Analysis of active surveillance uptake for localized prostate cancer in Quebec in 2016: A Canadian bicentric study and comparison with 2010 data.

INTRODUCTION: Active surveillance (AS) has emerged as a primary management strategy for low-risk prostate cancer (PC) patients. We aimed to assess AS uptake over a 1-year snapshot throughout Quebec and to compare it to 2010 multicentric Canadian data. METHODS: A retrospective chart review and data collection was performed in 1 academic and 2 non-academic community centres from Quebec, among men identified in 2016 with localized T1c-T2c PC on biopsy, fulfilling NCCN criteria of low-risk (LR)-PC, including very-low-risk (VLR) and non-VLR-PC, and favourable-intermediate risk (FIR)-PC. AS adherence was defined when chosen as initial strategy, without any radical treatment within 6 months. RESULTS: Overall, 259 patients fulfilled the inclusion criteria with 50.2% of VLR-PC patients. At 6 months, 81% patients in the LR group and 65% in the FIR group were considered as adherent to AS, in both centres, but with an increased use of AS in the community centres compared to 2010 data. The rates of AS maintenance decreased at 12 months to respectively 69% and 58%. Among the VLR group, the rate of initiation was 98% and decreased to 85% at 12 months. CONCLUSION: Our data suggest that the majority of low-risk PC patients indeed initiated an AS in 2016, with even a greater proportion of VLR-PC patients compared to 2010. This ideal strategy should be encouraged and improved at 12 months, and assessed with recent data and longer follow-up.

PREDICT Plus: development and validation of a prognostic model for early breast cancer that includes HER2.

BACKGROUND: Predict (www.predict.nhs.uk) is an online, breast cancer prognostication and treatment benefit tool. The aim of this study was to incorporate the prognostic effect of HER2 status in a new version (Predict+), and to compare its performance with the original Predict and Adjuvant!. METHODS: The prognostic effect of HER2 status was based on an analysis of data from 10 179 breast cancer patients from 14 studies in the Breast Cancer Association Consortium. The hazard ratio estimates were incorporated into Predict. The validation study was based on 1653 patients with early-stage invasive breast cancer identified from the British Columbia Breast Cancer Outcomes Unit. Predicted overall survival (OS) and breast cancer-specific survival (BCSS) for Predict+, Predict and Adjuvant! were compared with observed outcomes. RESULTS: All three models performed well for both OS and BCSS. Both Predict models provided better BCSS estimates than Adjuvant!. In the subset of patients with HER2-positive tumours, Predict+ performed substantially better than the other two models for both OS and BCSS. CONCLUSION: Predict+ is the first clinical breast cancer prognostication tool that includes tumour HER2 status. Use of the model might lead to more accurate absolute treatment benefit predictions for individual patients.

Prognostic value of various morphometric measurements of tumour extent in prostate needle core tissue.

AIMS: Predicting prostatic cancer patients' outcome is a major objective for clinicians and patients. Several nomograms are currently implemented prior to treatment to help predict clinical and pathological outcome. The aim of this study was to investigate the prognostic significance of morphometric measurements of cancer on the needle biopsy specimen in relation to the final pathological stage or the biochemical failure status following radical prostatectomy, and to determine which measurement of tumour length in cases with discontinuous foci of cancer (DFC) is most reliably reflective of the pathological stage. METHODS AND RESULTS: Of the 100 patients included in this study, 34% had high-stage disease (pT >or= 3 and/or pN1) and 16% experienced biochemical recurrence. The analysis showed that fraction of positive cores, total percentage of cancer and both total and greatest millimetric cancer lengths were the variables most closely associated with pathological stage and biochemical failure status. CONCLUSIONS: This study confirms the prognostic value of recording tumour extent in prostatic needle biopsy reporting. However, the results are inconclusive in determining the best method to record tumour length in cores with DFC and larger studies are needed to answer this question fully.

