Abstract
Recently developed antibodies against uroplakin II and ΔNp63 (p40) show utility in diagnosing primary bladder urothelial carcinoma, although application in metastatic bladder cancer and patient outcomes has been less well defined. We evaluated these antibodies by immunostain intensity and H-score, in conjunction with GATA-3 immunoreactivity, in 89 patients with muscle-invasive urothelial carcinoma and 35 paired metastasis. The maintenance of immunoreactivity in metastatic lesions and the association to disease recurrence and survival was assessed. Bladder urothelial carcinoma showed immunoreactivity for GATA-3 in 99% (88/89), p40 in 87% (77/89) and uroplakin II in 80% (71/89) of cases, with a positive correlation between GATA-3 and uroplakin II H-score (0.44; p<0.0001). All lesions were positive for at least one marker, reinforcing the use of these markers as a panel. In 35 patients with paired lymph node metastasis, uroplakin II and GATA-3 were retained in 90% and 75% of patients, respectively, suggesting these markers may have relatively high sensitivity in diagnosing metastatic urothelial carcinoma. High intensity p40 immunostain (3+), however, was significantly associated with reduced patient survival (p=0.03). These results suggest that whereas GATA-3 and uroplakin II may be most useful in the diagnosis of urothelial carcinoma metastasis, p40 may be additionally suited as a prognostic marker.
Highlights
Use of immunohistochemistry (IHC) in the context of urothelial carcinoma (UCa) is primarily required in distinguishing UCa from secondary malignancies involving the urinary tract and in correctly identifying the site of origin for metastasis of unknown primary
IHC markers commonly used in the diagnosis of muscleinvasive UCa include uroplakin III (UPIII), GATA-3, thrombomodulin, p63, high-molecular weight cytokeratins and cytokeratin 7.8 UPIII shows the highest specificity of this group, but is immunoreactive in only approximately 40–50% of these cases.[9,10]
GATA-3 was present in the full thickness of the urothelium, whereas p40 was most highly expressed in the basal and intermediate cells of the urothelium (Fig. 1)
Summary
Use of immunohistochemistry (IHC) in the context of urothelial carcinoma (UCa) is primarily required in distinguishing UCa from secondary malignancies involving the urinary tract and in correctly identifying the site of origin for metastasis of unknown primary. Application of IHC markers for assessment of metastatic risk and prognosis in UCa remains limited. New antibodies targeting uroplakin II (UPII) and p40 have been developed and show high sensitivity and specificity in the diagnosis of UCa;[1,2,3,4,5,6,7] few analyses have assessed these markers in combination or in the setting of patient outcomes. IHC markers commonly used in the diagnosis of muscleinvasive UCa include uroplakin III (UPIII), GATA-3, thrombomodulin, p63, high-molecular weight cytokeratins and cytokeratin 7.8 UPIII shows the highest specificity of this group, but is immunoreactive in only approximately 40–50% of these cases.[9,10] Improved sensitivity can be achieved through a combination of IHC markers, usefulness in the diagnosis of metastatic lesions and variant morphologies tends to be less robust
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