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Aim: Clinicopathologic characterisation of a contemporary series of neuroendocrine (NE) differentiation in the setting of prostatic carcinoma (PCa) was examined., Methods and Results: We reviewed institutional databases for in-house cases with a history of PCa and histopathologic evidence of NE differentiation during the disease course. In all, 79 cases were identified: 32 primary and 47 metastases. Metastatic lesions were in liver (n = 15), lymph node (n = 9), bone (n = 6), lung (n = 3), brain (n = 1), and other sites (n = 13). In all, 63 of 76 (82%) cases with NE differentiation and available history were posttherapy: six postradiation therapy (RT), 24 post- androgen-deprivation therapy (ADT), and 33 post-RT + ADT. Morphologic assessment (n = 79): (i) 23 pure small-cell/high-grade NE carcinoma (HGNEC): 20/23 metastatic; (ii) 10 combined high-grade PCa and small-cell/HGNEC: 9/10 primary; (iii) 15 PCa with diffuse NE immunohistochemistry (IHC) marker positivity/differentiation, associated with nested to sheet-like growth of cells with abundant cytoplasm and prominent nucleoli, yet diffuse positivity for at least one prostatic and one NE IHC marker: all metastatic; (iv) 11 PCa with patchy NE differentiation, displaying more than single-cell positivity for NE IHC: five primary / six metastatic; (v) nine PCa with focal NE marker positive cells: four primary / five metastatic; (vi) 11 PCa with 'Paneth cell-like' change: all primary., Conclusions: In this contemporary series, the majority of NE differentiation in the setting of PCa was seen posttherapy. We highlight the tendencies of small-cell/HGNEC and PCa with diffuse NE differentiation by IHC to occur in metastatic settings, while morphologically combined high-grade PCa + small-cell/HGNEC and 'Paneth cell-like' change occur in primary disease., (© 2022 John Wiley & Sons Ltd.)

Objective: To determine whether subclassification of positive surgical margins (PSMs) increases predictive ability for biochemical recurrence (BCR) and aids clinical decision-making in patients undergoing radical prostatectomy., Patients and Methods: We studied 2147 patients with pT2 and pT3a prostate cancer with detailed surgical margin parameters and BCR status. We compared a base model, a linear predictor calculated from the Memorial Sloan Kettering Cancer Center postoperative nomogram (prostate-specific antigen, pathological tumour grade and stage), with the addition of surgical margin status to five additional models (base model plus surgical margin subclassifications) to evaluate enhancement in predictive accuracy. Decision curve analysis (DCA) was performed to determine the clinical utility of parameters that enhanced predictive accuracy., Results: Among 2147 men, 205 had PSMs, and 231 developed BCR. Discrimination for the base model with addition of surgical margin status was high (c-index = 0.801) and not meaningfully improved by adding surgical margin subclassification in the full cohort. In analyses considering only men with PSMs (N = 55 with BCR), adding surgical margin subclassification to the base model increased discrimination for total length of all PSMs - alone or with maximum Gleason grade at the margin (c-index improvement = 0.717 to 0.752 and 0.753, respectively). DCA demonstrated a modest benefit to clinical utility with the addition of these parameters., Conclusions: Specific subclassification parameters add predictive accuracy for BCR and may aid clinical utility in decision-making for patients with PSMs. These findings may be useful for patient counselling and future adjuvant therapy trial design., (© 2021 The Authors BJU International © 2021 BJU International.)

