Faculty Bibliography

The use of percutaneous renal tumour biopsy (RTB) as a diagnostic tool for the histological characterization of renal masses has increased dramatically within the last 30 years. This increased utilization has paralleled advances in imaging techniques and an evolving knowledge of the clinical value of nephron sparing surgery. Improved biopsy techniques using image guidance, coupled with the use of smaller gauge needles has led to a decrease in complication rates. Reports from series containing a large number of cases have shown the non-diagnostic rate of RTB to range from 4% to 21%. Re-biopsy has been shown to reduce this rate, while the use of molecular markers further improves diagnostic sensitivity. In parallel with refinements of the biopsy procedure, there has been a rapid expansion in our understanding of the complexity of renal cell neoplasia. The 2013 Vancouver Classification is the current classification for renal tumours, and contains five additional entities recognized as novel forms of renal malignancy. The diagnosis of tumour morphotype on RTB is usually achievable on routine histology; however, immunohistochemical studies may be of assistance in difficult cases. The morphology of the main tumour subtypes, based upon the Vancouver Classification, is described and differentiating features are discussed.

BACKGROUND:Metallic airway stents are often used in the management of central airway malignancies. The presence of a metallic foreign body may affect radiation dose in tissue. We studied the effect of a metallic airway stent on radiation dose delivery in a phantom and an in vivo porcine model. METHODS:A metallic tracheal stent was fitted onto a support in a water phantom. Point dosimeters were positioned in the phantom around the support and the stent. Irradiation was then performed on a linear accelerator with and without the stent. Metallic tracheal stents were deployed in the trachea of three pigs. Dosimeters were implanted in the tissues near (Group 1) and away (Group 2) from the stent. The pigs were then irradiated, and the dose perturbation factor was calculated by comparing the actual dose detected by the dosimeters versus the planned dose. RESULTS:The difference in the dose detected by the dosimeters and the planned dose ranged from 1.8% to 6.1% for the phantom with the stent and 0%-5.3% for the phantom without the stent. These values were largely within the manufacturer's specified error of 5%. No significant difference was observed in the dose perturbation factor for Group 1 and Group 2 dosimeters (0.836 ± 0.058 versus 0.877 ± 0.088, P = 0.220) in all the three pigs. CONCLUSIONS:Metallic airway stents do not significantly affect radiation dose in the airway and surrounding tissues in a phantom and porcine model. Radiation treatment planning systems can account for the presence of the stent. External beam radiation can be delivered without concern for significant dose perturbation.

AIMS/OBJECTIVE:To assess the frequency and possible causes of downgrading from a Gleason score (GS) 7 at biopsy to a GS ≤6 at radical prostatectomy (RP) in a Canadian referral centre. METHODS:Data were extracted from diagnostic reports of inhouse biopsies and matching prostatectomy specimens from 2008 to 2011 with a GS 7 at biopsy. Biopsies and corresponding prostatectomy specimens of downgraded cases were reviewed. Pathological features were assessed and possible predictors for downgrading were identified. RESULTS:Based on pathology reports, 29 (8.9%, 95% CI 5.8% to 11.9%) of the 327 eligible cases were downgraded from biopsy GS 7 to RP GS 6, 72% of them representing a GS ≤6 with tertiary grade 4 at RP. Agreement at review of downgraded RP specimens for Gleason grading was fair and of borderline significance (κ=0.34, 95% CI -0.01 to 0.68, p=0.055) with 65% agreement for tertiary grade. The predominant Gleason grade 4 pattern found in the downgraded biopsies was ill-formed glands. The number of cores with Gleason grade 4 component was found to be the strongest negative predictor of downgrading (prereview OR=0.56 (95% CI 0.39 to 0.80, p=0.002), postreview OR=0.19 (95% CI 0.07 to 0.52, p=0.001)). CONCLUSIONS:The frequency of GS 7 in biopsies subsequently downgraded in RP is low and is associated with International Society of Urological Pathology modified Gleason grade 4 patterns. Downgrading could be attributed in most cases to the presence of a tertiary Gleason grade 4 pattern in the RP specimen. Inter-observer agreement for the presence of tertiary grade 4 in RP specimens is moderate.

