International society of urological pathology consensus conference on handling and staging of radical prostatectomy specimens

The 2009 International Society of Urological Pathology consensus conference on handling and staging of radical prostatectomy specimens issued recommendations for standardization of pathology reporting of radical prostatectomy specimens. The conference addressed specimen handling, T2 substaging, prostate cancer volume, extraprostatic extension, lymphovascular invasion, seminal vesicle invasion, lymph node metastases, and surgical margins. This review summarizes the conclusions and recommendations resulting from the consensus process.     

Comparative analysis of sampling methods for grossing radical prostatectomy specimens performed for nonpalpable (stage T1c) prostatic adenocarcinoma

Scant data are available comparing sampling methods of radical prostatectomy specimens performed for clinical stage T1c (nonpalpable) cancer. Seventy-eight stage T1c radical prostatectomies that had 1 or more of the following adverse pathologic findings-Gleason score > or = 7, positive margins, and extraprostatic extension-were compared using 10 different sampling techniques. Of the 78 entirely submitted cases, 52 had Gleason score > or = 7, 14 had positive margins, and 54 had extraprostatic extension (mean 34 slides). Of the partial sampling methods, we favor the following two methods. The first is submitting every posterior section plus 1 midanterior section from right and left sides; if either of these anterior sections show sizeable tumor, all ipsilateral anterior slides are examined. This method detects 98% of tumors with Gleason score > or = 7, 100% of positive margins, and 96% of cases with extraprostatic extension (mean 27 slides). The second method is to use the above method but restrict it to sections ipsilateral to the previous positive needle biopsy. This method detects 92% of tumors with Gleason score > or = 7, 93% of positive margins, and 85% of cases with extraprostatic extension (mean 17 slides). Partial sampling can detect important prognostic parameters. By balancing the extra expense and time involved to process and examine additional sections with the risk of missing important prognostic parameters, pathologists can decide which sampling method to use.     

The relationship between the extent of surgical margin positivity and prostate specific antigen recurrence in radical prostatectomy specimens

The presence of positive surgical margins is a negative prognostic indicator in patients undergoing prostatectomy for prostate cancer; whether the extent of the positive margins affects the clinical outcome with regards to prostate-specific antigen (PSA) recurrence remains uncertain. We evaluated the linear extent of margin positivity as a prognostic indicator in a series of radical prostatectomy specimens. One hundred seventy-four consecutive margin-positive prostatectomy specimens were evaluated. The linear extent of margin positivity was measured with an ocular micrometer and ranged from 0.05 to 75.0 mm (mean, 8.94; median, 5.0). The linear extent of margin positivity was associated with tumor volume (P = .03) but was not associated with patients' age at surgery, preoperative PSA level, prostate weight, pathologic stage, Gleason score, extraprostatic extension, seminal vesicle invasion, perineural invasion, high-grade prostatic intraepithelial neoplasia, or PSA recurrence. In the full model multiple Cox regression, significant predictors for PSA recurrence were Gleason score (P = .001) and preoperative PSA (P = .01); extent of margin positivity was not predictive of PSA recurrence (hazard ratio, 1.00; 95% confidence interval, 0.98-1.02; P = .97) nor was tumor volume a significant factor when adjusted for other covariates (P = .27). Preoperative PSA, tumor stage, and Gleason score remained significant prognostic factors in evaluating the likelihood of PSA recurrence in patients with positive surgical margins; the extent of margin positivity, however, is not a prognostic factor for PSA recurrence and should, therefore, not necessarily be included in the final report for radical prostatectomy specimens.     

Discrepancies between Gleason scores of needle biopsy and radical prostatectomy specimens

The purpose of this study was to determine the accuracy of Gleason scores in prostate needle biopsy diagnosis and to investigate factors affecting the accuracy of the tumor grade. A single pathologist reviewed 116 sets of prostate cancer biopsies and radical prostatectomy specimens. The following factors were examined to determine their effect on the accuracy of the biopsy Gleason scores: (i) relative tumor differentiation; (ii) pathological stage; (iii) amount of tissue in the biopsy specimen; (iv) amount of cancer tissue in the biopsy specimen; (v) tumor heterogeneity; (vi) clinical findings (prostate specific antigen value and digital rectal examination); and (vii) interobserver variability. In 53 cases the Gleason score of biopsy specimens was identical to the score of prostatectomy specimens (45.7%). Fifty-four cases (46.6%) of biopsy specimens were undergraded. The most common discrepancy was diagnosis of well-differentiated carcinoma in the biopsy but diagnosis of moderately differentiated tumor in the corresponding prostatectomy specimen. This discrepancy occurred when the amount of tumor in the biopsy was 3 mm or less. Biopsy and prostatectomy results showed less agreement when the original biopsy tumor grade rendered by nine different pathologists was used, suggesting that interobserver variability can adversely affect the accuracy of tumor grade. Clarifying the histologic criteria for distinguishing each grade, especially between Gleason grades 2 and 3, is important for accurate grading.     

