Primary Urethral Clear-Cell Adenocarcinoma

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Primary Urethral Clear-Cell Adenocarcinoma Rohit Mehra, Pankaj Vats, Shanker Kalyana-Sundaram, Aaron M. Udager, Michael Roh, Ajjai Alva, Jincheng Pan, Robert J. Lonigro, Javed Siddiqui, Alon Weizer, Cheryl Lee, Xuhong Cao, Yi-Mi Wu, Dan R. Robinson, Saravana M. Dhanasekaran, Arul M. Chinnaiyan The American Journal of Pathology Volume 184, Issue 3, Pages 584-591 (March 2014) DOI: 10.1016/j.ajpath.2013.11.023 Copyright © 2014 American Society for Investigative Pathology Terms and Conditions

Figure 1 Histomorphological features and immunophenotype of a case of primary urethral clear-cell adenocarcinoma. A and B: H&E and IHC staining for CK7 (C) and PAX8 (D). A: The tumor showed a predominantly papillary architecture with fibrovascular septae and cores. B: Tumor cells had vacuolated, clear cytoplasm and basally located pleomorphic nuclei without prominent nucleoli. IHC demonstrated that tumor cells diffusely and strongly expressed CK7 in a membranous pattern (C) and PAX8 in a nuclear manner (D). Original magnification: ×100 (A); ×400 (B–D). The American Journal of Pathology 2014 184, 584-591DOI: (10.1016/j.ajpath.2013.11.023) Copyright © 2014 American Society for Investigative Pathology Terms and Conditions

Figure 2 Cytomorphological findings of a voided urine specimen in a case of primary urethral clear-cell adenocarcinoma. A–C: Papanicolaou-stained ThinPrep slides. A voided urine specimen contained cohesive, three-dimensional clusters of epithelial cells with moderate to severe nuclear pleomorphism (A); pleomorphic, naked nuclei with delicate, finely granular chromatin texture and occasionally prominent nucleoli (B); and fungal spore forms and pseudohyphae, consistent with Candida organisms, intimately associated with elongated epithelial cell clusters (C). D: A cell block section demonstrated clusters of polygonal epithelial cells with clear cytoplasm (H&E stain). Original magnification: ×600 (A–C); ×400 (D). The American Journal of Pathology 2014 184, 584-591DOI: (10.1016/j.ajpath.2013.11.023) Copyright © 2014 American Society for Investigative Pathology Terms and Conditions

Figure 3 Next-generation sequencing of a case of primary urethral clear-cell adenocarcinoma. A: Copy number analysis demonstrated several regions of copy number gain, as well as copy number loss at 12q12 and 18q21.1, which contain the ARID2 and SMAD4 loci (black arrowheads), respectively: y axis = log2 transformed tumor-to-normal coverage ratio; and x axis = genomic position, ascending from left to right (chromosome number depicted above). B: Mutation analysis revealed a truncating somatic mutation in ATM, which results in a premature stop codon at amino acid position 1537; the truncated ATM protein is missing the FAT and PI3KC domains. C: Sanger sequencing validation of this ATM somatic mutation demonstrates a C-to-T nucleotide transition at chr11:108163518 in the tumor sample but not matched normal or control human genomic DNA. D: A novel ANKRD28-FNDC3B gene fusion. Wild-type ANKRD28 protein (ANKRD28-WT) contains 26 ankyrin repeats (ANK), and wild-type FNDC3B protein (FNDC3B-WT) contains nine type fibronectin type III domains (FN3) and a single C-terminal transmembrane domain (red box). The ANKRD28-FNDC3B gene fusion transcript joins the N-terminal portion of ANKRD28 and the C-terminal portion of FNDC3B (black arrows), generating a predicted translated peptide that contains only the FN3 and transmembrane domains of FNDC3B (ANKRD28-FNDC3B). E: Quantitative PCR validation of this ANKRD28-FNDC3B gene fusion. All expression values are normalized to the internal control GAPDH. F: High resolution of copy number losses at ARID2 and SMAD4: y axis, log2 transformed tumor-to-normal coverage ratio; and x axis, genomic position (in Mb), with each point representing a targeted exon and respective gene boundaries being highlighted by red vertical lines. The American Journal of Pathology 2014 184, 584-591DOI: (10.1016/j.ajpath.2013.11.023) Copyright © 2014 American Society for Investigative Pathology Terms and Conditions