Relapse patterns after low-dose-rate prostate brachytherapy.

PURPOSE: When biochemical failure (BF) develops after low-dose-rate prostate brachytherapy, the relapse site is frequently not found. We set out to find whether prostate-specific membrane antigen positron emission tomography -CT (PSMA PET-CT) scanning has improved knowledge of relapse patterns. METHODS AND MATERIALS: A database was analyzed, which contained information and long-term followup on 903 men who had an iodine-125 seed implant as monotherapy for early-stage prostate cancer. There was a total of 68 BFs. RESULT: In 38 men developing BF before PSMA PET-CT scanning was available, the site of relapse was local in six, distant in twelve, and unknown in twenty. In 30 men developing BF more recently who had a PSMA PET-CT scan, the relapse site was demonstrated in all cases, and 19 (63%) men had relapsed at the prostate base. Radiation dosimetry of base relapses and paired controls demonstrated that implants routinely delivered a lower radiation dose to the base than to the rest of the prostate. Eight of seventeen cases found to have prostate relapse only underwent salvage prostatectomy. CONCLUSION: PSMA PET-CT scanning is highly effective in demonstrating the relapse site(s) when BF develops after low-dose-rate prostate brachytherapy. Knowledge of the relapse site increases management options for men developing BF.

Dataset for the reporting of renal biopsy for tumour: recommendations from the International Collaboration on Cancer Reporting (ICCR).

The International Collaboration on Cancer Reporting (ICCR) has developed a suite of detailed datasets for international implementation. These datasets are based on the reporting protocols developed by the Royal College of Pathologists (UK), The Royal College of Pathologists of Australasia and the College of American Pathologists, with modifications undertaken by international expert groups appointed according to ICCR protocols. The dataset for the reporting of renal biopsy for tumour is designed to provide a structured reporting template containing minimum data recording key elements suitable for international use. In formulating the dataset, the ICCR panel incorporated recommendations from the 2012 Vancouver Consensus Conference of the International Society of Urological Pathology (ISUP) and the 2016 edition of the WHO Bluebook on tumours of the urinary and male genital systems. Reporting elements were divided into Required (Core) and Recommended (Non-core) components of the report. Required elements are as follows: specimen laterality, histological tumour type, WHO/ISUP histological tumour grade, sarcomatoid morphology, rhabdoid morphology, necrosis, lymphovascular invasion and coexisting pathology in non-neoplastic kidney. Recommended reporting elements are as follows: operative procedure, tumour site(s), histological tumour subtype and details of ancillary studies. In particular, it is noted that fluorescence in situ hybridisation studies may assist in diagnosing translocation renal cell carcinoma (RCC) and in distinguishing oncocytoma and eosinophilic chromophobe RCC. It is anticipated that the implementation of this dataset into routine clinical practice will facilitate uniformity of pathology reporting worldwide. This, in turn, should have a positive impact on patient treatment and the quality of demographic information held by cancer registries.

Data set for the reporting of carcinoma of renal tubular origin: recommendations from the International Collaboration on Cancer Reporting (ICCR).

AIMS: The International Collaboration on Cancer Reporting (ICCR) has provided detailed data sets based upon the published reporting protocols of the Royal College of Pathologists, the Royal College of Pathologists of Australasia and the College of American Pathologists. METHODS AND RESULTS: The data set for carcinomas of renal tubular origin treated by nephrectomy was developed to provide a minimum structured reporting template suitable for international use, and incorporated recommendations from the 2012 Vancouver Consensus Conference of the International Society of Urological Pathology (ISUP) and the fourth edition of the World Health Organisation Bluebook on tumours of the urinary and male genital systems published in 2016. Reporting elements were divided into those, which are required and recommended components of the report. Required elements are: specimen laterality, operative procedure, attached structures, tumour focality, tumour dimension, tumour type, WHO/ISUP grade, sarcomatoid/rhabdoid morphology, tumour necrosis, extent of invasion, lymph node status, surgical margin status, AJCC TNM staging and co-existing pathology. Recommended reporting elements are: pre-operative treatment, details of tissue removed for experimental purposes prior to submission, site of tumour(s) block identification key, extent of sarcomatoid and/or rhabdoid component, extent of necrosis, presence of tumour in renal vein wall, lymphovascular invasion and lymph node status (size of largest focus and extranodal extension). CONCLUSIONS: It is anticipated that the implementation of this data set in routine clinical practice will inform patient treatment as well as provide standardised information relating to outcome prediction. The harmonisation of data reporting should also facilitate international research collaborations.