CONTEXT/BACKGROUND:There is increasing interest in using whole slide imaging (WSI) for diagnostic purposes (primary and/or consultation). An important consideration is whether WSI can safely replace conventional light microscopy as the method by which pathologists review histologic sections, cytology slides, and/or hematology slides to render diagnoses. Validation of WSI is crucial to ensure that diagnostic performance based on digitized slides is at least equivalent to that of glass slides and light microscopy. Currently, there are no standard guidelines regarding validation of WSI for diagnostic use. OBJECTIVE:To recommend validation requirements for WSI systems to be used for diagnostic purposes. DESIGN/METHODS:The College of American Pathologists Pathology and Laboratory Quality Center convened a nonvendor panel from North America with expertise in digital pathology to develop these validation recommendations. A literature review was performed in which 767 international publications that met search term requirements were identified. Studies outside the scope of this effort and those related solely to technical elements, education, and image analysis were excluded. A total of 27 publications were graded and underwent data extraction for evidence evaluation. Recommendations were derived from the strength of evidence determined from 23 of these published studies, open comment feedback, and expert panel consensus. RESULTS:Twelve guideline statements were established to help pathology laboratories validate their own WSI systems intended for clinical use. Validation of the entire WSI system, involving pathologists trained to use the system, should be performed in a manner that emulates the laboratory's actual clinical environment. It is recommended that such a validation study include at least 60 routine cases per application, comparing intraobserver diagnostic concordance between digitized and glass slides viewed at least 2 weeks apart. It is important that the validation process confirm that all material present on a glass slide to be scanned is included in the digital image. CONCLUSIONS:Validation should demonstrate that the WSI system under review produces acceptable digital slides for diagnostic interpretation. The intention of validating WSI systems is to permit the clinical use of this technology in a manner that does not compromise patient care.

AIMS/OBJECTIVE:Pathological separation of poorly differentiated urothelial and prostate carcinoma is difficult, but imperative because of the impact on patient management. Tumour morphology, in conjunction with a panel of immunohistochemistry (IHC), such as prostate-specific antigen (PSA), prostatic acid phosphatase (PSAP), CK7, CK20, p63 and high molecular weight keratins (HMWKs) are usually employed to resolve this issue. Androgen receptor (AR) expression is maintained in high-grade, undifferentiated prostate carcinoma, and thus, could be considered as a potentially useful adjunct to the conventional panel of markers. METHODS:We performed an institutional review of all cases from 2006 to 2012 in which AR IHC had been performed to determine its diagnostic utility in discriminating between poorly differentiated urothelial and prostate carcinoma. Of the eligible cases (n=40), there were 9 high-grade urothelial carcinomas, 27 prostate carcinomas and 4 with both prostate and bladder tumours. All diagnoses were made by integrating the clinical, radiological, morphological and IHC results. RESULTS:In all the prostate carcinomas, there was diffuse, intense nuclear staining for AR. The urothelial tumours were either negative, had cytoplasmic staining or showed occasionally weak nuclear staining. The difference was highly significant with p<0.0001 (Mann-Whitney U test). CONCLUSIONS:We conclude that AR is an important marker as it is best able to distinguish between poorly differentiated urothelial and prostate carcinoma. AR appears superior to PSA and PSAP, which are not consistently expressed in high-grade prostate carcinoma. Also, high-grade urothelial carcinoma may be negative for CK20, p63/HMWK and occasionally CK7. We advocate the inclusion of AR in the panel of markers to differentiate these tumours.

