Immunohistochemiocal subtyping using CK20 and CK5 can identify urothelial carcinomas of the upper urinary tract with a poor prognosis

Abstract

PurposeGenome-wide analyses revealed basal and luminal subtypes of urothelial carcinomas of the bladder. It is unknown if this subtyping can also be applied to upper tract urothelial carcinomas.Materials and methodsTumor samples from 222 patients with upper tract urothelial carcinomas who were treated with radical nephroureterectomy were analyzed for the expression of seven basal/luminal immunohistochemical markers (CK5, EGFR, CD44, CK20, p63, GATA3, FOXA1).ResultsHierarchical clustering revealed a basal-like subtype (enrichment of CK5, EGFR and CD44) in 23.9% and a luminal-like subtype (enrichment of CK20, GATA3, p63 and FOXA1) in 13.1% of the patients. In 60.8%, little to no markers were expressed, whereas markers of both subtypes were expressed in 2.2%. By using CK5 and CK20 as surrogate markers for the basal and luminal subtypes, we defined four subtypes of upper tract urothelial carcinomas: (i) exclusively CK20 positive and CK5 negative (CK20+/CK5-), (ii) exclusively CK5 positive and CK20 negative (CK20-/ CK5+), (iii) both markers positive (CK20+/CK5+) and (iv) both markers negative (CK20-/CK5-). A receiver-operator analysis provided the optimal cut-off values for this discrimination. An immunoreactive score >1 for CK5 and >6 for CK20 were defined as positive. In multivariate Cox’s regression analysis, the CK20+/CK5- subtype was an independent negative prognostic marker with a 3.83-fold increased risk of cancer-specific death (p = 0.02) compared to the other three subtypes.ConclusionsImmunohistochemical subgrouping of upper tract urothelial carcinomas by analyzing CK5 and CK20 expression can be performed in a routine setting and can identify tumors with a significantly worse cancer-specific survival prognosis.

Immunohistochemistry of cytokeratin (CK) 5/6, CD44 and CK20 as prognostic biomarkers of non‐muscle‐invasive papillary upper tract urothelial carcinoma

“…UTUC was found to share similar genetic expression profiles and genetic alterations with urinary bladder urothelial carcinoma, especially in non‐muscle‐invasive tumours . By extrapolation of IHC biomarkers related to the molecular subtypes of MIBC, UTUC can be clustered into basal‐like and luminal‐like subtypes . When IHC staining for only CK5 and CK20 was employed, the CK5‐negative/CK20‐positive luminal‐like subtype was an independent prognostic factor for CSS in UTUC .…”

“…As basal IHC markers, we applied the same cut‐off used for CK5/6 to CD44. As for CK20, the cut‐off value of 1% discriminated patients’ progression better than the other values tested (10%, 20%, and 50%) . In the following sections, the results of positive, negative and normal pattern are simplified, for example, as CK5/6‐positive, CD44‐negative, and CK20‐normal, respectively.…”

“…Luminal‐type MIBC, which is a subtype with favourable clinical outcomes, expresses CK20, GATA3, and FOXA1, similarly to urothelial umbrella cells, possibly reflecting its differentiated phenotype . However, the prognostic significance of IHC biomarkers of molecular subtypes has not been thoroughly evaluated in UTUC …”

“…Sikic et al . risk‐stratified UTUC into subgroups by using CK5 and CK20, which are prognostic in MIBC.…”

“…6,17 However, the prognostic significance of IHC biomarkers of molecular subtypes has not been thoroughly evaluated in UTUC. [18][19][20][21] Sikic et al 21 risk-stratified UTUC into subgroups by using CK5 and CK20, which are prognostic in MIBC. However, the prognosis of UTUC subgroups was in opposition to what has been demonstrated in MIBC; UTUC showing both CK5 negativity and CK20 positivity was associated with a poor prognosis.…”