Brett Delahunt

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 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.

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.

Eosinophilic and classic chromophobe renal cell carcinomas have similar frequent losses of multiple chromosomes from among chromosomes 1, 2, 6, 10, and 17, and this pattern of genetic abnormality is not present in renal oncocytoma

That chromophobe renal cell carcinoma has an uncommon eosinophilic variant has been recognized for more than a decade. In sections stained with hematoxylin and eosin, the eosinophilic variant of chromophobe renal cell carcinoma and renal oncocytoma are similar in appearance. While it is well established that chromophobe renal cell carcinoma and renal oncocytoma have different patterns of genetic anomalies, little is known of the genetics of the eosinophilic variant of chromophobe renal cell carcinoma. This study was undertaken to elucidate the genetic lesions of eosinophilic chromophobe renal cell carcinoma and to compare them with those found in classic chromophobe renal cell carcinoma and in renal oncocytoma. A total of 29 renal neoplasms—nine eosinophilic chromophobe renal cell carcinomas, 10 classic chromophobe renal cell carcinomas, and 10 oncocytomas—were investigated by fluorescence in situ hybridization on 5 μm paraffin-embedded tissue sections with centromeric probes for chromosomes 1, 2, 6, 10, and 17. Signals were counted in 100–200 neoplastic nuclei from each tumor. Chromophobe renal cell carcinomas frequently showed loss of chromosomes 1 (70% of classic, 67% of eosinophilic), 2 (90% classic, 56% eosinophilic), 6 (80% classic, 56% eosinophilic), 10 (60% classic, 44% eosinophilic), and 17 (90% classic, 78% eosinophilic); Among the classic chromophobe renal cell carcinomas, only one had no loss of any of the chromosomes, while 50% had loss of all five chromosomes. Among the eosinophilic chromophobe renal cell carcinomas, one of nine had no loss and 44% had loss of all five chromosomes. One oncocytoma had loss of chromosome 1. No other chromosomal loss was detected in the oncocytomas. In conclusion, losses of chromosomes 1, 2, 6, 10, and 17 are frequent in both eosinophilic and classic chromophobe renal cell carcinomas. Loss of chromosome 1 occurs occasionally in oncocytoma but losses of chromosomes 2, 6, 10, and 17 are not found in oncocytomas. When the differential diagnostic problem is oncocytoma vs eosinophilic chromophobe renal cell carcinoma, detection of losses of chromosomes 2, 6, 10, or 17 effectively excludes the diagnosis of oncocytoma and supports the diagnosis of chromophobe renal cell carcinoma.

International Society of Urological Pathology (ISUP) Consensus Conference on Handling and Staging of Radical Prostatectomy Specimens. Working group 3: extraprostatic extension, lymphovascular invasion and locally advanced disease.

The International Society of Urological Pathology Consensus Conference on Handling and Staging of Radical Prostatectomy Specimens in Boston made recommendations regarding the standardization of pathology reporting of radical prostatectomy specimens. Issues relating to extraprostatic extension (pT3a disease), bladder neck invasion, lymphovascular invasion and the definition of pT4 were coordinated by working group 3. It was agreed that prostate cancer can be categorized as pT3a in the absence of adipose tissue involvement when cancer bulges beyond the contour of the gland or beyond the condensed smooth muscle of the prostate at posterior and posterolateral sites. Extraprostatic extension can also be identified anteriorly. It was agreed that the location of extraprostatic extension should be reported. Although there was consensus that the amount of extraprostatic extension should be quantitated, there was no agreement as to which method of quantitation should be employed. There was overwhelming consensus that microscopic urinary bladder neck invasion by carcinoma should be reported as stage pT3a and that lymphovascular invasion by carcinoma should be reported. It is recommended that these elements are considered in the development of practice guidelines and in the daily practice of urological surgical pathology.

Fuhrman grading is not appropriate for chromophobe renal cell carcinoma.

