John R. Srigley

The 2005 International Society of Urological Pathology (ISUP) Consensus Conference on Gleason Grading of Prostatic Carcinoma.

Five years after the last prostatic carcinoma grading consensus conference of the International Society of Urological Pathology (ISUP), accrual of new data and modification of clinical practice require an update of current pathologic grading guidelines. This manuscript summarizes the proceedings of the ISUP consensus meeting for grading of prostatic carcinoma held in September 2019, in Nice, France. Topics brought to consensus included the following: (1) approaches to reporting of Gleason patterns 4 and 5 quantities, and minor/tertiary patterns, (2) an agreement to report the presence of invasive cribriform carcinoma, (3) an agreement to incorporate intraductal carcinoma into grading, and (4) individual versus aggregate grading of systematic and multiparametric magnetic resonance imaging-targeted biopsies. Finally, developments in the field of artificial intelligence in the grading of prostatic carcinoma and future research perspectives were discussed.

The World Health Organization/International Society of Urological Pathology consensus classification of urothelial (transitional cell) neoplasms of the urinary bladder

In October 1997, Dr. F.K. Mostofi assembled a group of individuals interested in bladder neoplasia at a meeting in Washington DC. The participants included urologic pathologists, urologists, urologic oncologists, and basic scientists with an interest in bladder neoplasia. The purpose of this meeting was to discuss bladder terminology and make recommendations to the World Health Organization (WHO) Committee on urothelial tumors. Following this meeting, a group of the urologic pathologists who attended the Washington meeting decided to broaden the representation of the group and arranged a meeting primarily of the members of the International Society of Urologic Pathologists (ISUP) at the 1998 United States and Canadian Academy of Pathology Meeting held in Boston. Massachusetts. At this meeting. issues regarding terminology of bladder lesions, primarily neoplastic and putative preneoplastic lesions, were discussed, resulting in a consensus statement. The WHO/ ISUP consensus classification arises from this consensus conference committees recommendations to the WHO planning committee and their agreement with virtually all of the proposals presented herein. 29 The effort involved in reaching such a consensus was often considerable. Many of those involved in this process have compromised to arrive at a consensus. The aim was to develop a universally acceptable classification system for bladder neoplasia that could be used effectively by pathologists, urologists, and oncologists.

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

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.

International society of urological pathology (ISUP) consensus conference on handling and staging of radical prostatectomy specimens. Working group 5: Surgical margins

The 2009 International Society of Urological Pathology Consensus Conference in Boston, made recommendations regarding the standardization of pathology reporting of radical prostatectomy specimens. Issues relating to surgical margin assessment were coordinated by working group 5. Pathologists agreed that tumor extending close to the ‘capsular’ margin, yet not to it, should be reported as a negative margin, and that locations of positive margins should be indicated as either posterior, posterolateral, lateral, anterior at the prostatic apex, mid-prostate or base. Other items of consensus included specifying the extent of any positive margin as millimeters of involvement; tumor in skeletal muscle at the apical perpendicular margin section, in the absence of accompanying benign glands, to be considered organ confined; and that proximal and distal margins be uniformly referred to as bladder neck and prostatic apex, respectively. Grading of tumor at positive margins was to be left to the discretion of the reporting pathologists. There was no consensus as to how the surgical margin should be regarded when tumor is present at the inked edge of the tissue, in the absence of transected benign glands at the apical margin. Pathologists also did not achieve agreement on the reporting approach to benign prostatic glands at an inked surgical margin in which no carcinoma is present.

Prognostic factors and reporting of prostate carcinoma in radical prostatectomy and pelvic lymphadenectomy specimens

This paper, based on the activity of the Morphology-Based Prognostic Factors Committee of the 2004 World Health Organization-sponsored International Consultation, describes various methods of handling radical prostatectomy specimens for both routine clinical use and research purposes. The correlation between radical prostatectomy findings and postoperative failure is discussed in detail. This includes issues relating to pelvic lymph node involvement, detected both at the time of frozen section and in permanent sections. Issues of seminal vesicle invasion, including its definition, routes of invasion and relationship to prognosis, are covered in detail. The definition, terminology and incidence of extra-prostatic extension are elucidated, along with its prognostic significance relating to location and extent. Margins of resection are covered in terms of their definition, the etiology, incidence and sites of positive margins, the use of frozen sections to assess the margins and the relationship between margin positivity and prognosis. Issues relating to grade within the radical prostatectomy specimen are covered in depth, including novel ways of reporting Gleason grade and the concept of tertiary Gleason patterns. Tumor volume, tumor location, vascular invasion and perineural invasion are the final variables discussed relating to the prognosis of radical prostatectomy specimens. The use of multivariate analysis to predict progression is discussed, together with proposed modifications to the TNM system. Finally, biomarkers to predict progression following radical prostatectomy are described, including DNA ploidy, microvessel density, Ki-67, neuroendocrine differentiation, p53, p21, p27, Bcl-2, Her-2/neu, E-cadherin, CD44, retinoblastoma proteins, apoptotic index, androgen receptor status, expression of prostate-specific antigen and prostatic-specific acid phosphatase and nuclear morphometry.

