The distinction between CDC and UUC is critical for proper management but can represent a diagnostic challenge given the morphologic and immunohistochemical overlapping features between the 2 lesions. Both UUC and CDC are highly infiltrative carcinomas that induce strong desmoplastic host reaction and involve the renal medullary region occasionally colonizing preexisting collecting ducts. Furthermore, UUC may show foci of tubular differentiation whereas CDC can display occasional areas of urothelial-like morphology. Prior studies, addressed the use of immunohistochemical stains in resolving the differential diagnosis of CDC versus UUC in a high-grade renal sinus carcinoma.8,14
The WHO criteria list HMWCK and Ulex europeaus1
positivity as supportive evidence of CDC diagnosis. However, more recent studies illustrated the nonspecificity of these markers9
emphasizing the need to explore the role of additional markers in such setting.
PAX genes are regulators of tissue development and cellular differentiation, acting to promote cell survival, cell migration, and lineage specification. PAX8 is one member of the PAX gene family of transcription factors that is crucial for lineage commitment in thyroid, Mullerian duct, and metanephron.10
PAX8 is faithfully expressed by normal collecting ducts and differentiating nephrons.13
This study is the first to report on the expression of PAX8 in a large series of CDC. As expected, all 21 analyzed CDCs expressed PAX8 whereas 91% of examined UUC were negative for the marker (100% sensitivity and 93.9% specificity). In a separate study (results not shown),1
we have recently expanded our evaluation of PAX8 expression in urothelial neoplasms and found 95% of over 200 examined tumors to be negative for the marker regardless of stage. PAX8 expression was also lacking in normal urothelium of the renal pelvis. Our finding of lack of PAX8 expression in UUC is in agreement with the recent study by Tong et al16
who also showed absence of PAX8 expression in 76% of their 17 UUC tumors. Kobayashi et al9
doubted a role for immunohistochemical analysis in the differential diagnosis of CDC and UUC citing probable histologic continuity and similarities between the renal pelvic urothelium and its transition to collecting duct epithelia. Specifically, Kobayashi et al documented the lack of utility of Ulex europaeus
and HMWCK in this setting having found the former to be expressed universally by both CDC and UUC whereas the latter was positive in all tested UUC but also positive in almost one third of tested CDC. Our finding of universal PAX8 expression in CDC and its lack of expression in most UUC argues against the previously suggested common embryologic origin for the 2 types of neoplasms. PAX8 expression is largely limited to the urethric bud lineage-related tissue of mesodermal origin from which the collecting system develops from. The urothelium, in contrast, arises from the urogenital sinus of endodermal origin.2
In this regard, our PAX8 inverse profile between CDC and UUC is in keeping with different embryologic origins for these 2 types of tumors and thus may support a non-urothelial lineage for CDC.
The diagnostic utility of p63 expression in urothelial carcinoma of the bladder is well established.6
Likewise, p63 expression has been previously documented in majority of UUC.11
Our p63 findings in UUC are in agreement with these prior studies.
Using each marker individually achieved a very high sensitivity for CDC (PAX8: 100%) and UUC (p63: 97%) but a less than optimal specificity. In contrast, using the 2 markers in combination in a given unknown tumor increased the specificity of achieving the correct diagnosis to 100% resulting in a positive predictive value of 1.0. However, this gain in specificity was on the account of a decrease in the sensitivity of PAX8 alone from 100% to 85.7% in CDC and the sensitivity of p63 alone from 97% to 88.2% in UUC. The distinction between CDC and UUC was not possible based on immunohistochemistry alone only in the rare scenario of PAX8+/p63+ profile. The latter profile occurred only in 6 of 55 (11%) cases.
Needle biopsy technique is increasingly used in the diagnosis of renal masses identified on imaging modalities. Achieving the correct preoperative diagnosis is crucial in tumors that are amenable to nephron sparing surgery or ablation.7
Our finding of a strong correlation of PAX8 and p63 expressions between TMA sections (spot sampling) and routine sections is reassuring and support the potential reliability of the PAX8/p63 use on needle biopsies for diagnostic purposes. Validation of our current findings in a needle-biopsy cohort of CDC and UUC would further confirm such utilization. The role of PAX8/p63 combination in differentiating CDC from renal tumors other than UUC (eg, renal medullary carcinoma) needs to be explored.
In summary, the combined use of PAX8 and p63 markers can reliably distinguish CDC from UUC tumors. A profile of PAX8+/p63− strongly favors a diagnosis of CDC, whereas a profile of PAX8−/p63+ favors UUC.