Faculty Bibliography

AIMS/OBJECTIVE:Despite efforts to standardise grading of prostate cancer, even among experts there is still a considerable variation in grading practices. In this study we describe the use of Pathology Imagebase, a novel reference image library, for setting an international standard in prostate cancer grading. METHODS AND RESULTS/RESULTS:The International Society of Urological Pathology (ISUP) recently launched a reference image database supervised by experts. A panel of 24 international experts in prostate pathology reviewed independently microphotographs of 90 cases of prostate needle biopsies with cancer. A linear weighted kappa of 0.67 (95% confidence interval = 0.62-0.72) and consensus was reached in 50 cases. The interobserver weighted kappa varied from 0.48 to 0.89. The highest level of agreement was seen for Gleason score (GS) 3 + 3 = 6 (ISUP grade 1), while higher grades and particularly GS 4 + 3 = 7 (ISUP grade 3) showed considerable disagreement. Once a two-thirds majority was reached, images were moved automatically into a public database available for all ISUP members at www.isupweb.org. Non-members are able to access a limited number of cases. CONCLUSIONS:It is anticipated that the database will assist pathologists to calibrate their grading and, hence, decrease interobserver variability. It will also help to identify instances where definitions of grades need to be clarified.

The International Society of Urological Pathology held a conference on issues in testicular and penile pathology in Boston in March 2015, which included a presentation by the testis macroscopic features working group. The presentation focused on current published guidance for macroscopic handling of testicular tumors and retroperitoneal lymph node dissections with a summary of results from an online survey of members preceding the conference. The survey results were used to initiate discussions, but decisions on practice were made by expert consensus rather than voting. The importance of comprehensive assessment at the time of gross dissection with confirmation of findings by microscopic assessment was underscored. For example, the anatomic landmarks denoting the distinction of hilar soft tissue invasion (pT2) from spermatic cord invasion (pT3 category) can only be determined by careful macroscopic assessment in many cases. Other recommendations were to routinely sample epididymis, rete testis, hilar soft tissue, and tunica vaginalis in order to confirm macroscopic invasion of these structures or if not macroscopically evident, to exclude subtle microscopic invasion. Tumors 2 cm or less in greatest dimension should be completely embedded. If the tumor is >2 cm in greatest dimension, 10 blocks or a minimum of 1 to 2 additional blocks per centimeter should be taken (whichever is greater).

Metastasis remains a leading cause of cancer mortality due to the lack of specific inhibitors against this complex process. To identify compounds selectively targeting the metastatic state, we used the perinucleolar compartment (PNC), a complex nuclear structure associated with metastatic behaviors of cancer cells, as a phenotypic marker for a high-content screen of over 140,000 structurally diverse compounds. Metarrestin, obtained through optimization of a screening hit, disassembles PNCs in multiple cancer cell lines, inhibits invasion in vitro, suppresses metastatic development in three mouse models of human cancer, and extends survival of mice in a metastatic pancreatic cancer xenograft model with no organ toxicity or discernable adverse effects. Metarrestin disrupts the nucleolar structure and inhibits RNA polymerase (Pol) I transcription, at least in part by interacting with the translation elongation factor eEF1A2. Thus, metarrestin represents a potential therapeutic approach for the treatment of metastatic cancer.

OBJECTIVE: To determine if multiparametric MRI (mpMRI) identifies significant apical disease, thereby informing decisions regarding preservation of the membranous urethra. MATERIALS AND METHODS: Men undergoing radical prostatectomy between January 2012 and June 2016 who underwent a 12-core transrectal-ultrasound guided systematic biopsy, preoperative 3-T MRI, and sectioning of the prostate specimen with tumor foci mapping were extracted from a single surgeon's prospective longitudinal outcomes database. Apical systematic biopsy vs. mpMRI lesion were compared for predicting aggressive tumor in the prostatic apex defined as Prostate Cancer Grade Group >1. RESULTS: Of the 100 men who met eligibility criteria, 43 (43%) exhibited aggressive prostate cancer in the distal 5mm of the apex. A Likert score > 2 in the apical one-third of the prostate was found to be more reliable than any cancer found on apical systematic biopsy at detecting aggressive cancer in the apex. On multivariate regression that included Likert score in the apex, age, PSA, prostate size, and presence of any cancer on apical biopsy, only Likert score (p=.005) and PSA (p=.025) were significant and independent predictors of aggressive cancer in the distal apex. CONCLUSION: MRI is superior to systematic biopsy at identifying aggressive prostate cancer within the distal prostatic apex and may be useful for planning the extent of apical preservation during prostatectomy.