There are a variety of morphological patterns and processes that have been implicated in the pathogenesis of prostate cancer. Prostatic intraepithelial neoplasia (PIN), inflammation with or without atrophy, and adenosis (atypical adenomatous hyperplasia) have all been given candidate status as precursor lesions of prostatic adenocarcinoma. Based on decades of research, high grade prostatic intraepithelial neoplasia (HPIN), a proliferative lesion of prostatic secretory cells, has emerged as the most likely morphological pre-invasive lesion involved in the evolution of many but not all prostatic adenocarcinomas. In this manuscript, we briefly discuss other proposed precursors of prostatic adenocarcinoma and then focus on the history, diagnostic criteria and morphology of HPIN. The incidence of HPIN and its relationship to prostate cancer is reviewed. The differential diagnosis of large glandular patterns in the prostate is discussed in depth. Finally, we summarise the recent clinicopathological studies evaluating the clinical significance of HPIN and discuss follow-up strategies in men diagnosed with HPIN.

Prostatic adenocarcinoma is an epithelial malignancy characterized by marked histological heterogeneity. It most often has a multifocal distribution within the gland, and different Gleason grades may be present within different foci. Data from our group and others have shown that the genomic deletion of the phosphatase and tensin homolog deleted on chromosome 10 (PTEN) tumor suppressor gene and the disruption of the ETS gene family have a central role in prostate cancer and are likely to be associated with Gleason grade. In this study, prostate cancer samples were systematically analyzed to determine whether there was concordance between PTEN losses and TMPRSS2-ERG fusion rearrangements, within or between foci in multifocal disease, using well-annotated tissue microarrays (TMAs) consisting of 724 cores derived from 142 radical prostatectomy specimens. Three-color fluorescence in situ hybridization analysis of both the PTEN deletion and the TMPRSS2-ERG fusion was used to precisely map genetic heterogeneity, both within and between tumor foci represented on the TMA. PTEN deletion was observed in 56 of 134 (42%) patients (hemizygous=42 and homozygous=14). TMPRSS2-ERG fusion was observed in 63 of 139 (45%) patients. When analyzed by Gleason pattern for a given TMA core, PTEN deletions were significantly associated with Gleason grades 4 or 5 over grade 3 (P<0.001). Although TMPRSS2-ERG fusions showed a strong relationship with PTEN deletions (P=0.007), TMPRSS2-ERG fusions did not show correlation with Gleason grade. The pattern of genetic heterogeneity of PTEN deletion was more diverse than that observed for TMPRSS2-ERG fusions in multifocal disease. However, the marked interfocal discordance for both TMPRSS2-ERG fusions and PTEN deletions was consistent with the concept that multiple foci of prostate cancer arise independently within the same prostate, and that individual tumor foci can have distinct patterns of genetic rearrangements.

AIMS/OBJECTIVE:  The 2005 International Society of Urological Pathology (ISUP) modification of Gleason grading recommended that the highest grade should always be included in the Gleason score (GS) in prostate biopsies. We analysed the impact of this recommendation on reporting of GS 6 versus 7. METHODS AND RESULTS/RESULTS:  Fifteen expert uropathologists reached two-thirds consensus on 15 prostate biopsies with GS 6-7 cancer. Eighty-five microphotographs were graded by 337 of 617 members of the European Network of Uropathology (ENUP), representing 19 countries. There was agreement between expert and majority member GS in 12 of 15 cases, while members upgraded in three cases. Among members and the expert consensus, a GS >6 was assigned by 64.5% and 60%, respectively. Mean member GS was higher than consensus GS in nine of 15 cases. A Gleason pattern (GP) 5 was reported by 0.3-5.6% in 10 cases. Agreement between consensus and member GS was 58.2-89.3% (mean 71.4%) in GS 6 cases and 46.3-63.8% (mean 56.4%) in GS 7 cases (P = 0.009). CONCLUSIONS:  While undergrading of prostate cancer used to be prevalent, some now tend to overgrade. Minimum diagnostic criteria for GP 4 and 5 in biopsies need to be better defined. Image libraries reviewed by experts may be useful for standardization.