Context.—: In prostate cancer, "tertiary" higher-grade patterns (TPs) have been associated with biochemical recurrence after radical prostatectomy., Objective.—: To determine variation regarding definition and application of TPs., Design.—: Online survey regarding TPs in a range of grading scenarios circulated to 105 experienced urologic pathologists., Results.—: Among 95 respondents, 40 of 95 (42%) defined TPs as "third most common pattern" and 55 (58%) as "minor pattern/less than 5% of tumor." In a tumor with pattern 3 and less than 5% pattern 4, of the 95 respondents, 35 (37%) assigned 3 + 3 = 6 with TP4, while 56 (59%) assigned 3 + 4 = 7. In a tumor with pattern 4 and less than 5% pattern 5, of the 95 respondents, 51 (54%) assigned 4 + 4 = 8 with TP5, while 43 (45%) assigned 4 + 5 = 9. Six scenarios were presented in which the order of most common patterns was 3, 4, and 5 (Group 1) or 4, 3, and 5 (Group 2) with varying percentages. In both groups, when pattern 5 was less than 5%, we found that 98% and 93% of respondents would assign 3 + 4 = 7 or 4 + 3 = 7 with TP5. In scenarios with 15% or 25% pattern 5, most respondents (70% and 80%, respectively) would include pattern 5 as the secondary grade, that is, 3 + 5 = 8 (Group 1) or 4 + 5 = 9 (Group 2). For 85 of 95 (89%), a TP would not impact Grade Group assignment., Conclusions.—: This survey highlights substantial variation in practice patterns regarding definition and application of "tertiary" grading in radical prostatectomy specimens. High consistency was observed in 3 + 4 = 7/4 + 3 = 7 scenarios with truly minor pattern 5. These findings should inform future studies assessing the standardization and predictive value of "tertiary" patterns.

In the eighth edition AJCC staging, all organ-confined disease is assigned pathologic stage T2, without subclassification. We investigated whether total tumor volume (TTV) and/or maximum tumor diameter (MTD) of the index lesion are useful in improving prediction of biochemical recurrence (BCR) in pT2 patients. We identified 1657 patients with digital tumor maps and quantification of TTV/MTD who had pT2 disease on radical prostatectomy (RP). Multivariable Cox regression models were used to assess whether TTV and/or MTD are independent predictors of BCR when adjusting for a base model incorporating age, preoperative prostate-specific antigen, RP grade group, and surgical margin status. If either tumor quantification added significantly, we calculated and reported the c-index. Ninety-five patients experienced BCR after RP; median follow-up for patients without BCR was 5.7 years. The c-index was 0.737 for the base model. Although there was some evidence of an association between TTV and BCR (P=0.088), this did not meet conventional levels of statistical significance and only provided a limited increase in discrimination (0.743; c-index improvement: 0.006). MTD was not associated with BCR (P>0.9). In analyses excluding patients with grade group 1 on biopsy who would be less likely to undergo RP in contemporary practice (622 patients; 59 with BCR), TTV/MTD was not a statistically significant predictor (P=0.4 and 0.8, respectively). Without evidence that tumor quantitation, in the form of either TTV or MTD of the index lesion, is useful for the prediction of BCR in pT2 prostate cancer, we cannot recommend its routine reporting.

Purpose: We evaluated whether the prediction of biochemical recurrence after radical prostatectomy is enhanced by any of 6 parameters, including prostate volume, total tumor volume, high grade total tumor volume, the ratio of high grade total tumor volume to total tumor volume, the ratio of total tumor volume to prostate volume and/or the ratio of high grade total tumor volume to prostate volume., Materials and Methods: A total of 1,261 patients who underwent radical prostatectomy during a 3-year period had tumor maps constructed with the Gleason pattern denoted as low-3 or high-4 or 5 and volumetric data generated using commercially available software. Univariate Cox regression models were used to assess whether each volume related parameter was associated with biochemical recurrence after radical prostatectomy. A multivariable Cox regression base model (age, prostate specific antigen, Gleason score/grade group, pathological stage and margin status) was compared with 6 additional models (base model plus each volume related parameter) to evaluate enhancement in predictive accuracy. Decision curve analysis was performed to determine the clinical utility of parameters that enhanced predictive accuracy., Results: On univariate analysis each parameter was significantly associated with biochemical recurrence except prostate volume. Predictive accuracy of the multivariable base model was high (c-index = 0.861). Adding volume related parameters marginally enhanced discrimination. Decision curve analysis failed to show added benefit even for high grade total tumor volume/total tumor volume, which was the parameter with the highest discriminative improvement., Conclusions: Tumor volume related parameters are significantly associated with radical prostatectomy but do not add important discrimination to standard clinicopathological variables for radical prostatectomy prediction or provide benefit across a range of clinically relevant decision thresholds. Volume related measurement is not warranted in routine pathological evaluation and reporting.