Germline BRCA1/2 mutations and p27(Kip1) protein levels independently predict outcome after breast cancer.

PURPOSE: Decreased levels of the cyclin-dependent kinase inhibitor p27(Kip1) in breast cancer are associated with a poor outcome. The prognostic significance of BRCA1/2 mutations is less clear, and the relationship between BRCA1/2 mutation status, p27(Kip1) protein levels, and outcome has not been studied. PATIENTS AND METHODS: Pathology blocks from 202 consecutive Ashkenazi Jewish women with primary invasive breast cancer were studied. Tumor DNA was tested for the three common BRCA1/2 founder mutations present in Ashkenazi Jews, and p27(Kip1) expression was evaluated by immunohistochemistry. The median follow-up was 6.4 years. RESULTS: Thirty-two tumors (16%) were positive for a BRCA1/2 mutation. Low p27(Kip1) expression was seen in 110 tumors (63%) and was significantly associated with BRCA1/2 mutations (odds ratio, 4.0; 95% confidence interval [CI], 1.4 to 11.1; P =.009). BRCA1/2 mutation carriers had a significantly worse 5-year distant disease-free survival (DDFS) compared with women without BRCA1/2 mutations (58% v 82%; P =.003). Similar results were seen for women whose tumors expressed low levels of p27(Kip1), compared with those with high levels (5-year DDFS, 68% v 93%; P<.0001). In a multivariate analysis, both BRCA1/2 mutation and low p27(Kip1) expression were associated with a shorter DDFS (relative risk [RR], 2.1; 95% CI, 1.0 to 4.3; P =.05; and RR, 3.9; 95% CI, 1.4 to 11.1; P =.01, respectively). CONCLUSION: In this study, we showed that BRCA1/2 mutations were associated with low levels of p27(Kip1) in breast cancer. Both BRCA1/2 and p27(Kip1) status were identified as independent prognostic factors.

Germ-line BRCA1 mutation is an adverse prognostic factor in Ashkenazi Jewish women with breast cancer.

Germ-line mutations in BRCA1 confer an increased risk of developing breast and ovarian cancer, but little is known about the clinical course of breast cancer in BRCA1 mutation carriers compared with noncarriers. Two recurrent BRCA1 mutations (185delAG and 5382insC) are common ( approximately 1.3%) in Ashkenazi Jews and account for about 20% of breast cancers diagnosed before age 40 in this group. We assayed paraffin-embedded tumor blocks from 117 unselected Ashkenazi Jewish women with primary breast cancer, diagnosed before age 65 at a single institution, for the presence of either of the two BRCA1 mutations. We reviewed the medical records and constructed survival curves for BRCA1-positive and -negative subgroups. Twelve of the women (10.3%) were found to carry BRCA1 mutations (eight mutations were 185delAG, and four were 5382insC). The probability of death from breast cancer in the first 5 years was 35.7% in the BRCA1 mutation-positive group and 4.3% in the 100 women without a mutation (P = 0.0023). The 5-year distant disease-free survival was 68.2% in BRCA1 mutation carriers and 88.7% in noncarriers (P = 0.019). These data suggest that breast cancer occurring in an Ashkenazi Jewish woman carrying a germ-line BRCA1 mutation has an adverse prognosis. This information is available before the diagnosis of breast cancer, and therefore, this finding may have important implications for prevention of breast cancer in BRCA1 mutation carriers.

The protein tyrosine phosphatase PRL-2 interacts with the magnesium transporter CNNM3 to promote oncogenesis.