A prospective audit of the 10-year outcomes from low dose-rate brachytherapy for early stage prostate cancer.

AIM: New Zealand men diagnosed with early stage prostate cancer need to know what outcomes to expect from management options. METHODS: Between 2001 and 2016, 951 men were treated with low dose-rate brachytherapy (permanent iodine-125 seed implantation) by the Wellington Prostate Brachytherapy Group based at Southern Cross Hospital, Wellington. At follow up after treatment, men had their PSA measured and were scored for urinary, bowel and sexual side effects. RESULTS: Median follow-up of men was 7.9 years (range 2.0-16.3 years). Ten-year PSA control was 95% for the 551 men with low-risk prostate cancer and 82% for the 400 men with intermediate-risk prostate cancer. Adverse effects were generally minor and short-term only. Temporary urinary obstruction developed soon after the implant in 2.6% men, and the 10-year cumulative risk of urethral stricture was 2.6%. Erectile dysfunction developed in 29% men, two-thirds of whom had a good response to a PDE5 inhibitor. Most men returned to a normal routine within four days of the implant. CONCLUSION: LDR brachytherapy is a highly effective low-impact treatment option for New Zealand men with early stage prostate cancer.

Proteins Annexin A2 and PSA in Prostate Cancer Biopsies Do Not Predict Biochemical Failure.

BACKGROUND/AIM: We previously reported the use of mass spectrometry and western blotting to identify proteins from tumour regions of formalin-fixed paraffin-embedded biopsies from 16 men who presented with apparently localized prostate cancer, and found that annexin A2 (ANXA2) appeared to be a better predictor of subsequent biochemical failure than prostate-specific antigen (PSA). MATERIALS AND METHODS: In this follow-up study, ANXA2 and PSA were measured using western blotting of proteins extracted from biopsies from 37 men from a subsequent prostate cancer trial. RESULTS: No significant differences in ANXA2 and PSA levels were observed between men with and without biochemical failure. The statistical effect sizes were small, d=0.116 for ANXA2, and 0.266 for PSA. CONCLUSION: ANXA2 and PSA proteins measured from biopsy tumour regions are unlikely to be good biomarkers for prediction of the clinical outcome of prostate cancer presenting with apparently localized disease.

Mucinous adenocarcinoma of prostate and prostatic adenocarcinoma with mucinous components: a clinicopathological analysis of 143 cases.

AIM: The clinical significance of mucinous prostatic adenocarcinoma (PCa) remains uncertain. METHODS: From 6440 cases of PCa treated by radical prostatectomy from 2009 to 2014, mucinous components of 5-100% were found in 143 (2.2%) cases. RESULTS: The mean age was 61.4 years, mean pre-operative serum prostate-specific antigen (PSA) was 7.8 ng/ml and clinical stage category was cT1 in 81% and cT2 in 19% of cases. Cases were graded using the 2014 International Society of Urological Pathology recommendation of grading underlying architecture, and Gleason scores (GS) were 3 + 4 in 13.3%, 4 + 3 in 54.5%, 4 + 4 in 2.1%, 3 + 4 or 4 + 3 with tertiary 5 in 11.9% and 9-10 in 18.2%. The mucinous component invariably had a high-grade component. Extraprostatic extension was found in 46.8% of cases. In 21.6%, tumour volume was ≥3 cm³ and 9.7% had surgical margin positivity. Seminal vesicle involvement was found in 6.9%. In 73 cases the mucinous component was >25%, and when cases were divided on the basis of the area of mucin present (≤25 versus >25%) there was no significant difference between clinical or pathological features. Similar findings were achieved when cases were compared with grade-matched non-mucinous carcinoma controls. The 5-year biochemical recurrence rates for mucinous versus non-mucinous cancer were 12.5 versus 17% (P = 0.15). CONCLUSION: PCa with mucinous components is often high grade; however, the prognosis appears to be similar to non-mucinous cancers of similar GS.