This study was undertaken to assess the prognostic effectiveness of Fuhrman nuclear grading and the individual components of this grading system, in a series of chromophobe renal cell carcinomas. Eighty-seven cases of chromophobe renal cell carcinoma were investigated. There were 47 males and 40 females, 28 to 78 years of age. The carcinomas ranged from 25 to 180 mm in size and on TNM staging there were 38 stage I, 25 stage II, 22 stage III, and 2 stage IV tumors. Whole tumor Fuhrman grading was grade 1, 6 cases; grade 2, 72 cases; grade 3, 8 cases; and grade 4, 1 case, whereas focal (single high power field) grading was grade 1, 1 case; grade 2, 62 cases; grade 3, 21 cases; and grade 4, 3 cases. On assignment of nucleolar grading using Fuhrman criteria there were 37 grade 1, 44 grade 2, and 4 grade 3 tumors on whole tumor assessment and 3 grade 1, 63 grade 2, and 21 grade 3 tumors on assessment of the high power field showing the greatest degree of nuclear pleomorphism. Measurements of nuclear size showed nuclear area to range from 26.14 to 100.74 μm2, nuclear perimeter from 19.73 to 39.28 μm, and nuclear major axis from 6.49 to 13.21 μm, whereas the ranges of measures of nuclear shape were; shape factor 0.798 to 0.890, compactness 14.260 to 15.843, and feret diameter 5.694 to 11.242. Follow-up ranged from 1 to 150 months and 8 patients died of tumor-related causes 5 to 53 months from diagnosis. On log rank testing against survival, only patient age (P=0.016) and tumor maximum diameter (P=0.0055) were significant, whereas patient sex and TNM stage were not significant. Whole tumor and focal Fuhrman grading, as well as all measures of nucleolar prominence, nuclear size, and nuclear shape showed no significant association with outcome. It is concluded that neither Fuhrman grading, nor any of the components of the Fuhrman grading system, is useful as prognostic indicators for this tumor type.

Clear cell tubulopapillary renal cell carcinoma: A study of 36 distinctive low-grade epithelial tumors of the kidney

Recently several low-grade renal cell tumors, distinct from those recognized by the 2004 World Health Organization classification of renal tumors, have been described. These tumors had similar clinicopathologic features, being low-stage tumors with cystic, tubuloacinar, and/or papillary architecture. The tumor cells were low grade with variable amounts of clear cytoplasm that was positive for cytokeratin 7 (CK7), but negative for CD10. Genetic changes characteristic of clear cell or papillary renal cell carcinoma were not seen in these tumors. We investigated the morphologic, immunohistochemical, and genetic features of 36 additional tumors. Immunohistochemistry was carried out for CK7, carbonic anhydrase 9, α-methylacyl-CoA racemase, CD10, TFE-3, and desmin. Interphase fluorescence in situ hybridization was carried out with centromeric probes for chromosomes 3, 7, 17, and a subtelomeric probe for 3p25. Sequencing of von Hippel-Lindau gene and analysis of the methylation status of the promoter region was also carried out in 2 tumors. Thirty-six tumors from 33 patients (mean age: 60.4 , range: 26 to 88; 17 men and 16 women) were studied. Three patients had bilateral tumors and 1 patient had von Hippel-Lindau disease. Follow-up was available in 60% (20/33) of the patients for a mean of 27.4 (range 1 to 85) months. No patient had evidence of the disease after surgery except for the patient with von Hippel-Lindau disease, who was alive with stable disease in the contralateral kidney. All 36 tumors were small (mean size 2.4 cm; range 0.9 to 4.5 cm) and low stage (pT1). The majority was cystic and had prominent fibrous capsule and stroma. The tumors were composed of variable amount of cysts, papillae, tubules, acini, and solid nests. The most characteristic histologic features were branching tubules and acini and anastomosing clear cell ribbons with low-grade nuclei. All tumors were strongly positive for CK7 and variably positive for CA9, but largely negative for CD10, and negative for α-methylacyl-CoA racemase and TFE-3. All but 1 tumor had no gains of chromosomes 7 and 17 and deletion of 3p. Only 1 tumor had low copy number gains of chromosomes 7 and 17. VHL gene mutation and promoter methylation were negative in 2 tumors analyzed. We show that these tumors, which we term as “clear cell tubulopapillary renal cell carcinoma,” constitute a unique subtype in the spectrum of renal epithelial neoplasia based on their characteristic morphologic and immunohistochemical features.

Sarcomatoid renal carcinoma: the final common dedifferentiation pathway of renal epithelial malignancies

Sarcomatoid renal carcinoma (SRC) is an aggressive neoplasm with an age and gender distribution similar to that of conventional (clear cell) renal cell carcinoma (RCC). Genetic and morphologic evidence indicates that the tumor results from de-differentiation of renal epithelial malignancy and associations with RCC, papillary renal carcinoma, chromophobe renal carcinoma and collecting duct carcinoma have been reported. The tumor is composed of sheets of malignant spindle cells that have immunohistochemical and ultrastructural features of both stromal and epithelial cells, and may contain myxoid areas containing osteoclast-like giant cells or pleomorphic sarcomatoid spindle cells resembling rhabdomyoblasts. Rare cases of osteogenic SRC have been described. The tumor shows marked proliferative activity in growth kinetic studies and is usually associated with a poor patient survival that is best predicted by staging.