The three PRL (phosphatases of regenerating liver) protein tyrosine phosphatases (PRL-1, -2 and -3) have been identified as key contributors to metastasis in several human cancers, yet the molecular basis of their pro-oncogenic property is unclear. Among the subfamily of PRL phosphatases, overexpression of PRL-2 in breast cancer cells has been shown to promote tumor growth by a mechanism that remains to be uncovered. Here we show that PRL-2 regulates intracellular magnesium levels by forming a functional heterodimer with the magnesium transporter CNNM3. We further reveal that CNNM3 is not a phosphorylated substrate of PRL-2, and that the interaction occurs through a loop unique to the CBS pair domains of CNNM3 that exists only in organisms having PRL orthologs. Supporting the role of PRL-2 in cellular magnesium transport is the observation that PRL-2 knockdown results in a substantial decrease of cellular magnesium influx. Furthermore, in PRL-2 knockout mice, serum magnesium levels were significantly elevated as compared with control animals, indicating a pivotal role for PRL-2 in regulating cellular magnesium homeostasis. Although the expression levels of CNNM3 remained unchanged after magnesium depletion of various cancer cell lines, the interaction between endogenous PRL-2 and CNNM3 was markedly increased. Importantly, xenograft tumor assays with CNNM3 and a mutant form that does not associate with PRL-2 confirm that CNNM3 is itself pro-oncogenic, and that the PRL-2/CNNM3 association is important for conferring transforming activities. This finding is further confirmed from data in human breast cancer tissues showing that CNNM3 levels correlate positively with both PRL-2 expression and the tumor proliferative index. In summary, we demonstrate that oncogenic PRL-2 controls tumor growth by modulating intracellular magnesium levels through binding with the CNNM3 magnesium transporter.

Florid soft-tissue decidual reaction: a potential mimic of neoplasia.

While undergoing a repeat Caesarian section, a 21-year-old woman was found to have a subcutaneous, 3.5-cm tumor-like lesion in the abdominal wall. It had a lobulated contour and consisted of gelatinous tan nodules with intervening fibrous septa. It had a composite histology, including a solid pattern of large glassy cells with a predominant perivascular and pericystic/cisternal topography (35% surface area); a pattern of dyscohesive, vacuolated cells including physaliphorous-like forms (35% surface area); and a myxoid pattern of spindle to stellate cells showing frequent cell contact and lying within an optically clear or pale eosinophilic and bubbly extracellular matrix with a prominent capillary framework. A strong and diffuse cytoplasmic expression of vimentin (only) was present in all cytoarchitectural patterns. The extracellular matrix and intracytoplasmic vacuoles contained abundant acid mucosubstance, mostly hyaluronic acid. No distinct endometrial gland, stigma of hemorrhage, or nuclear estrogen/progesterone receptor protein expression was observed. There were variously sized and shaped cystic spaces lined by a flat to cuboidal cytokeratin-positive cell lining and focally containing neutral and acid mucosubstance. These spaces are interpreted as dilated endometrial glands rather than mechanically entrapped inclusions of mesothelial origin. In this setting, florid decidual reaction represents a potential diagnostic pitfall because it could be confused with more commonly encountered myxoid or epithelioid tumors of mesenchymal, epithelial, or melanocytic cell lineage.

Spindle cell myoepithelioma of the nasal cavity.

Minor salivary gland neoplasms with mesenchymal-like features are uncommon in the sinonasal tract. We herein report a case of spindle cell myoepithelioma of the nasal cavity in a 69-year-old woman who presented with a rapidly expanding tumor accompanied by episodes of epistaxis. Although initially considered as a mesenchymal neoplasm, ultrastructural and immunophenotypical characterization demonstrated its myoepithelial nature. In the sinonasal setting, this unusual neoplasm may be confused with soft tissue tumors showing spindle cell or myxoid features. Staining for cytokeratin is found to be the most useful adjunct to diagnosis.

Glycogen-rich clear cell rhabdomyosarcoma of the mediastinum. Potential diagnostic pitfall.

