Spatial transcriptomic analysis of virtual prostate biopsy reveals confounding effect of tissue heterogeneity on genomic signatures.

Genetic signatures have added a molecular dimension to prognostics and therapeutic decision-making. However, tumour heterogeneity in prostate cancer and current sampling methods could confound accurate assessment. Based on previously published spatial transcriptomic data from multifocal prostate cancer, we created virtual biopsy models that mimic conventional biopsy placement and core size. We then analysed the gene expression of different prognostic signatures (OncotypeDx®, Decipher®, Prostadiag®) using a step-wise approach with increasing resolution from pseudo-bulk analysis of the whole biopsy, to differentiation by tissue subtype (benign, stroma, tumour), followed by distinct tumour grade and finally clonal resolution. The gene expression profile of virtual tumour biopsies revealed clear differences between grade groups and tumour clones, compared to a benign control, which were not reflected in bulk analyses. This suggests that bulk analyses of whole biopsies or tumour-only areas, as used in clinical practice, may provide an inaccurate assessment of gene profiles. The type of tissue, the grade of the tumour and the clonal composition all influence the gene expression in a biopsy. Clinical decision making based on biopsy genomics should be made with caution while we await more precise targeting and cost-effective spatial analyses.

Primary peri-anal adenocarcinoma of intestinal type - a new proposed entity.

AIMS: The currently recognised subtypes of anal canal/peri-anal adenocarcinoma are those arising from low rectal mucosa or columnar cuff, fistula-related tumours and anal gland carcinoma. This report presents two examples of a hitherto undescribed subtype of peri-anal adenocarcinoma with an intestinal phenotype. METHODS AND RESULTS: A 74-year-old man had a peri-anal tumour locally excised, whereas a 73-year-old female underwent an abdominoperineal resection for peri-anal Paget's disease with an underlying carcinoma. Neither patient had a history of perineal fistulae, Crohn's disease or previous gastrointestinal neoplasia, and neither showed clinical, radiological or endoscopic evidence of another abdominal or pelvic tumour. Both resection specimens contained adenocarcinoma, which were similar in demonstrating an intestinal morphology and CDX2 immunopositivity. The man has shown a disease-free outcome thus far, but the woman has suffered with nodal and pelvic recurrence within a few months of surgery. CONCLUSIONS: The name 'primary peri-anal adenocarcinoma of intestinal type' is proposed for this previously unrecognised subtype of perineal neoplasia. Awareness of its distinct existence - by recognising its intestinal morphology and immunophenotype while excluding metastasis from the intestinal tract - should help to collate data to determine its specific prognosis and to formulate its best management.

Variation between specialist uropatholgists in reporting extraprostatic extension after radical prostatectomy.

AIMS: Extraprostatic extension of prostate cancer in radical prostatectomy specimens significantly affects patient management. We evaluated the degree of interobserver variation between uropathologists at a tertiary referral teaching hospital in assessing the extraprostatic extension of prostate cancer in radical prostatectomy specimens. METHODS: Histopathological data from a consecutive series of 293 radical prostatectomy specimens (January 2007-December 2012) were reviewed. A subset of 50 consecutive radical prostatectomy cases originally staged as tumours confined to the prostate (pT2) or tumours extending into periprostatic tissue (pT3a) during this period were reviewed by four specialist uropathologists. RESULTS: Five consultant histopathologists reported these specimens with significant differences in the reported stage (p=0.0164) between pathologists. Double-blind review by 4 uropathologists of 50 consecutive radical prostatectomy cases showed a lack of consensus in 16/50 (32%) cases (κ score 0.58, moderate agreement). A consensus meeting was held, but consensus could still not be reached in 9/16 cases. CONCLUSIONS: Our findings highlight variability in the reporting of pT stage in radical prostatectomy specimens even by specialist uropathologists. Assessment of extraprostatic extension has important implications for patient management and there is a need for more precise guidance.