Handling and reporting of radical prostatectomy specimens in Europe: a web-based survey by the European Network of Uropathology (ENUP)

Aims:  To survey current European practices in handling and reporting of radical prostatectomy (RP) specimens.
Methods and results:  A European Network of Uropathology (ENUP) was organized for the dissemination of information, survey studies and research collaborations. Contact data of uropathologists were collected from 321 pathology laboratories in 15 West European countries. In the first ENUP survey, 67.6% (217/321) of the members replied to a web-based questionnaire. Some practices were adopted by a large majority, e.g. inking of the specimen (96.6%), Gleason grading (99.5%), stratifying extraprostatic extension (EPE) according to extent (88.2%), reporting TNM stage (88.6%) and reporting location of positive margins (98%). As many as 71.6% of respondents always embedded the entire prostate and only 10.8% always practised partial embedding. Whole mounts were routinely used by 37.5% and standard blocks by 55.5%. Among areas with variable routines were methods to define focal versus extensive EPE and methods to quantify margin positivity, probably reflecting that the optimal method has yet to be determined.
Conclusions:  Some practices are almost universally adopted in Europe, whereas others still need to be standardized. The results of the study may be helpful when judging what recommendations are reasonable to issue.     

The significance of modified Gleason grading of prostatic carcinoma in biopsy and radical prostatectomy specimens

At an International Society of Urological Pathology consensus conference in 2005, the Gleason grading system for prostatic carcinoma underwent its first major revision. Gleason pattern 4 now includes most cribriform patterns and also fused and poorly formed glands. Our aims were to compare the grade distributions and assess the agreement between biopsy and radical prostatectomy specimens for the modified and conventional Gleason grading. More than 3,000 radical prostatectomy (RP), needle biopsies (NB) and transurethral resection specimens were assigned modified Gleason score (GS). In NB, modified GS 3 + 3 = 6 and 3 + 4 = 7a were almost equally common, while in RP, 3 + 4 = 7a was most common followed by 4 + 3 = 7b. After application of the modified GS on NB, a substantial shift in GS distribution occurred: The proportion of GS 6 and 7 were 48 and 26%, respectively, with conventional Gleason grading as compared to 22 and 68%, respectively, with modified grading. In 368 men, the agreement between NB and RP with a modified GS 6, 7a, 7b and 8–10 in NB was 28, 88, 68 and 64–100%, respectively. The overall agreement improved from 58 to 72% (p < 0.001) compared to conventional GS. The higher agreement with modified Gleason grading may facilitate therapeutic decisions.     

Clinical map document based on XML (cMDX): document architecture with mapping feature for reporting and analysing prostate cancer in radical prostatectomy specimens

Background  

The pathology report of radical prostatectomy specimens plays an important role in clinical decisions and the prognostic evaluation in Prostate Cancer (PCa). The anatomical schema is a helpful tool to document PCa extension for clinical and research purposes. To achieve electronic documentation and analysis, an appropriate documentation model for anatomical schemas is needed. For this purpose we developed cMDX.     

IMP3 expression in biopsy specimens of colorectal cancer predicts lymph node metastasis and TNM stage

IMP3 is associated with lymph node metastasis and TNM stage and is a good independent prognostic biomarker for colorectal cancer (CRC). However, the expression status and clinical implication of IMP3 in biopsy specimens have not yet been studied. We aim to address whether the presence of IMP3 expression in preoperative biopsies of CRC could predict lymph node metastasis and TNM stage. In this study, we examined IMP3 expression in paired biopsy and resection specimens of 71 CRC and analyzed the correlation of IMP3 expression with clinicopathological parameters. In the biopsy specimens, IMP3 positive expression was observed in 56 of 71 cases (78.9%) whereas negative expression was observed in 15 of 71 cases (21.1%). In the resection specimens, IMP3 positive expression was detected in 83.1% cases (59/71) whereas negative expression was detected in 16.9% cases (12/71). The absolute concordance rate between biopsy and resection specimens was 90.1% (64/71). The Spearman correlation test documented the existence of a strong linear correlation between the percentage of IMP3-positive cells in the biopsy and resection specimen (r = 0.629; P < 0.001). IMP3 expression in resection specimens was significantly related to histological grade (P = 0.043), T classification (P = 0.035), lymph node metastasis (P = 0.023), TNM stage (P = 0.007), tumor border (P = 0.049) and tumor budding (P = 0.012). IMP3 expression in biopsy specimens was significantly related to lymph node metastasis (P = 0.004), TNM stage (P = 0.005) and tumor budding (P = 0.001). In conclusion, IMP3 expression in biopsy specimens could be used to predict lymph node metastasis and TNM stage in CRC patients.     