A 63-year-old black man of Caribbean origin, seropositive for human T-cell lymphoma virus type I (HTLV-I), presented with a 4-week history of progressive dyspnea, and was found to have a tumor of the anterior mediastinum. Incisional biopsy revealed a malignant neoplasm with a solid pattern of glycogen-rich clear cells. Diffuse expression of vimentin was observed, whereas only rare cells were immunoreactive for muscle-specific actin and desmin. Ultrastructure revealed a large amount of mono-particulate glycogen in most cells and features of rhabdomyogenic differentiation in occasional cells. The autopsy revealed a 23 x 14-cm (1,345 g), soft and white mediastinal neoplasm bulging in the right thorax with right pleural metastases. HTLV-1 proviral genome was not detected within tumor cells by polymerase chain reaction. This rhabdomyosarcoma is best classified as the solid subtype of the alveolar variant, with an unusually large amount of cytoplasmic glycogen. Clear cell rhabdomyosarcoma could be potentially confused with more commonly encountered clear cell tumors, particularly in the mediastinum.

Pleomorphic soft tissue myogenic sarcomas of adulthood. A reappraisal in the mid-1990s.

325 diverse sarcomas, 39 rhabdomyosarcomas (RMS), including all histologic variants, and 135 leiomyosarcomas (LMS) were identified. Within these two groups, 18 (46%) of the RMS and 14 (10%) of the LMS represented pleomorphic variants. These neoplasms were studied by morphology (histology and ultrastructure) and by immunohistochemical methods employing antibodies to intermediate filaments (vimentin and desmin) and actin isoforms [alpha-smooth (sm) and alpha-sarcomeric (sr) actins]. Twenty-four pleomorphic malignant fibrous histiocytomas (MFH) and eight pleomorphic liposarcomas (LS) were examined in a similar fashion. By light microscopy, the pleomorphic RMS, LMS, and MFH were indistinguishable, as each was dominated by pleomorphic cells disposed in a haphazard growth pattern; moreover, many featured fascicular, storiform, and sclerotic zones. The distinction between these neoplasms became apparent only following immunohistochemistry and/or ultrastructural study. All pleomorphic RMS disclosed rudimentary sarcomeres and exhibited the following cytoskeletal profile: vimentin (+) (18 of 18), desmin (+) (14 of 18), alpha-sr actin (+) (18 of 18) and alpha-sm actin (+) (five of 18). All the pleomorphic LMS featured smooth-muscle differentiation of variable degrees in the form of cytoplasmic bundles of microfilaments and associated dense bodies; their cytoskeletal profile was vimentin (+) (14 of 14), desmin (+) (seven of 14), alpha-sr actin (+) (none of 14), and alpha-sm actin (+) (eight of 14). The latter was demonstrated in all moderately differentiated, but absent or only focally expressed in poorly differentiated variants. All pleomorphic MFH and LS were devoid of myogenic (skeletal or smooth) ultrastructural features and expressed vimentin solely. This combined morphological and immunohistochemical study illustrates the following: First, these pleomorphic sarcomas are often indistinguishable by histologic growth pattern alone; thus, an accurate diagnosis requires study with all of these techniques. Second, pleomorphic myogenic sarcomas are restricted to adults and are not uncommon neoplasms among pleomorphic sarcomas: RMS (28%), LMS (21%), MFH (38%), and LS (13%). Third, the study defines desmin-negative and alpha-sm actin-positive pleomorphic RMS, and desmin-negative and alpha-sm-actin-negative pleomorphic LMS.

Minimal or no cancer in radical prostatectomy specimens. Report of 13 cases of the "vanishing cancer phenomenon".