Atypical adenomatous hyperplasia of the prostate: Morphologic criteria for its distinction from well-differentiated carcinoma

Atypical adenomatous hyperplasia (AAH) is a localized proliferation of small glands within the prostate that may be mistaken for carcinoma. To determine the diagnostic criteria for separating AAH from carcinoma, seven observers independently evaluated 54 selected lesions from 44 transurethral resection specimens. Three patterns of glandular proliferation were observed, all arising in association with nodular hyperplasia: AAH (38 foci), atypical small acinar proliferation of uncertain significance (eight foci), and well-differentiated carcinoma (eight foci). Of 24 architectural and cytologic features evaluated, the following were useful in separating these three patterns: variation in nuclear size (14%, 22%, and 25%, respectively), mean nucleolar diameter (0.69 micron, 1.43 microns, and 1.78 microns, respectively), largest nucleolar diameter (mean, 1.66 microns, 2.71 microns, and 2.81 microns, respectively), percentage of nucleoli greater than 1 micron in diameter (17.6%, 58.1%, and 77.5%, respectively), crystalloids within suspicious glands (16%, 13%, and 75%, respectively), luminal basophilic mucinous secretions, infiltrative borders, discontinuity of the basal cell layer in AAH (compared with complete absence in carcinoma; shown with basal cell-specific anti-keratin monoclonal antibody 34 beta E12 immunostaining), and intact basement membrane in AAH (compared with discontinuity in carcinoma; shown with type IV collagen immunostaining). Features that could not reliably separate AAH from carcinoma included lesion shape, circumscription, multifocality, average gland size, variation in gland size and shape, nuclear shape, chromatin pattern, and amount and tinctorial quality of cytoplasm. Although the biologic significance of AAH is uncertain, its light microscopic appearance and immunophenotype allow it to be distinguished from carcinoma in most cases.

Renal oncocytosis: a morphologic study of fourteen cases.

Diffuse renal involvement by numerous oncocytic nodules has rarely been described. We report 14 cases (19 specimens) with innumerable oncocytic nodules in the kidney. Invariably, these kidneys showed additional associated findings. We suggest the term renal oncocytosis for this entire morphologic spectrum. Six (43%) cases had histologically or radiologically proven bilateral involvement. Each specimen had at least one dominant tumor (2.0-10.5 cm) in addition to numerous other microscopic to macroscopic oncocytic nodules. Additional features observed were: interstitial pattern, with the oncocytic tubules and acini diffusely intermingling with and infiltrating between non-neoplastic parenchyma (one case); diffuse oncocytic change in the nonneoplastic tubules, cytologically difficult to separate from the oncocytic nodules (seven cases); and benign oncocytic cortical cysts (four cases). The dominant mass in 13 specimens was a renal oncocytoma and in two, a chromophobe renal cell carcinoma. In four specimens, the largest tumor was considered a hybrid tumor because of the presence of mixed histologic features of both tumor types. Most smaller nodules had the morphologic features of renal oncocytoma, but a few had the appearance of chromophobe renal cell carcinoma or nodules with hybrid features. We conclude that the presence of numerous oncocytic nodules may be associated with a wide spectrum of oncocytic changes in the kidney. The association of numerous renal oncocytoma-like nodules with lesions having a mixed morphology or a morphology of pure chromophobe renal cell carcinoma suggests that they may constitute a morphologic spectrum of oncocytic tumors and that renal oncocytoma and chromophobe renal cell carcinoma may arise from a common progenitor lesion.