Purpose: To our knowledge the ideal methodology of quantifying secondary Gleason pattern 4 in men with Grade Group 2/Gleason score 3 + 4 = 7 on biopsy remains unknown. We compared various methods of Gleason pattern 4 quantification and evaluated associations with adverse pathology findings at radical prostatectomy., Materials and Methods: A total of 457 men with Grade Group 2 prostate cancer on biopsy subsequently underwent radical prostatectomy at our institution. Only patients with 12 or more reviewed cores were included in analysis. We evaluated 3 methods of quantifying Gleason pattern 4, including the maximum percent of Gleason pattern 4 in any single core, the overall percent of Gleason pattern 4 (Gleason pattern 4 mm/total cancer mm) and the total length of Gleason pattern 4 in mm across all cores. Adverse pathology features at radical prostatectomy were defined as Gleason score 4 + 3 = 7 or greater (Grade Group 3 or greater), and any extraprostatic extension, seminal vesical invasion and/or lymph node metastasis. A training/test set approach and multivariable logistic regression were used to determine whether Gleason pattern 4 quantification methods could aid in predicting adverse pathology., Results: On multivariable analysis all Gleason pattern 4 quantification methods were significantly associated with an increased risk of adverse pathology (p <0.0001) and an increased AUC beyond the base model. The largest AUC increase was 0.044 for the total length of Gleason pattern 4 (AUC 0.728, 95% CI 0.663-0.793). Decision curve analysis demonstrated an increased clinical net benefit with the addition of Gleason pattern 4 quantification to the base model. The total length of Gleason pattern 4 clearly provided the largest net benefit., Conclusions: Our findings support the inclusion of Gleason pattern 4 quantification in the pathology reports and risk prediction models of patients with Grade Group 2/Gleason score 3 + 4 = 7 prostate cancer. The total length of Gleason pattern 4 across all cores provided the strongest benefit to predict adverse pathology features.

From the advent of the Gleason grading system for prostate cancer, cancer displaying intraluminal necrotic cells and/or karyorrhexis within cribriform/solid architecture, a phenomenon termed "comedonecrosis," has been assigned pattern 5. Intraductal carcinoma (IDC-P) shows morphologic overlap with high-grade cribriform/solid adenocarcinoma architecturally and cytologically and may also show central necrosis, yet due to the presence of basal cells at the duct periphery is not currently assigned a grade in clinical practice. On the basis of observations from routine clinical cases, we hypothesized that comedonecrosis was more significantly associated with IDC-P than invasive disease. From a large series of mapped radical prostatectomy specimens (n=933), we identified 125 high-grade (≥Gleason score 4+3=7), high-volume tumors with available slides for review. All slides were examined for the presence of unequivocal comedonecrosis. Standard immunohistochemistry for basal cell markers was performed to detect basal cell labeling in these foci. In total, 19 of 125 (15%) cases showed some ducts with comedonecrosis-9 cases with 1 focus and 10 cases with ≥2 foci; in all, a total of 73 foci of true comedonecrosis were evaluated. Immunohistochemical stains revealed labeling for basal cell markers in a basal cell distribution for at least some comedonecrosis foci in 18 of 19 (95%) cases, 12 with IDC-P exclusively and 6 with a mix of IDC-P and invasive carcinoma comedonecrosis foci. These results suggest that comedonecrosis is strongly associated with IDC-P and hence, the routine assignment of pattern 5 to carcinoma exhibiting comedonecrosis should be reconsidered.

