Pathology and genetics of tumours of the urinary system and male genital organs

Rapid improvements in sequencing and array-based platforms are resulting in a flood of diverse genome-wide data, including data from exome and whole-genome sequencing, epigenetic surveys, expression profiling of coding and noncoding RNAs, single nucleotide polymorphism (SNP) and copy number profiling, and functional assays. Analysis of these large, diverse data sets holds the promise of a more comprehensive understanding of the genome and its relation to human disease. Experienced and knowledgeable human review is an essential component of this process, complementing computational approaches. This calls for efficient and intuitive visualization tools able to scale to very large data sets and to flexibly integrate multiple data types, including clinical data. However, the sheer volume and scope of data pose a significant challenge to the development of such tools.

Integrative Genomics Viewer

In November, 2014, 65 prostate cancer pathology experts, along with 17 clinicians including urologists, radiation oncologists, and medical oncologists from 19 different countries gathered in a consensus conference to update the grading of prostate cancer, last revised in 2005. The major conclusions were: (1) Cribriform glands should be assigned a Gleason pattern 4, regardless of morphology; (2) Glomeruloid glands should be assigned a Gleason pattern 4, regardless of morphology; (3) Grading of mucinous carcinoma of the prostate should be based on its underlying growth pattern rather than grading them all as pattern 4; and (4) Intraductal carcinoma of the prostate without invasive carcinoma should not be assigned a Gleason grade and a comment as to its invariable association with aggressive prostate cancer should be made. Regarding morphologies of Gleason patterns, there was clear consensus on: (1) Gleason pattern 4 includes cribriform, fused, and poorly formed glands; (2) The term hypernephromatoid cancer should not be used; (3) For a diagnosis of Gleason pattern 4, it needs to be seen at 10x lens magnification; (4) Occasional/seemingly poorly formed or fused glands between well-formed glands is insufficient for a diagnosis of pattern 4; (5) In cases with borderline morphology between Gleason pattern 3 and pattern 4 and crush artifacts, the lower grade should be favored; (6) Branched glands are allowed in Gleason pattern 3; (7) Small solid cylinders represent Gleason pattern 5; (8) Solid medium to large nests with rosette-like spaces should be considered to represent Gleason pattern 5; and (9) Presence of unequivocal comedonecrosis, even if focal is indicative of Gleason pattern 5. It was recognized by both pathologists and clinicians that despite the above changes, there were deficiencies with the Gleason system. The Gleason grading system ranges from 2 to 10, yet 6 is the lowest score currently assigned. When patients are told that they have a Gleason score 6 out of 10, it implies that their prognosis is intermediate and contributes to their fear of having a more aggressive cancer. Also, in the literature and for therapeutic purposes, various scores have been incorrectly grouped together with the assumption that they have a similar prognosis. For example, many classification systems consider Gleason score 7 as a single score without distinguishing 3+4 versus 4+3, despite studies showing significantly worse prognosis for the latter. The basis for a new grading system was proposed in 2013 by one of the authors (J.I.E.) based on data from Johns Hopkins Hospital resulting in 5 prognostically distinct Grade Groups. This new system was validated in a multi-institutional study of over 20,000 radical prostatectomy specimens, over 16,000 needle biopsy specimens, and over 5,000 biopsies followed by radiation therapy. There was broad (90%) consensus for the adoption of this new prostate cancer Grading system in the 2014 consensus conference based on: (1) the new classification provided more accurate stratification of tumors than the current system; (2) the classification simplified the number of grading categories from Gleason scores 2 to 10, with even more permutations based on different pattern combinations, to Grade Groups 1 to 5; (3) the lowest grade is 1 not 6 as in Gleason, with the potential to reduce overtreatment of indolent cancer; and (4) the current modified Gleason grading, which forms the basis for the new grade groups, bears little resemblance to the original Gleason system. The new grades would, for the foreseeable future, be used in conjunction with the Gleason system [ie. Gleason score 3+3=6 (Grade Group 1)]. The new grading system and the terminology Grade Groups 1-5 have also been accepted by the World Health Organization for the 2016 edition of Pathology and Genetics: Tumours of the Urinary System and Male Genital Organs.

The 2014 International Society of Urological Pathology (ISUP) Consensus Conference on Gleason Grading of Prostatic Carcinoma: Definition of Grading Patterns and Proposal for a New Grading System.

The 2016 WHO Classification of Tumours of the Urinary System and Male Genital Organs-Part A: Renal, Penile, and Testicular Tumours.

https://www.europeanurology.com/article/S0302-2838(13)01040-3/pdf/eau-guidelines-on-prostate-cancer-part-1-screening-diagnosis-and-local-treatment-with-curative-intent-update-2013

EAU Guidelines on Prostate Cancer. Part 1: Screening, Diagnosis, and Local Treatment with Curative Intent—Update 2013

Reply to M. Baboudjian et al.

