, Urakami S, Shigeno K, Shiina H, Igawa M. Urachal carcinoma associated with increased carbohydrate antigen 19-9 and carcinoembryonic antigen. J Urol 2001;166:604.  Back to cited text no. 11
    
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Shimada K, Nakamura M, Ishida E, Konishi N. Urothelial carcinoma with plasmacytoid variants producing both human chorionic gonadotropin and carbohydrate antigen 19-9. Urology 2006;68:891.e7-10.  Back to cited text no. 12
    
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Kato M, Onishi T, Hoshina A, Yabana T. Successful treatment with paclitaxel/carboplatin chemotherapy in advanced adenocarcinoma of the urinary tract producing carcinoembryonic antigen, carbohydrate antigen 19-9 and carbohydrate antigen 125. Urol Int 2010;84:116-8.  Back to cited text no. 13
    
14.
Tizzani A, Cassetta G, Cicigoi A, Piana P, Cerchier A, Pecchio F, et al. Tumor markers (CEA, TPA and CA 19-9) in urine of bladder cancer patients. Int J Biol Markers 1987;2:121-4.  Back to cited text no. 14
    
15.
Vestergaard EM, Wolf H, Orntoft TF. Increased concentrations of genotype-interpreted Ca 19-9 in urine of bladder cancer patients mark diffuse atypia of the urothelium. Clin Chem 1998;44:197-204.  Back to cited text no. 15
    
16.
Nagao K, Itoh Y, Fujita K, Fujime M. Evaluation of urinary CA19-9 levels in bladder cancer patients classified according to the combinations of Lewis and Secretor blood group genotypes. Int J Urol 2007;14:795-9.  Back to cited text no. 16
    
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Pal K, Roy S, Mondal SA, Chatterjee U, Tiwari P, Bera M. Urinary level of CA19-9 as a tumor marker in urothelial carcinoma of the bladder. Urol J 2011;8:203-8.  Back to cited text no. 17
    
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Escorcia FE, Steckler JM, Abdel-Atti D, Price EW, Carlin SD, Scholz WW, et al. Tumor-Specific Zr-89 Immuno-PET Imaging in a Human Bladder Cancer Model. Mol Imaging Biol 2018;20:808-15.  Back to cited text no. 19
    
20.
Margel D, Tal R, Baniel J. Serum tumor markers may predict overall and disease specific survival in patients with clinically organ confined invasive bladder cancer. J Urol. 2007;178:2297-301.  Back to cited text no. 20
    
21.
Margel D, Harel A, Yossepowitch O, Baniel J. A novel algorithm to improve pathologic stage prediction of clinically organ-confined muscle-invasive bladder cancer. Cancer 2009;115:1459-64.  Back to cited text no. 21
    
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Aybek H, Aybek Z, Sinik Z, Demir S, Sancak B, Tuncay L. Elevation of serum and urinary carbohydrate antigen 19-9 in benign hydronephrosis. Int J Urol 2006;13:1380-4.  Back to cited text no. 27
    
28.
Margel D, Tal R, Baniel J. Serum tumor markers may predict overall and disease specific survival in patients with clinically organ confined invasive bladder cancer. J Urol 2007;178:2291-7.  Back to cited text no. 28
    
29.
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