Aim: To study prostate cancer zonal differences in TMPRSS2-ERG gene rearrangement., Methods and Results: We examined 136 well-characterized dominant anterior prostatic tumours, including 61 transition zone (TZ) and 75 anterior peripheral zone (PZ) lesions, defined using strict anatomical considerations. TMPRSS2-ERG FISH and ERG protein immunohistochemistry were performed on tissue microarrays. FISH results, available for 56 TZ and 71 anterior PZ samples, were correlated with ERG staining and TZ-associated 'clear cell' histology. Fewer TZ cancers (four of 56; 7%) were rearranged than anterior PZ cancers (18 of 71; 25%) (P = 0.009); deletion was the sole mechanism of TZ cancer rearrangement. ERG protein overexpression was present in 4% (two of 56; both FISH+) and 30% (21 of 71; 17 FISH+) of TZ and anterior PZ tumours, respectively. 'Clear cell' histology was present in 21 of 56 (38%) TZ and eight of 71 (11%) anterior PZ tumours. Seven per cent of cancers with and 21% without this histology had rearrangement, regardless of zonal origin., Conclusions: TMPRSS2-ERG rearrangement occurs in dominant TZ and anterior PZ prostate cancers, with all rearranged TZ cancers in this cohort showing deletion. ERG immunohistochemistry demonstrated excellent sensitivity (86%) and specificity (96%) for TMPRSS2-ERG rearrangement. TMPRSS2-ERG fusion is rare in TZ tumours and present at a low frequency in tumours displaying 'clear cell' histology., (© 2013 John Wiley & Sons Ltd.)