Gleason and Fuhrman no longer make the grade.

Grading is an important prognostic parameter for prostate adenocarcinoma and renal cell carcinoma (RCC); however, the most frequently used classifications fail to account for advances in our understanding of the diagnostic features, classification and/or behaviour of these tumours. In 2005 and 2014, the International Society of Urological Pathology (ISUP) proposed changes to Gleason scoring with the adoption of the ISUP grading for prostate cancer in 2014 (grade 1, score 3 + 3; grade 2, score 3 + 4; grade 3, score 4 + 3; grade 4, score 8; grade 5, score 9-10). Internationally the Fuhrman grading system is widely employed despite criticisms related to its application, validity, and reproducibility. In 2012, the ISUP established a grading system for RCC (grade 1, the nucleolus is not seen or is inconspicuous and basophilic at ×400 magnification; grade 2, nucleoli are eosinophilic and clearly visible at ×400 magnification; grade 3, nucleoli are clearly visible at ×100 magnification; grade 4, tumours show extreme pleomorphism or rhabdoid and/or sarcomatoid morphology). This grading has been validated for clear cell RCC and papillary RCC. It was further recommended that chromophobe RCC not be graded. For other morphotypes of RCC, ISUP grading has not been validated as a prognostic parameter, but can be used for descriptive purposes.

Pleomorphic giant cell carcinoma of the urinary bladder: an extreme form of tumour de-differentiation.

AIMS: Vesical pleomorphic giant cell carcinoma (PGCC) is a variant of urothelial carcinoma (UC) characterized by highly pleomorphic tumour with giant cells. Fewer than 10 cases have been reported, and our aim was to determine the clinical and pathological features of a series of tumours from a specialized uropathology laboratory. METHODS AND RESULTS: Thirteen cases of PGCC of the bladder were identified. There were nine males and four females, ranging in age from 53 to 92 years (mean 72 years). Associated conventional high-grade UC was seen in eight cases, while three cases also had micropapillary UC and one plasmacytoid UC. UC in situ (CIS) was present in five cases and occasional bizarre cells were seen in both UC and CIS. The proportion of PGCC present varied from 40% to 100% of tumour. Immunostaining performed on 10 cases showed uniform positivity for CK 8/18 and AE1/AE3, while most tumours were positive for CK7, CK20, uroplakin III and GATA binding protein 3 (GATA3). ß-human chorionic gonadotrophin (ß-hCG) was negative. Of 10 patients with follow-up, five died within 1 year and four are alive with tumour. CONCLUSIONS: The association of PGCC with UC and an overlap in immunoexpression suggests that PGCC represents an extreme form of UC de-differentiation.

Proteins from formalin-fixed paraffin-embedded prostate cancer sections that predict the risk of metastatic disease.

BACKGROUND: Prostate cancer is the most frequently diagnosed cancer in men and the third leading cause of cancer related deaths among men living in developed countries. Biomarkers that predict disease outcome at the time of initial diagnosis would substantially aid disease management. RESULTS: Proteins extracted from formalin-fixed paraffin-embedded tissue were identified using nanoflow liquid chromatography-MALDI MS/MS or after separation by one- or two-dimensional electrophoresis. The proteomics data have been deposited to the ProteomeXchange with identifier PXD000963. A list of potential biomarker candidates, based on proposed associations with prostate cancer, was derived from the 320 identified proteins. Candidate biomarkers were then examined by multiplexed Western blotting of archival specimens from men with premetastatic disease and subsequent disease outcome data. Annexin A2 provided the best prediction of risk of metastatic disease (log-rank Chi squared p = 0. 025). A tumor/control tissue >2-fold relative abundance increase predicted early biochemical failure, while <2-fold change predicted late or no biochemical failure. CONCLUSIONS: This study confirms the potential for use of archival FFPE specimens in the search for prognostic biomarkers for prostate cancer and suggests that annexin A2 abundance in diagnostic biopsies is predictive for metastatic potential. Protein profiling each cancer may lead to an overall reduction in mortality from metastatic prostate cancer as well as reduced treatment associated morbidity.

