Polyoma virus-associated carcinomas of the urologic tract: a clinicopathologic and molecular study.

In recent years, there has been increased interest in carcinomas of the urologic tract, that demonstrate association with the polyoma virus BK arising in immunosuppressed individuals, though the nature of this association is uncertain. To begin to understand this phenomenon, we reviewed the clinical, morphological, and immunohistochemical features of 11 carcinomas of the urologic tract, mainly urothelial (N = 9) and collecting duct carcinomas (N = 2), occurring during immunosuppression, and expressing polyoma virus T-antigen by immunohistochemistry. These were compared to a control group of carcinomas (N = 8), also arising during immunosuppression, but without T-antigen expression. A subset of both groups were also studied by hybrid capture-based DNA sequencing, probing not only for 479 cancer-related human genes, but also for polyoma and other viral sequences. Polyoma T-antigen-expressing tumors arose in 7 males and 4 females, at a median age of 66, and were aggressive, high-grade tumors with more than 1 variant morphologic pattern identified in 81% of cases, and a majority (73%) presenting at high stage category (>pT3). Diffuse polyoma T-antigen staining was seen in 91% of cases, with co-localization of aberrant p53 staining in 89%. Sequencing detected a lower number of deleterious mutations among T-antigen-expressing cases (average 1.62; 1/8 with TP53 mutation) compared to control cases (average 3.5, 2/4 with TP53 mutation). Only BK virus was detected with clonal integration and breakpoints randomly distributed across the human and viral genomes in 5/5 of the polyoma T-antigen-expressing carcinomas, and in none of the controls (0/4). In summary, these findings identify aggressive clinicopathologic features of polyoma T-antigen-expressing carcinomas, document BK as the strain involved, and associate BK viral integration with T-antigen expression and p53 aberrancy. While the apparent randomness of viral insertion sites is functionally unclear, the differing rates of mutations between T-antigen-expressing and control cases is intriguing.

TROP-2, 5hmC, and IDH1 Expression in Anaplastic Thyroid Carcinoma.

BACKGROUND: Anaplastic thyroid carcinoma (ATC), a highly aggressive malignancy, has no effective treatment to date. Trophoblast cell-surface antigen 2 (TROP-2), a transmembrane glycoprotein, has been suggested to be a promising novel target for sacituzumab govitecan, an antibody-drug conjugate. 5-Hydroxymethylcytosine (5hmC) has a role in tumor suppression and promoting modification. Additionally, isocitrate dehydrogenase 1 (IDH1) mutations are strongly associated with increased overall survival in gliomas and worse prognosis in leukemias. This study attempts to evaluate the immunoexpression of TROP-2, 5hmC, and IDH1 in ATCs and to determine their potential impact in targeted therapy. METHODS: Twenty-four ATCs were retrieved, with 9 cases that occurred de novo and 15 cases derived from either papillary thyroid carcinoma (PTC) or follicular thyroid carcinoma (FTC). Sections were immunostained with TROP-2, 5hmC, and IDH1 antibodies, and evaluated using the QuPath program. The t tests were performed using SPSS software. RESULTS: TROP-2 was detected in 12 ATCs with 9 cases demonstrating a high expression and in all PTC components, and absent in all FTC components of secondary ATCs. 5hmC expression was moderately reduced in PTC and FTC components and markedly reduced in ATC. The entire cohort showed a total absence of IDH1. CONCLUSIONS: Increased TROP-2 immunoexpression in some ATCs supports that these patients may potentially benefit from an antibody-drug conjugate therapy targeting TROP-2. Markedly reduced 5hmC expression suggests that 5hmC may be used as potential therapeutic targets for ATC. The total lack of IDH1 R132H mutation by immunostain indicates that it has no prognostic and therapeutic value in ATC.