Frameshift mutations of poly(adenosine diphosphate-ribose) polymerase genes in gastric and colorectal cancers with microsatellite instability

Poly(adenosine diphosphate-ribose) polymerases consist of 16 members that modify nuclear proteins by building adenosine diphosphate-ribose polymers. Poly(adenosine diphosphate-ribose) polymerase 1, the prototype poly(adenosine diphosphate-ribose) polymerase, and some poly(adenosine diphosphate-ribose) polymerases are involved in many cellular processes including DNA damage response/repair, cell death, and inflammation. Inactivation of poly(adenosine diphosphate-ribose) polymerase proteins frequently enhances genomic instability and apoptosis inactivation, suggesting their roles in cancer development. However, genetic alterations of poly(adenosine diphosphate-ribose) polymerase genes have not been reported in cancers. In a public database, we found that poly(adenosine diphosphate-ribose) polymerase 1, poly(adenosine diphosphate-ribose) polymerase 11, poly(adenosine diphosphate-ribose) polymerase 14, poly(adenosine diphosphate-ribose) polymerase 15, tankyrase-1 (TNKS1), and tankyrase-2 (TNKS2) genes have mononucleotide repeats in coding DNA sequences. To see whether these genes are mutated in cancers with microsatellite instability, we analyzed the mononucleotide repeats in 30 gastric cancers with high microsatellite instability, 13 gastric cancers with low microsatellite instability, 45 gastric cancers with stable microsatellite instability, 40 colorectal cancers with high microsatellite instability, 14 colorectal cancers with low microsatellite instability, and 45 colorectal cancers with stable microsatellite instability by single-strand conformation polymorphism. We found poly(adenosine diphosphate-ribose) polymerase 14, TNKS1, and TNKS2 mutations in 8, 4, and 18 cancers, respectively. They were detected in cancers with high microsatellite instability but not in cancers with low microsatellite instability or stable microsatellite instability. The gastric cancers and colorectal cancers with high microsatellite instability harbored one or more mutations of the poly(adenosine diphosphate-ribose) polymerase genes in 50.0% and 27.5%, respectively. Of the genes with mutations, we analyzed poly(adenosine diphosphate-ribose) polymerase 14 protein expression in gastric and colorectal cancers with high microsatellite instability. Loss of poly(adenosine diphosphate-ribose) polymerase 14 expression was observed in 33% of the gastric cancers and 35% of the colorectal cancers with high microsatellite instability, whereas its loss was observed in 31% of the gastric cancers and 36% of the colorectal cancers with low microsatellite instability/stable microsatellite instability. Our data indicate that frameshift mutations of poly(adenosine diphosphate-ribose) polymerases genes and losses of expression of poly(adenosine diphosphate-ribose) polymerase 14 protein are features of gastric and colorectal cancers with high microsatellite instability and suggest that these alterations might contribute to development of cancers with high microsatellite instability by deregulating poly(adenosine diphosphate-ribose) polymerase-mediated signaling.     

保乳手术标本定位全部取材病理检查的意义

目的探讨保证保乳手术标本切缘阴性的病理取材诊断方法及意义。方法（1）术中对145例保乳手术标本进行定位全切片检查,79例进行选择性取材检查;（2）术后对84例保乳手术标本进行定位全切片检查,226例进行选择性取材检查;（3）对两组手术病例进行随访观察。结果（1）术中定位全切片取材切缘阳性检出率（24．1％,35／145）明显高于选择性取材（6．3％,5／79）,差异具有统计学意义（P〈0．01）;（2）术后定位全切片取材切缘阳性检出率（29／84,34．5％）亦明显高于选择性取材（12．0％,27／226）,差异具有统计学意义（P〈0．01）;（3）经2～46个月随访,保乳手术标本选择性取材病例中有3例分别于术后6、15、28个月局部复发,定位全切片取材病例无复发。结论定位全切片取材和诊断可以降低保乳手术标本切缘阳性的漏诊率,并能够定位切缘阳性的部位,对减小二次手术和术后复发的风险,保证保乳手术的成功具有重要作用。     

The significance of the P504S expression pattern of high-grade prostatic intraepithelial neoplasia (HGPIN) with and without adenocarcinoma of the prostate in biopsy and radical prostatectomy specimens

