Ki-67 is an independent predictor of prostate cancer death in routine needle biopsy samples: proving utility for routine assessments.

Standard clinical parameters fail to accurately differentiate indolent from aggressive prostate cancer. Our previous studies showed that immunohistochemical testing for Ki-67 improved prediction of prostate cancer death in a previous cohort of conservatively treated clinically localized prostate cancer. However there is a need for validation of usage with whole biopsy sections rather than tissue micro-arrays for use in routine diagnostics. Prostate cancer biopsy cases were identified in the UK, between 1990 and 2003, treated conservatively. Tumor extent and prostate-specific antigen (PSA) serum measurements were available. Biopsy cases were centrally reviewed by three uropathologists and Gleason conformed to contemporary ISUP 2014 criteria. Follow-up was through cancer registries up until 2012. Deaths were divided into those from prostate cancer and those from other causes. The percentage of Ki-67 in tumor cells was evaluated by immunohistochemistry on whole biopsy sections and was available for 756 patients. This percentage was used in analysis of cancer specific survival using a Cox proportional hazards model. In univariate analysis, the interquartile hazard ratio (HR) (95% confidence intervals) for continuous Ki-67 was 1.68 (1.49, 1.89), χ12 = 47.975, P < 0.001. In grade groups 1 and 2, continuous Ki-67 was a statistically significant predictor of time to death from prostate cancer, HR (95% CI) = 1.97 (1.34, 2.88), χ12 = 9.017, p = 0.003. In multivariate analysis, continuous Ki-67 added significant predictive information to that provided by grade groups, extent of disease and serum PSA, HR (95% CI) = 1.34 (1.16, 1.54), Δχ12 = 13.703, P < 0.001. We now advocate the introduction of Ki-67 as a viable and practicable prognostic biomarker in clinical practice. The association of Ki-67 with mortality was highest in grade groups 1 and 2, showing that Ki-67 can be used as a routine biomarker in patients being considered for active surveillance.

The percentage of high-grade prostatic adenocarcinoma in prostate biopsies significantly improves on Grade Groups in the prediction of prostate cancer death.

AIMS: It has been recommended that the percentage of high-grade (HG) Gleason patterns 4 and 5 should be quantified in prostate cancer. However, this has not been assessed in a cohort using prostate cancer death as an outcome, and there is debate as to whether the biopsy with the 'worst' percentage of HG disease or an 'overall' percentage of HG disease should be reported. Such data may assist in active surveillance decisions. METHODS AND RESULTS: Men with clinically localised prostate cancer diagnosed by needle biopsy from 1990 to 2003 were included. The endpoint was prostate cancer death. Clinical variables included Gleason score (GS), prostate-specific antigen level, age, clinical stage, and disease extent. Deaths were divided into those from prostate cancer and those from other causes, according to World Health Organization criteria. Nine hundred and eighty-eight biopsy cases were centrally reviewed according to criteria agreed at the Chicago International Society of Urological Pathology conference in 2014. Cores were given individual GSs and Grade Groups (GGs), and a percentage of each grade was given for each core. Both the worst percentage of HG disease seen in a biopsy series and overall percentage of HG disease were calculated. The overall percentage of HG disease was highly significant, with a hazard ratio of 4.45 for the interquartile range (95% confidence interval 3.30-6.01, P < 2.2 × 10-16 ), and was similar to the percentage of HG disease seen in the worst core. In multivariate analysis, both were highly significant. GG2 cases with ≤5% Gleason pattern 4 showed similar survival to GG1 cases. CONCLUSIONS: These data validate the use of percentage of HG disease to predict prostate cancer death. As both worst and overall percentage of HG disease are powerful predictors of outcome, either could be chosen to provide prognostic information.

Validation of a contemporary prostate cancer grading system using prostate cancer death as outcome.

BACKGROUND: Gleason scoring (GS) has major deficiencies and a novel system of five grade groups (GS⩽6; 3+4; 4+3; 8; ⩾9) has been recently agreed and included in the WHO 2016 classification. Although verified in radical prostatectomies using PSA relapse for outcome, it has not been validated using prostate cancer death as an outcome in biopsy series. There is debate whether an 'overall' or 'worst' GS in biopsies series should be used. METHODS: Nine hundred and eighty-eight prostate cancer biopsy cases were identified between 1990 and 2003, and treated conservatively. Diagnosis and grade was assigned to each core as well as an overall grade. Follow-up for prostate cancer death was until 31 December 2012. A log-rank test assessed univariable differences between the five grade groups based on overall and worst grade seen, and using univariable and multivariable Cox proportional hazards. Regression was used to quantify differences in outcome. RESULTS: Using both 'worst' and 'overall' GS yielded highly significant results on univariate and multivariate analysis with overall GS slightly but insignificantly outperforming worst GS. There was a strong correlation with the five grade groups and prostate cancer death. CONCLUSIONS: This is the largest conservatively treated prostate cancer cohort with long-term follow-up and contemporary assessment of grade. It validates the formation of five grade groups and suggests that the 'worst' grade is a valid prognostic measure.

Transitional cell carcinoma of the ureteric stump: a systematic review of the literature.

