Perineural invasion by prostate adenocarcinoma in needle biopsies predicts bone metastasis: Ten year data from the TROG 03.04 RADAR Trial.

AIMS: Perineural invasion (PNI) by prostatic adenocarcinoma is debated as a prognostic parameter. This study investigates the prognostic predictive value of PNI in a series of patients with locally advanced prostate cancer treated with radiotherapy and androgen deprivation using 10 years outcome data from the TROG 03.04 RADAR trial. METHODS: Diagnostic prostate biopsies from 976 patients were reviewed and the presence of PNI noted. Patients were followed for 10 years according to the trial protocol or until death. The primary endpoint for the study was time to bone metastasis. Secondary endpoints included time to soft tissue metastasis, transition to castration resistance, prostate cancer-specific mortality and all-cause mortality. RESULTS: PNI was detected in 449 cases (46%), with 234 cases (24%) having PNI in more than one core. The presence of PNI was significantly associated with higher ISUP grade, clinical T staging category, National Comprehensive Cancer Network risk group, and percent positive biopsy cores. The cumulative probability of bone metastases according to PNI status was significant over the 10 years follow-up interval of the study (log-rank test P < 0.0001). PNI was associated with all endpoints on univariable analysis. After adjusting for baseline clinicopathological and treatment factors, bone metastasis was the only endpoint in which PNI retained its prognostic significance (hazard ratio 1.42, 95% confidence interval 1.05-1.92, P = 0.021). CONCLUSIONS: The association between PNI and the development of bone metastases supports the inclusion of this parameter as a component of the routine histology report. Further this association suggests that evaluation of PNI may assist in selecting those patients who should be monitored more closely during follow-up.

Impact of androgen suppression and zoledronic acid on bone mineral density and fractures in the Trans-Tasman Radiation Oncology Group (TROG) 03.04 Randomised Androgen Deprivation and Radiotherapy (RADAR) randomized controlled trial for locally advanced prostate cancer.

OBJECTIVE: To study the influence of adjuvant androgen suppression and bisphosphonates on incident vertebral and non-spinal fracture rates and bone mineral density (BMD) in men with locally advanced prostate cancer. PATIENTS AND METHODS: Between 2003 and 2007, 1071 men with locally advanced prostate cancer were randomly allocated, using a 2 × 2 trial design, to 6 months i.m. leuprorelin (androgen suppression [AS]) before radiotherapy alone ± 12 months additional leuprorelin ± 18 months zoledronic acid (ZdA), commencing at randomization. The main endpoint was incident thoraco-lumbar vertebral fractures, which were assessed radiographically at randomization and at 3 years, then reassessed by centralized review. Subsidiary endpoints included incident non-spinal fractures, which were documented throughout follow-up, and BMD, which was measured in 222 subjects at baseline, 2 years and 4 years. RESULTS: Incident vertebral fractures at 3 years were observed in 132 subjects. Their occurrence was not increased by 18 months' AS, nor reduced by ZdA. Incident non-spinal fractures occurred in 72 subjects and were significantly related to AS duration but not to ZdA. Osteopenia and osteoporosis prevalence rates at baseline were 23.4 and 1.4%, respectively, at the hip. Treatment for 6 and 18 months with AS caused significant reductions in hip BMD at 2 and 4 years (P < 0.01) and ZdA prevented these losses at both time points. CONCLUSION: In an AS-naïve population, 18 months of ZdA treatment prevented the sustained BMD losses caused by 18 months of AS treatment; however, the study power was insufficient to show that AS duration or ZdA influenced vertebral fracture rates.

Therapy-associated effects in the prostate gland.