Early detection efforts identify prostate cancer at lower clinical and pathologic stages, often resulting in smaller volumes of tumor in radical prostatectomy specimens. In some cases, complete sampling of the radical prostatectomy specimen for biopsy-proven adenocarcinoma reveals minimal or no residual cancer. We evaluated the clinical and pathologic findings in 13 such cases in an effort to document this finding, which we refer to as the "vanishing cancer phenomenon." The mean number of prostate slides examined per case was 79 (range, 34-248). Carcinoma was absent in two cases, present in a single focus in eight cases, and present in two foci in three cases. Mean cancer volume in the 10 cases with residual tumor was 0.019 cc (range, 0.003-0.038); the largest single dimension of any tumor focus was 3 mm. All cancers were well differentiated or moderately differentiated in the biopsy and prostatectomy. Our results indicate that in some cases cancer may be extremely difficult or impossible to find in the prostatectomy specimen despite exhaustive sampling. The incidence of this "vanishing cancer phenomenon" is probably increasing because more low-stage cancers are being treated by prostatectomy. The inability to identify cancer in a prostate removed for needle biopsy-proven carcinoma may not indicate technical failure.

Vascular endothelial growth factor and signaling in the prostate: more than angiogenesis.

In cloning tyrosine kinase genes in dog prostate cells, a fragment of the vascular endothelial growth factor (VEGF) receptor 1 or Flt-1 was sequenced. To test for a functional protein, Flt-1 antibodies were used to probe immunoprecipitated tyrosine phosphorylated proteins. Western blotting revealed a major 170-180 kDa band and a few bands below 116 kDa in dog prostate and human prostatic carcinoma PC-3 cells, with higher levels in PC-3. Similar results were obtained with human placental membranes used as a source of Flt-1. That the major Flt-1 tyrosine phosphorylated protein was likely VEGF-R1 and part of VEGF signaling pathways was shown by enhanced level of only this protein when PC-3 cells were exposed to VEGF. Accordingly specific cell surface receptor complexes, displaced by VEGF but not EGF and compatible with Flt-1 in size, were revealed by chemical cross-linking after 125I-VEGF binding. Similarly to the prostatic neuroproduct, gastrin-releasing peptide/bombesin, VEGF directly triggered the tyrosine phosphorylation of focal adhesion kinase and stimulated PC-3 cell motility. The titration of prostate tissue sections with VEGF-A antibodies revealed a confined staining in chromogranin A and/or serotonin positive neuroendocrine (NE) cells, including in primary tumors and lymph node metastases. Given that NE differentiation is associated with advanced disease, that NE cells are a significant source of VEGF in prostatic tumors, and that VEGF directly act on prostate cancer cells in vitro, VEGF-A may be more than angiogenic in prostate cancer and hence favor progression by affecting tumor cells.

Family with Graves disease, multinodular goiter, nonmedullary thyroid carcinoma, and alveolar rhabdomyosarcoma.

Benign thyroid disease is a risk factor for nonmedullary thyroid carcinoma [Houlston and Stratton: Q J Med 88:685-693, 1995]. We report on a family with 7 members with benign and/or malignant thyroid neoplasia; one affected female died of a paravertebral alveolar rhabdomyosarcoma at age 20. The occurrence of thyroid nodular hyperplasia, nonmedullary thyroid cancer, and rhabdomyosarcoma in the same family may be due to chance, common environmental factors, or, most likely, genetic predisposition.

Myofibroblastoma of the tunica testis: evolving phase of so-called fibrous pseudotumor?

A collagen-rich stromal tumor attached to the testicular tunica albuginea of a 22-year-old male is reported. Immunocytochemical and ultrastructural characterization revealed a predominant population of myofibroblasts, an as yet unrecognized observation in tumors arising from testicular tunics. The possible relationship with so-called fibrous pseudotumor (nodular fibrous proliferation) is discussed. The myofibroblastic nature of the cell population would support the hypothesis of a reactive contractile process if one accepts this tumor as an evolving phase of fibrous pseudotumor.

Aggressive angiomyxoma of pelvic soft parts: a clinicopathologic study of nine cases.