OBJECTIVE: To provide insights into the role of mpMRI for predicting oncological control following two focal ablation (FA) templates for selective cases of prostate cancer (PCa). MATERIALS AND METHODS: 59 radical prostatectomies were performed between 2012 and 2016 on cases that fulfilled criteria for FA. The Gleason score (GS), extent of Gleason pattern (GP) 4, maximum linear cross sectional length (MLCSL) and location of tumor foci were recorded and related to scale on corresponding 3mm transverse slice prostate maps. Gleason pattern 4 extra-focal disease (GP4EFD) was defined as PCa with any GP 4 not detected by mpMRI and transrectal ultrasound systematic biopsy observed outside a specified ablation zone. The location of these GP4EFD relative to the MRI lesion (MRI-L) (contralateral or ipsilateral) was recorded and used to predict oncological control following a hypothetical margin and ipsilateral hemi-ablation templates. RESULTS: Overall, 15/59 (25.4%) of the prostate specimens had at least one GP4EFD. Of the total 20 GP4EFD, 7/20 (35%) were ipsilateral and 13/20 (65%) were contralateral to the MRI-L. Of the GP4EFD, 16/20 (80%), 2/20 (10%), and 2/20 (10%) were GS 3+4, GS 4+3, and GS 4+4, respectively. Of these GP4EFD, 10/20 (50%) exhibited a MLCSL < 5mm. Ablating only the MRI-L+10mm or performing a ipsilateral hemi-ablation would leave residual GP4 in 14/59 (23.7%) and 11/59 (18.6%) of cases, respectively. CONCLUSIONS: Since a significant proportion of candidates for FA based on mpMRI and systematic biopsy will have pre-existing GP4EFD outside ablation templates, active surveillance of the untreated prostate is mandatory.

AIMS/OBJECTIVE:Despite efforts to standardize histopathology practice through the development of guidelines, the interpretation of morphology is still hampered by subjectivity. We here describe Pathology Imagebase, a novel mechanism for establishing an international standard for the interpretation of pathology specimens. METHODS AND RESULTS/RESULTS:The International Society of Urological Pathology (ISUP) established a reference image database through the input of experts in the field. Three panels were formed, one each for prostate, urinary bladder and renal pathology, consisting of 24 international experts. Each of the panel members uploaded microphotographs of cases into a non-public database. The remaining 23 experts were asked to vote from a multiple-choice menu. Prior to and while voting, panel members were unable to access the results of voting by the other experts. When a consensus level of at least two-thirds or 16 votes was reached, cases were automatically transferred to the main database. Consensus was reached in a total of 287 cases across five projects on the grading of prostate, bladder and renal cancer and the classification of renal tumours and flat lesions of the bladder. The full database is available to all ISUP members at www.isupweb.org. Non-members may access a selected number of cases. CONCLUSIONS:It is anticipated that the database will assist pathologists in calibrating their grading, and will also promote consistency in the diagnosis of difficult cases.

Eosinophilic solid and cystic renal cell carcinoma (ESC RCC) has been recently described as a unique and indolent renal neoplasm, found in female patients with and without tuberous sclerosis complex. Although ESC RCC has a distinct morphology and frequent CK20 reactivity, its molecular karyotype has been previously studied only in few cases. We identified 19 ESC RCC from multiple institutions; all patients were female individuals without clinical features of tuberous sclerosis complex. Molecular karyotyping was performed in 13 cases (12 with informative result). The median age was 55 years (range: 32 to 79 y). The tumors were yellow-gray with a median size of 31 mm (range: 12 to 135 mm) and showed solid and cystic gross appearance. All tumors demonstrated typical microscopic features with solid areas admixed with variably sized macrocysts and microcysts. The cells showed eosinophilic cytoplasm with granular cytoplasmic stippling and round-to-oval nuclei. CK20 was positive in 14/19 (74%) cases. Stage pT1 was found in 17/19 (89%) patients (pT1a in 12, pT1b in 5); 1 patient each had pT2a and pT3a. A total of 15/16 patients with available follow-up were alive and without evidence of disease progression, after 1 to 169 months (median: 44 mo; mean: 49.6 mo); 3 died of other causes. The most common copy number gains were 16p13.3-16q23.1 (33% to 67%), 7p21.2-7q36.2 (42% to 50%), 13q14.2 (33%), and 19p12 (33%). The most common copy number losses included Xp11.21 (42%) and 22q11.23 (33%). Loss of heterozygosity was most frequently found at 16p11.2-11.1 (75%), Xq11.1-13.1 (75%), Xq13.1-21.1 (33%), 11p11.2-11.11 (33%), 9q21.1-22.2 (33%), and 9q33.1 (33%). ESC RCC demonstrates common molecular karyotype alterations, which further support its distinct nature.