Uncommon and recently described renal carcinomas

Major consensus conferences held over a decade ago laid the foundations for the current (2004) WHO classification of renal carcinoma. Clear cell, papillary and chromophobe carcinomas account for 85–90% carcinomas seen in routine practice. The remaining 10–15% of carcinomas consist of rare sporadic and hereditary tumors, some of which had been long recognized, but many of which only emerged as distinct entities in the decade leading up to the WHO publication. Collecting-duct carcinoma is a rare, often lethal form of carcinoma. Medullary carcinoma associated with sickle cell trait, has emerged as a distinctive tumor showing some overlapping features with upper tract urothelial carcinoma. Mucinous tubular and spindle-cell carcinoma and tubulocystic carcinoma were earlier considered as patterns of low-grade collecting-duct carcinoma, but are now recognized as separate tumor entities. Carcinomas associated with somatic translocations of TFE3 and TFEB comprise a significant proportion of pediatric renal carcinomas. Oncocytoid renal carcinomas in neuroblastoma survivors was recognized as a unique tumor category in the WHO classification. Renal carcinoma associated with end-stage renal disease is now recognized as having distinct morphological patterns and behavior. In addition there is a group of rare recently described carcinomas, including clear cell papillary carcinoma, oncocytic papillary renal cell carcinoma, follicular renal carcinoma and leiomyomatous renal cell carcinoma. It behooves the surgical pathologist to not only be capable of diagnosing the common forms of renal cancer, but also to be aware of the rare types of renal carcinoma, many of which have emerged in recent years.

International society of urological pathology (ISUP) consensus conference on handling and staging of radical prostatectomy specimens. working group 2: T2 substaging and prostate cancer volume

The 2009 International Society of Urological Pathology consensus conference in Boston made recommendations regarding the standardization of pathology reporting of radical prostatectomy specimens. Issues relating to the substaging of pT2 prostate cancers according to the TNM 2002/2010 system, reporting of tumor size/volume and zonal location of prostate cancers were coordinated by working group 2. A survey circulated before the consensus conference demonstrated that 74% of the 157 participants considered pT2 substaging of prostate cancer to be of clinical and/or academic relevance. The survey also revealed a considerable variation in the frequency of reporting of pT2b substage prostate cancer, which was likely a consequence of the variable methodologies used to distinguish pT2a from pT2b tumors. Overview of the literature indicates that current pT2 substaging criteria lack clinical relevance and the majority (65.5%) of conference attendees wished to discontinue pT2 substaging. Therefore, the consensus was that reporting of pT2 substages should, at present, be optional. Several studies have shown that prostate cancer volume is significantly correlated with other clinicopathological features, including Gleason score and extraprostatic extension of tumor; however, most studies fail to demonstrate this to have prognostic significance on multivariate analysis. Consensus was reached with regard to the reporting of some quantitative measure of the volume of tumor in a prostatectomy specimen, without prescribing a specific methodology. Incorporation of the zonal and/or anterior location of the dominant/index tumor in the pathology report was accepted by most participants, but a formal definition of the identifying features of the dominant/index tumor remained undecided.

Protocol for the Examination of Specimens From Patients With Carcinoma of the Prostate Gland

Authors John R. Srigley, MD, FCAP* Department of Laboratory Medicine, Credit Valley Hospital, Mississauga, Ontario, Canada Peter A. Humphrey, MD, PhD, FCAP* Department of Pathology, Washington University School of Medicine and Barnes-Jewish Hospital, St. Louis, Missouri Mahul B. Amin, MD, FCAP* Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California Sam S. Chang, MD Department of Urologic Surgery, Vanderbilt-Ingram Cancer Center, Nashville, Tennessee Lars Egevad, MD Department of Pathology and Cytology, Karolinska University Hospital, Stockholm, Sweden Jonathan I. Epstein, MD Department of Pathology, Johns Hopkins Hospital, Baltimore, Maryland David J. Grignon, MD Department of Pathology, Indiana University School of Medicine, Indianapolis, Indiana James M. McKiernan, MD Columbia University College of Physicians and Surgeons, New York, New York Rodolfo Montironi, MD, FRCPath Institute of Pathological Anatomy and Histopathology, University of Ancona School of Medicine, Ancona, Italy Andrew A. Renshaw, MD Department of Pathology, Baptist Hospital of Miami, Miami, Florida Victor E. Reuter, MD Pathology Department, Memorial Sloan-Kettering Cancer Center, New York, New York Thomas M. Wheeler, MD, FCAP Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas Ming Zhou, MD, PhD, FCAP† Department of Pathology, New York University Langone Medical Center, New York, New York For the Members of the Cancer Committee, College of American Pathologists