Nine cases of aggressive angiomyxoma (AAM) of the pelvic soft parts were studied by light and electron microscopy and immunohistochemistry. The tumors were confined to the vulva, vagina, pelvic floor, and perineum in the seven women. The perineum and the para-anal region were involved in the two men. The patients ranged in age from 18 to 63 years. Aggressive angiomyxoma presented as a slowly growing, polypoid or cyst-like tumor. Six of the nine cases were followed up; all of the tumors recurred within nine to 84 months, and one recurred for the second time at 144 months. Recurrences were attributed to incomplete tumor excision. None of the six patients died or had metastases. The aggressive angiomyxomas had infiltrative borders and rubbery, white or soft, gelatinous cut surfaces. Histologically, the lesions were composed of stellate and spindle-shaped neoplastic cells embedded in a collagenous and hyaluronic acid-containing stroma. Nuclear atypia and mitoses were absent. Typically, the lesions had an important vascular component, often displaying medial hypertrophy and vascular grouping. Ultrastructurally, the neoplastic cells resembled fibroblasts rather than myofibroblasts. They showed strong immunoreactivity for actin but were negative for S-100 protein, Factor VIII, carcinoembryonic antigen, and keratin. The morphoimmunocytochemical characteristics of AAM cells favor a fibroblastic origin and differentiation. Aggressive angiomyxoma should be distinguished from the more common benign and malignant myxoid neoplasms or tumor-like conditions of the pelvic soft parts. Recurrence of AAM may be avoided by wide, local excision.

Metastatic carcinoma resulting in hepar lobatum.

Hepar lobatum is an acquired liver deformity mostly known as the end-stage of tertiary syphilis. The authors report two cases of hepar lobatum resulting from metastatic mammary ductal carcinoma in the liver and reassess the clinicopathologic features of seven previously reported cases (two in the German language). A liver of near-normal weight with an irregularly lobulated contour, capsular indentations/crevices from which intersecting (carcinoma-bearing) fibrous septa extended deep into the parenchyma, a predominant centrifugal distribution of lesional areas, and many septa abutting on the degenerated center of tumor nodules were the salient gross features. No significant tumor/fibrous occlusion of intrahepatic branches of portal or hepatic veins, nor cirrhotic type nodular hepatocellular regeneration was observed. Both of these patients experienced a drastic decrease in CEA serum levels during multiagent palliative chemotherapy. In one patient, abundant macrophages in conjunction with minimal residual tumor were present within intrahepatic septa. The pathogenesis of this condition appears largely related to an active phase of chemo-induced tumor regression with subsequent tissue collapse, followed by an organizing phase of healing and scar contraction.

Anastomotic ulcer-induced aortoenteric fistula after esophagogastroplasty.

A 67-year-old woman underwent an esophagogastrectomy and esophagogastrostomy for carcinoma of the distal esophagus. She died of massive hematemesis and exsanguination on the 14th postoperative day. An acute peptic ulcer-induced aortoenteric fistula was present at the anastomotic line. The literature on peptic ulcer-induced aortoenteric fistulas after esophagogastroplasty is reviewed.

Neurogenic erectile dysfunction: the course of nicotinamide adenine dinucleotide phosphate diaphorase-positive nerve fibers on the surface of the prostate.

OBJECTIVES: Nitric oxide (NO) plays an important role as a neurotransmitter in the peripheral neural regulation of erection. A histochemical stain able to localize fibers releasing NO in combination with an in vivo study were used to evaluate the course and physiologic significance of the nerve fibers innervating the cavernous smooth muscle. METHODS: Morphologic studies in 6 rats and 6 human cadavers were performed, tracing the course of branches of the cavernous nerve branches using a nicotinamide adenine dinucleotide phosphate diaphorase staining technique. Electrostimulations in rats were performed before and after transection of the anterolateral part of the prostate capsule. RESULTS: Multiple nerve fibers were documented running on the lateral and ventral surfaces of the prostate distinct from the classically described dorsolateral neurovascular bundle. Transection of these fibers resulted in a loss of electrically induced intracavernous pressure (59.4 +/- 5.6 cm H2O versus 27.0 +/- 4.6 cm H2O). CONCLUSIONS: These preliminary morphologic and physiologic studies support a significant role for these nerve fibers in erection.