Patterns of failure after iodine-125 seed implantation for prostate cancer.

PURPOSE: To determine the site of relapse when biochemical failure (BF) occurs after iodine-125 seed implantation for prostate cancer. MATERIALS AND METHODS: From 2001-2009, 500 men underwent implantation in Wellington, New Zealand. Men who sustained BF were placed on relapse guidelines that delayed restaging and intervention until the prostate-specific antigen (PSA) was ⩾20 ng/mL. RESULTS: Most implants (86%) had a prostate D90 of ⩾90%, and multivariate analysis showed that this parameter was not a variable that affected the risk of BF. Of 21 BFs that occurred, the site of failure was discovered to be local in one case and distant in nine cases. Restaging failed to identify the site of relapse in two cases. In nine cases the trigger for restaging had not been reached. CONCLUSIONS: If post-implant dosimetry is generally within the optimal range, distant rather than local failure appears to be the main cause of BF. Hormone treatment is therefore the most commonly indicated secondary treatment intervention (STI). Delaying the start of STI prevents the unnecessary treatment of men who undergo PSA 'bounce' and have PSA dynamics initially mimicking those of BF.

A comparison of cancer statistics in New Zealand and Australia: 1996-2007.

AIM: To compare the burden and outcomes of cancer in New Zealand with those in Australia. METHODS: For the years 1996-1997 and 2006-2007, the incidence and mortality of cancer in New Zealand and Australia was compared to determine if differences between the two countries had changed over the decade under study. Summarised cancer data from New Zealand and Australia, age standardised to the 2002 World Health Organisation's standard population, were used to make the comparisons. RESULTS: For the 11 year timeframe of this study, total rates of cancer incidence reduced in New Zealand and increased in Australia. The incidence of cancer in New Zealand, relative to Australia, changed from an excess of +10.3 to a deficit of -27.5 per 100,000 people. When considering the excess in terms of gender, the annual excess of cancer registrations for New Zealand females fell from +19.9 to +0.9 per 100,000, and male cancer registration fell from an excess of +3.7 to a deficit of -58.0 per 100,000, due almost entirely to a surge in prostate cancer registration in Australia. Over the same 11-year timeframe, cancer-specific mortality rates decreased in both countries, but there was no change in the difference between New Zealand and Australian rates, which remained 10% higher in New Zealand. Similar to findings on 1996/7 data, the main cancer sites responsible for the overall excess mortality in 2006/7 were colorectal cancer in both sexes, and lung and breast cancer in females. CONCLUSION: The persisting different cancer mortality rates between the two countries is likely to have been partly due to lifestyle and ethnic differences in the populations, and partly due to New Zealanders presenting with more advanced cancers and having less easy access to some treatments. Until we know the relative contributions of these factors, it will be difficult for New Zealand to plan interventions in the future which have a good chance of lifting our cancer survival rates to those of our closest neighbour. The collection of clinical stage on all new cancer registrations would provide the base information required.

Total submission of pelvic lymphadenectomy tissues removed during radical prostatectomy for prostate cancer increases lymph node yield and detection of micrometastases.