A single-institution review of the national institutes of health recommendation for prognostication of gastrointestinal stromal tumors

In 2010, the ISUP drafted the most current classification of renal neoplasm. Among the major additions to the prior 2004 WHO classification are the recognition of tubulocystic RCC, acquired cystic disease-associated RCC, clear cell (tubulo) papillary RCC, MiT family translocation RCC, and hereditary leiomyomatosis RCC syndrome-associated RCC as distinct subtypes of RCC. Innovations were made to several traditional tumor types, and some emerging tumor entities are provisionally acknowledged. The 2010 ISUP classification forms the basis for the 2016 WHO classification of renal tumors. Stage is vital to the therapeutic decisions and prognostication of renal cancer. Over the years, the UICC/AJCC TNM staging system underwent several modifications intended to enhance its components into more robust prognostic categories. The latest TNM stage for renal cancer published in 2010 included several revisions such as subdivision of T2 into T2a and T2b, designation of renal vein involvement under T3a, upstage of contiguous ipsilateral adrenal gland invasion to T4, and simplification of nodal involvement into N0 and N1. In order to align with the updates and to resolve some issues in pathological staging of nephrectomies, the ISUP conducted a consensus conference regarding handling and staging of renal cancer. Several validation studies demonstrated the prognostic ability of the new 2010 TNM system; however, its advantages from the 2002 TNM system are only modest at best. The new revision brought about an increase in T3a renal cancers, and potentially this group of tumors is prognostically heterogeneous. It is suggested that among T3a renal cancers, tumors with sinus invasion are more aggressive than tumors with perinephric fat invasion. So far, studies regarding the prognostic relevance of T2 subdivision are conflicting, although some are showing a statistical difference. The tumor stage division of renal vein/vena caval involvement (T3a–T3c) has been confirmed in a multi-institutional study.

Overview and Staging of Renal Neoplasms

Background: Personalization of cancer therapy requires molecular evaluation of tumor tissue. Traditional tissue preservation involves formalin fixation, which degrades the quality of nucleic acids. Strategies to bank frozen prostate tissue can interfere with diagnostic studies. PAXgene is an alternative fixative that preserves protein and nucleic acid quality. Methods: Portions of prostates obtained from autopsy specimens were fixed in either 10% buffered formalin or PAXgene, and processed and embedded in paraffin. Additional sections were immediately embedded in OCT and frozen. DNA and RNA were extracted from the formalin-fixed, PAXgene-fixed, or frozen tissue. Quantitative PCR was used to compare the quality of DNA and RNA obtained from all three tissue types. In addition, 5 μm sections were cut from specimens devoid of cancer and from prostate cancer specimens obtained at prosta- tectomy and fixed in PAXgene. They were either stained with hematoxylin and eosin or interrogated with antibodies for p63, PSA and p504. Results: Comparable tissue morphology was observed in both the formalin and PAXgene- fixed specimens. Similarly, immunohistochemical expression of the P63, PSA and P504 proteins was comparable between formalin and PAXgene fixation techniques. DNA from the PAXgene-fixed tissue was of similar quality to that from frozen tissue. RNA was also amplified with up to 8-fold greater efficiency in the PAXgene fixed tissue compared to the formalin-fixed tissue. Conclusions: Prostate specimens fixed with PAXgene have preserved histologic morphol- ogy, stain appropriately, and have preserved quality of nucleic acids. PAXgene fixation facilitates the use of prosta - tectomy tissue for molecular biology techniques such as next-generation sequencing.

Original Article Next-gen tissue: preservation of molecular and morphological fidelity in prostate tissue

Our patient presented with a small, well-differentiated neuroendocrine tumor (NET) of the ileal neobladder 21-years after radical cystectomy for urothelial cell carcinoma. Given the rarity of NETs in urinary diversions, there are no established guidelines regarding management in this unique population. We propose that transurethral resection and close cystoscopic surveillance of the neobladder is a feasible, low morbidity approach to management of a well-differentiated, solitary ileal NET tumor.

Gladell P. Paner

Papers

Reply to M. Baboudjian et al.

A single-institution review of the national institutes of health recommendation for prognostication of gastrointestinal stromal tumors

Overview and Staging of Renal Neoplasms

Original Article Next-gen tissue: preservation of molecular and morphological fidelity in prostate tissue

Transurethral resection and surveillance of a well-differentiated neuroendocrine tumor in a ileal neobladder