Morphologic changes induced by neoadjuvant androgen ablation may result in underdetection of positive surgical margins and capsular involvement by prostatic adenocarcinoma.

OBJECTIVE: Neoadjuvant androgen ablation (NAAA) causes significant cytoarchitectural changes in both benign and malignant prostatic epithelial cells that may contribute to underdetection of prostate cancer capsular involvement and positive surgical margins. METHODS: The aim of this study is to determine the ability of cytokeratin immunohistochemistry to enhance the determination of pathologic stage of prostate cancer following NAAA. RESULTS: Cytokeratin AE1/AE3 immunohistochemistry identified 6 (27.3%), 15 (68.2%), 5 (22.7%), and 5 (22.7%) cases of organ-confined disease, capsule penetration, positive surgical margin, and seminal vesicle involvement, respectively, as compared with 10 (45.5%), 10 (45.5%), 3 (13.6%), and 5 (22.7%) cases by hematoxylin-eosin (H&E) staining, respectively. Two cases without detectable tumor by H&E staining had demonstrable residual tumor by cytokeratin immunohistochemical staining. CONCLUSIONS: Cytokeratin immunohistochemistry revealed more extensive intracapsular, capsular, and extracapsular tumor involvement and higher rate of positive surgical margin than did conventional H&E staining. Therefore, the beneficial pathologic effects of NAAA observed may, in part, be attributable to the artifact of observation.

Role of prostate-specific antigen density after applying age-specific prostate-specific antigen reference ranges.

OBJECTIVES: To determine the potential role of prostate-specific antigen (PSA) density (PSAD) in the early detection of prostate carcinoma if we apply age-specific PSA reference ranges (2.5 ng/mL or less for ages 40 to 49 years, 3.5 or less for ages 50 to 59, 4.5 or less for ages 60 to 69, and 6.5 or less for ages 70 to 79. METHODS: We retrospectively reviewed 3234 cases referred to us by urologists for transrectal ultrasound (TRUS) between January 1, 1991, and September 28, 1993. We included 2429 patients in the study, ages 40 to 79 years, with Hybritech or Abbott IMx serum PSA determinations and without previously diagnosed prostate cancer. We performed digital rectal examination (DRE) and TRUS in all cases, and TRUS-guided biopsies when indicated. We used stringent criteria to define 736 cases without clinical evidence of malignancy that were designated as a "benign group." RESULTS: In the benign group, we found serum PSA to increase with age in parallel with the increase in prostate volume with age (r = 0.25 and r = 0.26, respectively). The association between serum PSA and prostate volume was stronger (r = 0.46). Using multiple regression analysis, prostate volume accounted for 18% of the variation in serum PSA, whereas age accounted for only an additional 2%. PSAD, which directly relates serum PSA to prostate volume, showed a weak association with age (r = 0.1). In the entire study population of 2429 cases, 555 patients had negative DRE and TRUS results and a serum PSA level between the age-specific upper limit of normal and 10.0 ng/mL. According to the proposed age-specific algorithm, these patients would have required automatic biopsies. Of these, 315 cases (56.8%) still had a PSAD of less than 0.15. We performed biopsies in 108 of these 315 and detected only two cancers, for a positive biopsy rate (PBR) of 1.9%. The remaining 240 cases had a PSAD of 0.15 or higher, and we performed biopsies in 217 of these cases and detected 59 cancers, for a PBR of 27.2%. CONCLUSIONS: The use of age-specific PSA reference ranges does not totally account for the effect of prostate volume on serum PSA. Therefore PSAD can still be used to reduce safely the number of biopsies performed in patients with negative DRE and TRUS results and a serum PSA level 10.0 ng/mL or less and above the age-specific upper limit of normal.