AIMS: The detection of lymph node metastases has prognostic and therapeutic implications for patients undergoing radical prostatectomy for prostate cancer. Macroscopic identification of pelvic lymph nodes in surgical lymphadenectomy specimens can be difficult, with a potential for incomplete submission of lymph nodes for microscopic examination. This study was undertaken to determine whether complete sampling of lymphadenectomy specimens would improve the detection of metastatic disease in patients undergoing radical prostatectomy. METHODS AND RESULTS: We examined 109 pelvic lymphadenectomies accompanying radical prostatectomy specimens to assess the benefit of complete submission of the lymph node packets to detect extra lymph nodes and metastatic disease. We found that blocking the residual tissue, after all palpable lymph nodes had been identified, increased the mean number of lymph nodes from 3.8 to 10.8, with an average of 0.84 macroscopically undetectable nodes being recovered per block submitted. Metastatic prostate cancer was identified in eight cases, one of which had cancer in an impalpable lymph node only. CONCLUSIONS: Submission of all pelvic lymphadenectomy tissue for histological examination improves the yield of lymph nodes and the detection of metastatic prostate cancer.

Clinical significance of cancer in radical prostatectomy specimens: analysis from a contemporary series of 2900 men.

With prostate specific antigen (PSA) testing, up to 49% of detected tumours are small and in some of these cases there is a possibility that the tumour will remain clinically insignificant during the patient's remaining lifetime. The current study was performed to characterise the extent of cancer in men treated by radical prostatectomy (RP) in a community without population-based PSA screening. Clinical and pathological data of 2900 patients who underwent RP between 2008 and 2012 were analysed. Specimens were entirely embedded and evaluated by routine haematoxylin and eosin staining. Tumours were graded using recent modifications to the International Society of Urological Pathology (ISUP) modified Gleason grading system, and staged according to the ISUP recommendations. Tumours were considered pathologically insignificant if organ confined, with a volume of <0.5  cc and a Gleason score (GS) of <7. The mean age of patients in the series was 63 years (range 32-79 years) and the mean pre-operative PSA was 7.16  ng/mL (range 0.4-69). In total, 2614 (90.1%) were classified as cT1; however, insignificant tumours were found in only 150 (5.2%) patients following examination of the radical prostatectomy specimen. A total of 2681 cases (92.4%) had a final GS of ≥7, 1144 (39.4%) had extraprostatic extension (EPE), of which 88.7% were classified as established; 669 (23.1%) had a tumour volume of >3  cc and 284 (9.8%) had surgical margin positivity. Seminal vesicle involvement was seen in 159 (5.5%) cases. Of 693 patients who had a lymphadenectomy, 31 (4.5%) had lymph node metastases. Aged ≤50 years were 212 (7.3%) patients (mean age 47 years). Of these, 194 were classified as cT1 while 192 (90.6%) were found to have significant cancer on examination of the radical prostatectomy specimen. We have shown in our series that although 90.1% of tumours were cT1, an overwhelming majority of tumours were found to be pathologically significant following RP, with a high proportion of cases showing high stage disease, seminal vesicle involvement and lymph node metastasis. These results suggest that, contrary to estimates from international trials, ad hoc PSA testing is associated with low levels of over-treating.

Prostate cancer: the new evidence base for diagnosis and treatment.

Although prostate cancer (PC) has a significant mortality, there is debate regarding the utility of PC screening. This debate continues as major studies investigating the value of population-based screening have yet to be concluded. Despite this, there is increasing evidence from preliminary reports from these series, as well as numerous others relating to outcome prediction for PC, that early detection leads to improved outcomes and a decrease in the burden of metastatic disease on our healthcare system. PC is rarely symptomatic until it has metastasised to bone and because of this PSA-based screening remains the only widely available and reliable method of diagnosis for organ-confined disease. There is now compelling evidence to show that: 1. Cancers diagnosed by screening are more likely to be early stage, when most can be cured by a number of different treatment options. 2. The maximum benefits of screening are for men aged 50-70 years. Older men have a greater chance of a clinically insignificant cancer being diagnosed for which treatment is not necessary. 3. The familial risks of PC are well recognised. In particular, men with one or more first-degree relatives already diagnosed with the disease should be actively encouraged to undergo screening. 4. Modern histopathological assessment of fine core needle biopsies of the prostate allows for the likely behaviour of cancer present to be accurately predicted. Changes that mimic those of malignancy can be confidently identified, so these cases are no longer incorrectly diagnosed. These improvements mean that now most men aged 50-70 years diagnosed with PC will have clinically significant cancers that require treatment.