OBJECTIVE: To present a review of the literature using evidence-based criteria for diagnosis and treatment of malignant growths in the ureteric remnant following nephrectomy for non-malignant disease. METHODS: A database search using the key search words was performed, producing a total of 16 articles published between 1952 and 2009. The Oxford Centre for Evidence-Based Medicine classification was used. Statistical significance was tested by Pearson correlation. Demographic data, reason for nephrectomy, symptoms, time to diagnosis since initial nephrectomy, imaging modality and treatment option chosen, as well as histology and overall survival were reviewed. RESULTS: Analysis was possible for 33 out of 63 cases reported in the literature. There was a male predominance (82%). Visible, painless haematuria was the presenting symptom in 72% of cases. Open ureterectomy was performed in the majority of patients (85%), while none had laparoscopic surgery. Transitional cell carcinoma was found in 66% of cases. Mean follow-up was 2.7 years. Metastases were detected in 36% and correlated significantly with cancer-specific mortality (95% CI: p < 0.001). Tumour stage, grade and cell type did not correlate significantly with mortality. CONCLUSION: Gross, painless haematuria is a feature highly suggestive of neoplastic change. Diagnosis often involves multimodality imaging and endoscopy. Complete ureterectomy with removal of bladder cuff, previously resected endoscopically, is the treatment of choice. Metastases at diagnosis and follow-up carry a worse prognosis.

Histopathologic False-positive Diagnoses of Prostate Cancer in the Age of Immunohistochemistry.

There are few studies into the rate and causes of histopathologic false-positive diagnosis of prostate cancer. Only 2 of these, including a previous one from our group, incorporate survival data. In addition, in none of the previous studies had immunohistochemistry (IHC) been originally requested on any of the misdiagnosed cases. Diagnostic biopsies (n=1080) and transurethral resection of prostate specimens (n=314) from 1394 men with clinically localized prostate cancer diagnosed in the United Kingdom but treated conservatively between 1990 and 2003 were reviewed by a panel of 3 genitourinary pathologists. Thirty-five cases were excluded for being potentially incomplete. Of the remaining 1359, 30 (2.2%) were reassigned to a nonmalignant category (26 benign and 4 suspicious for malignancy). IHC had been originally performed on 7 of these. The reasons for the errors were recorded on each case: adenosis (19), partial atrophy (3), prostatic intraepithelial neoplasia (2), seminal vesicle epithelium (1), and hyperplasia (1). Follow-up of these men revealed only one prostate cancer-related death, possibly due to unsampled tumor. In conclusion, a relatively small number of prostate cancer mimics were responsible for a large proportion of the false-positive prostate cancer diagnoses and the use of IHC did not prevent the overcall of benign entities as cancer in approximately a quarter of these cases. Targeting these mimics at educational events and raising awareness of the pitfalls in the interpretation of IHC in prostate cancer diagnosis, emphasizing that glands within a suspicious focus should be treated as a whole rather than individually, may be beneficial in lowering the rate of false-positive diagnosis.

Should reporting of peri-neural invasion and extra prostatic extension be mandatory in prostate cancer biopsies? correlation with outcome in biopsy cases treated conservatively.

The identification of perineural invasion (PNI) and extraprostatic extension (ECE) in prostate cancer (PC) biopsies is time consuming and can be difficult. Although this is required information in many datasets, there is little evidence on their effect on outcome in patients treated conservatively. Cases of PC were identified from three cancer registries in the UK from men with clinically localized prostate cancer diagnosed by needle biopsy from 1990-2003. The endpoint was prostate cancer death (DOD). Patients treated radically within 6 months, those with objective evidence of metastases or who had prior hormone therapy were excluded. Follow-up was through cancer registries up until 2012. Deaths were divided into those from PC and those from other causes, according to WHO criteria. 988 biopsy cases (6522 biopsy cores) were centrally reviewed by three uropathologists and assigned a Gleason score and Grade Group (GG). The presence of both PNI and ECE was recorded. Of 988 patients, PNI was present in 288 (DOD = 75) and ECE in 23 (DOD = 5). On univariable analysis PNI was highly significantly associated with DOD (hazard ratio [HR] 2.28, 95% CI: 1.68, 3.1, log-rank test p-value = 4.8 × 10-8), but ECE was not (log-rank test p-value = 0.334). On multivariable analysis with GG, serum PSA (per 10%), clinical stage and extent of disease (per 10%), PNI lost significance (HR 1.16, 95% CI: 0.83, 1.63, likelihood ratio test p-value = 0.371). The utility of routinely examining prostate biopsies for ECE and PNI is doubtful as it is not independently associated with higher grade, stage or prognosis.

Community-acquired Klebsiella pneumoniae meningitis in an alcoholic patient with an infected pancreatic pseudocyst; a case report and review of literature.

We report a case of a 49-year-old male with a history of chronic alcoholism and evidence of a pancreatic pseudocyst on CT scanning. He presented with a 3-days history of fever, loss of appetite and upper abdominal pain. Blood cultures grew Klebsiella pneumoniae and he improved clinically with a seven-day course of intravenous co-amoxiclav and metronidazole. Two weeks later he was readmitted to hospital with impaired consciousness and septic shock, and died three days later in intensive care. Post mortem examination revealed bacterial meningitis and an infected pancreatic pseudocyst. Klebsiella pneumoniae was isolated from the pancreas and meninges.