Purpose: We evaluated the relationship of progression to positive surgical margin linear length and Gleason grade at a positive surgical margin., Materials and Methods: We studied 2,150 prostatectomies done for pT2 or pT3a disease to determine grade, stage and surgical margin status. In patients with positive surgical margins we recorded the location, number, positive margin linear length and highest Gleason grade at a positive margin. The Kaplan-Meier method and log rank test were used to determine differences in progression-free probability among positive margin features. The concordance index was used to discriminate the accuracy of grouping surgical margin status as negative/positive vs positive margin linear length/highest Gleason grade., Results: A total of 207 cases (10%) showed positive surgical margins, including 93 (45%) that were pT2+ and 114 (55%) that were pT3a. Patients with pT3a and positive margins had greater prostate specific antigen and tumor volume, and Gleason score 7 or greater than those with pT2+. A total of 45 patients with positive margins progressed. We then subcategorized positive margins. Of the patients 164 (79%) had 1 positive margin. Positive margin linear length was 1 mm or less, 1.1 to 3 and greater than 3 in 104 (50%), 55 (27%) and 48 cases (23%), respectively. Two-year progression-free probability was 95%, 91%, 83% and 47% in patients with negative margins and the 3 positive margin linear length groups, respectively (p <0.001). Gleason grade at a positive margin was 3 and 4/5 in 154 (74%) and 53 patients (26%), respectively. The latter group was significantly more likely to progress (p <0.001). The overall margin status concordance index was 0.636. It was not considerably enhanced by categorizing by positive surgical margin linear length/highest Gleason grade at positive margins., Conclusions: The linear extent of and highest Gleason grade at a positive surgical margin are associated with progression. However, subcategorization does not importantly add to predictive models using margin status only. More robust markers are needed in patients with positive surgical margins to warrant routine reporting and identify those at risk for biochemical recurrence., (Copyright © 2013 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Advances in whole slide digital imaging in the past decade necessitate validation of these tools in each organ system in advance of clinical adoption. We assessed reproducibility in reporting prostate needle biopsy parameters among urologic pathologists using routine and digital microscopy in a consultation/second opinion-like setting. Four urologic pathologists evaluated a single core level from 50 diagnostically challenging needle biopsy specimens by routine microscopy and whole slide digital imaging. Interobserver and intraobserver agreement were calculated for primary and secondary Gleason grades, Gleason score, tumor quantitation (percentage and size in millimeters), and perineural invasion. Interobserver agreement for routine microscopy was excellent for primary Gleason grade (κ = 0.72) and good for all other parameters (κ ranging from 0.36 to 0.55). Whole slide digital imaging assessment yielded similar agreement for all parameters. Intraobserver agreement for primary Gleason grade and Gleason score was very good to excellent for all pathologists (all κ ≥ 0.65 and ≥ 0.73, respectively). Size of tumor in millimeters consistently displayed higher levels of agreement than percentage of tumor across media and pathologists. Digital assessment of routinely reported cancer parameters on prostatic needle biopsy for a given scanned core level is comparable to that of routine microscopy. These findings imply that histologic interpretation using dynamic whole slide images may accurately simulate routine microscopic evaluation in the consultation setting. Implementation of whole slide digital imaging in these scenarios may significantly reduce the workload of large referral centers in the near future and impact the manner in which pathologists seek second opinion consultation on challenging cases., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Pelvic lymph node (LN) metastasis is a well-recognized route of prostate cancer spread. However, the relationship between topography and the pathologic features of primary prostatic cancers and patterns of pelvic LN metastasis has not been well studied. We reviewed original slides of radical prostatectomies and pelvic LN dissections from 125 patients with LN metastasis and recorded a total number of LN excised/laterality of positive LN, and localization, staging parameters, lymphovascular invasion, and volume of primary tumors., Ln Quantity and Distribution: 14.6 (mean) and 13 (median) LNs were resected. Seventy-six (61%), 33 (26%), and 16 (13%) cases had 1, 2, and >2 positive LNs; whereas 58, 44, and 20 cases had LN metastasis on the right, left, and bilaterally., Pathologic Features: Eighty-six percent (108 of 125) and 37% (46 of 125) of the cases showed extraprostatic extension and seminal vesicle invasion, whereas 64% cases showed lymphovascular invasion. Mean and median total tumor volumes were 6.39 and 3.92 cm, with ≥50% and ≥90% Gleason patterns 4/5 in 105 (84%) and 73 (58%) cases, respectively., Correlation With Dominant Tumor Location: Dominant lesions on radical prostatectomy were as follows: 50 right lobe, 44 left lobe, and 31 bilateral lobe tumors. Fifteen of 50 (30%) right lobe and 18 of 44 (41%) left lobe dominant tumors had LN metastasis on the contralateral side. Only 4% (5 of 125) of the cases were associated with anterior dominant tumors., Conclusion: Thirty percent to 40% of LN metastases occurred contralateral to the dominant tumor. LN metastasis is overwhelmingly associated with high-grade, high-stage, and large volume disease. LN positivity is rarely associated with anterior dominant tumors.

TMPRSS2-ERG gene rearrangement is seen in about half of clinically localized prostate cancers, yet controversy exists with regard to its prognostic implications. Similarly, the relationship of TMPRSS2-ERG fusion to Gleason score and morphology remains uncertain. We assigned Gleason scores and recorded morphological features for 521 clinically localized prostate cancers sampled in triplicate and arrayed in eight tissue microarray blocks. Fluorescence in situ hybridization was performed to delineate TMPRSS2-ERG aberrations. Using maximum Gleason score, based on three core evaluation, and overall Gleason score, based on prostatectomy sections, Fisher's exact test was performed for tumors with TMPRSS2-ERG translocation/deletion, copy number increase (≥ 3) of the TMPRSS2-ERG region without translocation/deletion, and copy number increase and concomitant translocation/deletion. In all, 217 (42%) translocation/deletion and 30 (5.9%) copy number increase-alone cases were detected. Among 217 translocation/deletion cases, 32 had translocation/deletion with copy number increase. In all, 237, 200, and 75 cancers had maximum core-specific Gleason score of 6, 7, and 8-10, respectively. Tumors with translocation/deletion tended toward lower Gleason scores than those without (P=0.002) with similar results for overall Gleason score (P=0.02); copy number increase cases tended toward higher Gleason scores than those without (P<0.001). Gleason score of 8-10 tumors demonstrated lower odds of translocation/deletion (odds ratio (OR) 0.38; 95% CI 0.21-0.68) and higher odds of copy number increase alone (OR 7.33; 95% CI 2.65-20.31) or copy number increase+translocation/deletion (OR 3.03; 95% CI 1.12-8.15) relative to Gleason score of <7 tumors. No significant difference in TMPRSS2-ERG incidence was observed between patients with and without cribriform glands, glomerulations, signet-ring cells, or intraductal cancer (P=0.821, 0.095, 0.132, 0.375). TMPRSS2-ERG gene fusion is associated with lower core-specific and overall Gleason scores and not with high-grade morphologies. Conversely, TMPRSS2-ERG copy number increase, with or without rearrangement, is associated with higher Gleason score. These findings indicate that translocation/deletion of TMPRSS2-ERG is not associated with histological features of aggressive prostate cancer.

