Nested Variant of Urothelial Carcinoma Is a Luminal Bladder Tumor With Distinct Coexpression of the Basal Marker Cytokeratin 5/6

Abstract

Objectives The nested variant of urothelial carcinoma (NVUC) is a rare bladder tumor that may possess a luminal molecular phenotype. We sought to determine whether a small immunohistochemical (IHC) panel using common surrogates for molecular phenotypes would reliably classify a cohort of pure NVUC cases. Methods IHC staining with a panel composed of markers for basal subtypes (CK5/6, CK14) and luminal subtypes (FOXA1, GATA3) was performed on pure small NVUC cases (n = 23) and 5 large NVUC cases (n = 5). Scoring of IHC stains was performed semiquantitatively. Individual cases were analyzed using previously reported IHC-based surrogates for molecular subtype. Results The phenotype of NVUC was classified as luminal from 60.1% (FOXA1+/CK5/6−) to 100% (GATA3+/CK14−) of cases using composite phenotypes. No cases possessed a basal or squamous cell carcinoma–like phenotype. The majority of small NVUC cases (69.5%) showed subset CK5/6 expression distinctly localized to the basal layers of tumor cell nests. Intratumoral heterogeneity was also noted in CK5/6 (21.7% of small NVUC cases) but no other markers. Conclusions NVUC appears to express markers of both basal and luminal bladder tumors. Definitive gene expression profiling may be valuable to further characterize this unique histologic variant.

Are We Ready to Implement Molecular Subtyping of Bladder Cancer in Clinical Practice? Part 2: Subtypes and Divergent Differentiation

“…Divergent Differentiation/Histological Subtype IHC-Based Molecular Cluster [13,22,25,26,48,101] Squamous Mostly basal [22,25,27,35,102] Glandular Variable [13,32,67,101,[103][104][105] Micropapillary Mostly luminal (LumNS) [13,68,[106][107][108][109] Nested and large nested Mostly luminal (LumP) [27,29,69,101,107,110] Plasmacytoid Mostly luminal [23,26,29,32,34] Sarcomatoid Variable…”

“…Recently, Johnson et al reported on the co-expression of luminal (FOXA1, GATA3) and basal (CK5/6) markers in a cohort of NCs, the latter displaying marked heterogeneity in a subset of cases [109], in keeping with the results from the study by Warrick et al [102], consisting with the Uro subtype according to the Lund classification [23,101]. Tumors belonging to this subtype share with NCs some histological features, such as a smooth tumor-stroma interface and nuclear monomorphism, as seen in pure NCs [22].…”

The Genitourinary Pathology Society Update on Classification of Variant Histologies, T1 Substaging, Molecular Taxonomy, and Immunotherapy and PD-L1 Testing Implications of Urothelial Cancers

“…The low Ki67 proliferation rate in nested carcinoma renders this immunostain less useful 12,14. TERT promoter mutations occur in the majority of nested UC cases but not benign mimickers 16–19. Nested UCs express PAX8, which may represent a diagnostic pitfall vis a vis nephrogenic adenoma in cases with microcystic components20,21 Nested UCs appear to express luminal markers more frequently than basal markers and harbor an exceptionally low frequency of FGFR3 mutations (<5%), likely limiting the usefulness of treatments that target FGFR3 -mutated cancers 13,19.…”

“…12,14 TERT promoter mutations occur in the majority of nested UC cases but not benign mimickers. [16][17][18][19] Nested UCs express PAX8, which may represent a diagnostic pitfall vis a vis nephrogenic adenoma in cases with microcystic components 20,21 Nested UCs appear to express luminal markers more frequently than basal markers and harbor an exceptionally low frequency of FGFR3 mutations (< 5%), likely limiting the usefulness of treatments that target FGFR3-mutated cancers. 13,19 From a practical viewpoint, the correct diagnosis in most settings requires careful histologic examination; the value of ancillary studies is fairly limited.…”

Molecular Subtypes of Bladder Cancer: Component Signatures and Potential Value in Clinical Decision-making

“…19,37 Micropapillary, plasmacytoid, nested, and large nested subtypes typically have a luminal expression subtype. 33,[38][39][40][41][42][43] Invasive carcinoma with divergent differentiation may differ in molecular subtype from invasive urothelial carcinoma NOS, or other histomorphologies, present in spatially distinct parts of the same tumor. 21,33,36,38,[44][45][46][47] This is best studied in urothelial carcinoma with squamous differentiation.…”