Diverse therapies are used to treat both benign prostatic hyperplasia and adenocarcinoma. Transurethral resection, a common surgical procedure, may give rise to characteristic necrobiotic granulomas that manifest in subsequent pathology samples. Radiation and hormone therapy have traditionally been used in prostatic adenocarcinoma. Morphological effects are often identified in needle biopsy specimens, transurethral resectates, and radical prostatectomy specimens. A range of histological changes are noted in the non-neoplastic prostate tissue, as well as in the pre-neoplastic and carcinomatous areas. Other ablative therapies, such as cryotherapy, and emerging focal therapies, including high-intensity focused ultrasound, photodynamic therapy, and interstitial laser thermotherapy, may have morphological effects on prostate tissue. It is important for the pathologist to be aware of the spectrum of histological changes affecting the prostate gland post-therapy. The treatment effects may obscure residual carcinoma, and make measurements of tumour extent and stage difficult. Furthermore, some therapies can profoundly alter the neoplastic glands to such an extent that Gleason scoring is no longer valid. As new therapies are developed for prostate cancer, it is important to document their effects on benign and malignant prostate tissue and to understand possible implications for traditional prognostic factors, especially Gleason grade.

Utility of racemase and other immunomarkers in the detection of adenocarcinoma in prostatic tissue damaged by high intensity focused ultrasound therapy.

AIMS: High intensity focused ultrasound (HIFU) is an emerging alternative for the treatment of prostate adenocarcinoma. Alpha-methylacyl-CoA racemase (AMACR) has been shown to be a sensitive immunomarker for prostate cancer, however, there is no information available concerning its utility and that of other immunomarkers for the detection of malignancy after HIFU therapy. METHODS: AMACR expression was examined in 11 cases of prostatic carcinoma treated by HIFU, with histological evidence of residual carcinoma. In seven cases tumour was examined from thin core biopsies and in four cases from tissue fragments obtained by transurethral resection of prostate (TURP). In addition to AMACR, immunostaining was also undertaken for p63, cytokeratin 34betaE12, cytokeratin 5, cytokeratin 8-18, prostate specific alkaline phosphatase (PSAP), prostate specific antigen (PSA), chromogranin and CD56. RESULTS: In two of the cases foci of tumour were cut out in serial sections. AMACR was expressed in eight of nine evaluable cases (4/5 biopsies and 4/4 TURP specimens). Cytokeratin 8-18 and PSAP were positive in all cases, whereas PSA was positive in five of nine cases. Cytokeratin 34betaE12, cytokeratin 5, and p63 marked the basal layer in normal prostatic glands, but were negative in neoplastic glands. In four cases we found tumour cells with positive staining for CD56 and chromogranin. CONCLUSIONS: A panel with positive markers for AMACR, and negative markers for p63/cytokeratin 5/cytokeratin 34betaE12 confirms the neoplastic nature of the residual glands on biopsies or TURP fragments sampled after HIFU therapy.

Demographic and clinical factors as determinants of serum levels of prostate specific antigen and its derivatives.

BACKGROUND: To characterise the association between demographic and clinical factors and levels of total prostate specific antigen (tPSA) and its molecular derivatives complexed PSA (cPSA), free PSA (fPSA) and the ratio of free to total PSA (%fPSA)] in New Zealand Maori, Pacific Islanders and Europeans, in order to determine whether reported ethnic differences in PSA can be explained by lifestyle and social factors. MATERIALS AND METHODS: Demographic and clinical factors were examined in relation to tPSA, fPSA and cPSA levels, in 1405 Maori, Pacific Island and New Zealand European men with no clinical evidence of prostate cancer, in the Wellington region of New Zealand. Any associations between levels of PSA and PSA derivatives and body mass index, smoking status, family cancer history, non-steroidal anti-inflammatory/vitamin supplement usage, number of sexual partners, age at first intercourse, previous vasectomy, marital/partnership status, educational level and socioeconomic status were investigated by backwards stepwise regression analysis, correcting for age, ethnicity and urinary symptoms. RESULTS: Not being married/partnered was associated with increased tPSA, fPSA and cPSA. tPSA and cPSA decreased with regular non-steroidal anti-inflammatory use. cPSA was decreased in subjects with a first degree relative with any form of cancer. tPSA and fPSA were decreased if the body mass index was > 34. fPSA and %fPSA were decreased in current and former smokers. CONCLUSION: Demographic and clinical factors appear to have a significant effect on levels of PSA and its various derivatives and may account for previously observed ethnic differences. It is important that these associations are taken into account when comparing individual PSA results with standard reference ranges.