Purpose: We compared prostate cancer detected in transition zone directed needle biopsies with those in corresponding radical prostatectomy specimens., Materials and Methods: We reviewed needle biopsy and radical prostatectomy slides from 61 patients in whom cancer was present on transition zone directed needle biopsy. We assessed needle biopsy cancer features as well as transition zone lesions and dominant tumor sites on radical prostatectomy., Results: Prostate cancer was detected in 25 of 61 left (41%), 23 of 61 right (38%) and 13 of 61 bilateral (21%) transition zone directed needle biopsies. On radical prostatectomy 24 of 61 cases (39.5%) had no tumor in the transition zone, 24 of 61 (39.5%) had nondominant transition zone cancer and 13 of 61 (21%) had a dominant transition zone lesion. Of cases with cancer in the left and right transition zone directed needle biopsy 18 of 38 (47%) and 17 of 36 (47%), respectively, had no transition zone tumor or showed tumor in the contralateral transition zone only at radical prostatectomy. In 8 cases the transition zone directed core was the only one with cancer on needle biopsy and 2 of 8 (25%) such cases showed dominant transition zone cancer at radical prostatectomy., Conclusions: Cancer identified in transition zone directed needle biopsy cores was not from the transition zone or did not reflect a dominant transition zone lesion in almost 80% of cases. Cancer identified in a left or right transition zone directed needle biopsy did not predict ipsilateral transition zone cancer in almost 50% of cases. These findings suggest that such biopsies do not adequately characterize transition zone tumors. Thus, care should be taken in their interpretation.

A significant number of prostate cancers have been shown to have recurrent chromosomal rearrangements resulting in the fusion of the androgen-regulated TMPRSS2 promoter to a member of the ETS transcription factor family, most commonly ERG. This results in ERG overexpression, which may have a direct causal role in prostate tumorigenesis or progression. However, the clinical significance of the rearrangement is unclear, and in particular, relationship to outcome has been inconsistent in recent reports. We analyzed TMPRSS2-ERG gene rearrangement status by fluorescence in situ hybridization in 521 cases of clinically localized surgically treated prostate cancer with 95 months of median follow-up and also in 40 unmatched metastases. Forty-two percent of primary tumors and 40% of metastases had rearrangements. Eleven percent had copy number increase (CNI) of the TMPRRS2-ERG region. Rearrangement alone was associated with lower grade, but not with stage, biochemical recurrence, metastases, or death. CNI with and without rearrangement was associated with high grade and advanced stage. Further, a subgroup of cancers with CNI and rearrangement by deletion, with two or more copies of the deleted locus, tended to be more clinically aggressive. DNA index assessment revealed that the majority of tumors with CNI of TMPRSS2-ERG had generalized aneuploidy/tetraploidy in contrast to tumors without TMPRSS2-ERG CNI, which were predominantly diploid. We therefore conclude that translocation of TMPRSS2-ERG is not associated with outcome, and the aggressive clinical features associated with CNI of chromosome 21 reflect generalized aneuploidy and are not due to CNI specifically of rearranged TMPRSS2-ERG.

