High prevalence of TERT promoter mutations in micropapillary urothelial carcinoma

Abstract

Somatic activating mutations in the promoter of the telomerase reverse transcriptase (TERT) gene are the most common genetic alterations in urothelial carcinoma (UC) of the bladder and upper urinary tract. Little is known, however, about TERT-mutation status in the relatively uncommon but clinically aggressive micropapillary (MPC) variant. We evaluated the presence of TERT promoter mutations in MPC of the bladder and upper urinary tract. A retrospective search of our archives for MPC and UC with micropapillary features (2005-2014) was performed. All slides were reviewed to confirm the histologic diagnosis. Thirty-three specimens from 31 patients had FFPE blocks available for DNA analysis and were included in the study. Intratumoral areas of non-micropapillary histology were also evaluated when present. Samples were analyzed with Safe-SeqS, a sequencing error reduction technology, and sequenced using the Illumina MiSeq platform. TERT promoter mutations were detected in all specimens with pure MPC (18 of 18) and UC with focal micropapillary features (15 of 15). Similar to conventional UC, the predominant mutations identified occurred at positions -124 (C228T) (85 %) and -146 (C250T) (12 %) bp upstream of the TERT ATG start site. In heterogeneous tumors with focal variant histology, intratumoral concordant mutations were found in variant (MPC and non-MPC) and corresponding conventional UC. We found TERT promoter mutations, commonly found in conventional UC, to be frequently present in MPC. Our finding of concordant intratumoral mutational alterations in cases with focal variant histology lends support to the common oncogenesis origin of UC and its variant histology.

Keywords: Micropapillary; Mutation; TERT; Telomerase reverse transcriptase; Urothelial carcinoma.

Figure 1

Two mutational “hotspots” that are repeatedly seen in the TERT promoter occur at position 250 and position 228. Both of the mutations are a C > T base substitution mutations.

Fig. 2

(H&E, 10X) Invasive urothelial carcinoma with glandular differentiation (a) and separate focus of noninvasive micropapillary carcinoma showing typical tufts of urothelial cells lacking fibrovascular cores (b) in the same patient sample. (H&E, 20X) Invasive micropapillary carcinoma composed of multiple uniformly sized nests of urothelial cells occupying stromal spaces (c, d). (H&E, 20X) Invasive urothelial carcinoma with micropapillary features composed of irregularly sized nests of urothelial cells (>4 cells across in the most narrow focus) occupying stromal spaces (e, f). The type of TERT promoter mutation corresponding to each of the represented tumors is shown. Note the identical type of mutation shared by areas represented in a and b of the same patient.