Previous studies have proposed that the morphologic spectrum of prostatic glands of variable size with tall columnar cells displaying basally oriented nuclei and clear to pale pink cytoplasm (TZ-LOOK) is characteristic of the well to moderately differentiated component of transition zone (TZ) tumors. However, the specificity of these findings has not been well studied. In a recent report, we identified dominant peripheral zone (PZ) and TZ tumors situated anterior to the prostatic urethra. Currently, we evaluate the histopathologic features of 215 dominant tumors, including 63 TZ and 73 anterior PZ lesions and an additional cohort of 79 posterior PZ tumors, in radical prostatectomy specimens, to identify the prevalence of this morphology in tumors of different zonal origin. Each dominant tumor was assigned a TZ-LOOK extent score of 0 to 4, with 0 = no such morphology, 1 = 1% to 25%, 2 = 26% to 50%, 3 = 51% to 75%, and 4 = >75%. Overall, 121/215 (56%) tumors showed some degree of this histology, including 56 of 63 (89%) TZ tumors and 65 of 152 (43%) PZ tumors (P<0.0001). Thirty-seven of 215 (17%) lesions had scores of 3 to 4, with 31 (84%) of these being of TZ origin. However, only 31/63 (49%) TZ tumors had >50% TZ-LOOK. Among PZ tumors, 6/152 (4%) had predominant (>50%) TZ-LOOK morphology, yet 23/152 (15%) of all PZ tumors and 23/65 (35%) of PZ tumors displaying any degree of TZ-LOOK had scores of 2 to 3 (>25%; nonfocal). In tumors of both zones with predominant (scores 3 to 4; >50%) TZ-LOOK histology, darker glands of usual acinar adenocarcinoma was often seen at the periphery. Conversely, in tumors with nonpredominant TZ-LOOK (scores 1 to 2; 50% of this histology are very likely of TZ origin, but this scenario occurs in only half of TZ tumors. Importantly, the TZ-LOOK is nonfocal in up to 35% of PZ tumors exhibiting any degree of this morphology. Given this lack of specificity, caution should be exercised in assigning zone of origin based on this histologic appearance, especially in limited samples such as prostate needle biopsy.

Aggressive screening and prostate needle biopsy protocols have been successful in early detection of low-volume posterior tumors. Consequently, we have observed an increased incidence of anterior-predominant prostate cancers. However, the zones of origin, patterns of spread, and patterns of extraprostatic extension of this group of tumors have not been well studied. Of 1312 radical prostatectomies performed at our institution over a span of 4.5 years, 197 had predominant (largest) tumors anterior to the urethra in whole-mounted radical prostatectomy specimens. Detailed histopathologic analysis of this cohort was undertaken emphasizing the variability in anterior prostatic anatomy from apex through base to determine zone of origin and pathologic staging. Using this approach, 97/197 (49.2%) anterior-predominant tumors (ATs) were assigned to the anterior peripheral zone (APZ), 70 (35.5%) to the transition zone (TZ), 16 (8.1%) were of indeterminate zone, and 14 (7.1%) were of both zones. Comparing APZ and TZ tumors, there were no significant differences in Gleason scores, incidence of extraprostatic extension, overall surgical margin positivity rate, or laterality. Involvement of the anterior fibromuscular stroma was significantly more likely in tumors of TZ origin (P< or =0.01), yet was observed in 50.5% of APZ tumors. Conversely, APZ tumors were more commonly localized within the apical one third of the prostate. Most of the prostates (91.4%) also showed additional PZ tumors, which were occasionally stage determining (7/197; 3.9%). In conclusion, ATs of APZ origin are more prevalent than those arising from the TZ. Contrary to previous reports comparing TZ tumors to all PZ tumors, ATs of both zones exhibit similar grading and staging parameters in this series. Given these similarities, long-term clinical outcomes and future molecular analyses will be necessary to assess whether true differences in biology and behavior exist between tumors of TZ and APZ origin.