Diagnosis of prostatic adenocarcinoma is usually not difficult in biopsy specimens. Problems may occur in biopsy specimens, containing only a few suspicious lesions. Recently, P504S has been tested as a new marker for prostatic carcinoma. When over-expressed in atypical glands without basal cells, it establishes the diagnosis of prostatic carcinoma. We analysed the staining intensity of P504S in 208 biopsy specimens from prostates (1) with adenocarcinoma (n=132), (2) with high-grade prostatic intraepithelial neoplasia (HGPIN) with adenocarcinoma (n=36), (3) with HGPIN alone (n=40) and in radical prostatectomy specimens with HGPIN adjacent to (n=54) or distant from adenocarcinoma (n=64). P504S expression was negative to weakly positive in biopsy specimens showing HGPIN without carcinoma and weakly positive in radical prostatectomy specimens revealing HGPIN distant from adenocarcinoma. In biopsy specimens with a combination of HGPIN and adenocarcinoma and in radical prostatectomy specimens with HGPIN adjacent to adenocarcinoma, P504S was strongly expressed. The same findings were made in radical prostatectomy specimens containing adenocarcinoma and HGPIN adjacent to or distant from adenocarcinoma and in preoperative biopsies revealing adenocarcinoma and HGPIN. These results suggest that moderate to strong P504S expression in HGPIN of biopsy specimens is indicative of an associated adenocarcinoma and may be helpful in the choice of therapy.     

Expression of prostatic acid phosphatase (PSAP) in transurethral resection specimens of the prostate is predictive of histopathologic tumor stage in subsequent radical prostatectomies

Clinical management of incidental prostate cancer (IPC) remains challenging since its clinical course cannot be predicted by conventional histopathology. Aiming to define predictive factors in IPC, we correlated the immunohistochemically detected expression of prostate-specific antigen (PSA), prostatic acid phosphatase (PSAP), alpha-methylacyl-CoA racemase (AMACR, p504s), and androgen receptor in transurethral resection specimens with Gleason scores and histologic staging on the corresponding radicals in a cohort of 54 patients (mean age, 65.9 years; range, 49–80 years). PSAP expression showed a significant correlation with tumor staging (ρ = −0.37; p = 0.02) but not with Gleason scores (ρ = −0.06; p = 0.69). K-statistics revealed a highly significant moderate interobserver agreement concerning the evaluation of PSAP staining (K = 0.47; p < 0.001). In contrast, the other markers assessed failed to correlate with conventional histopathology. Therefore, PSAP might be predictive of tumor stage in IPC and represent a valuable adjunct for clinical decisions in terms of individual therapeutic management.     

Identification of isolated and early prostatic adenocarcinoma in radical prostatectomy specimens with correlation to biopsy cores: clinical and pathogenetic significance

Prostatic adenocarcinoma (PAC) is a multifocal disease. In this study, we identified isolated and small foci of PAC (ISPAC) in radical prostatectomy specimens, described the histopathologic features, investigated their zonal distribution in the prostate and their relationship with large tumor nodules, and correlated the findings with those of preceding biopsy cores. One hundred and thirty radical prostatectomy specimens performed for PAC or for urothelial carcinoma of the urinary bladder with incidental PAC were reviewed for identification of ISPAC. Prostates were serially sectioned in the horizontal plane and submitted in toto for microscopic examination. ISPAC were defined as foci of PAC measuring less than 3 mm in maximum diameter. There were 461 ISPAC identified in 114 cases. They were distributed in the transitional zone (TZ) (18 foci), the apex (73 foci), the anterior horn of the non-TZ (NTZ) (118 foci), the base (8 foci), and the remaining NTZ (244 foci). ISPAC usually consisted of groups of small acini with a GS ranging from 2 to 7 (3 + 4). GSs of ISPAC consisted of single grade or two consecutive grades equal to or lower than those of the main PAC. ISPAC were more often located in close proximity to large tumor nodules. The number of ISPAC increased with the tumor volume up to 3 cm3, then decreased as the PAC became more extensive (p value = 0.02, statistically significant). Prostates with NTZ PAC <1.5 cm3 and TZ PAC or prostates containing 4 or more than 4 ISPAC tended to be frequently associated with small foci of PAC in biopsy cores In this study, we identified ISPAC that likely represent foci of PAC in early development and account for the multicentricity and heterogeneity of PAC. ISPAC in the NTZ were common and may account for small foci of PAC or atypia in biopsy cores. Although these small foci of PAC or atypia in biopsy cores without accompanying higher GS PAC were often associated with significant PAC, they may also occasionally represent insignificant or vanishing PAC in subsequent radical prostatectomies.     

Anatomic distribution and pathologic characterization of small-volume prostate cancer (<0.5 ml) in whole-mount prostatectomy specimens.

Some investigators consider small-volume prostate cancer (0.5 ml or less) without Gleason pattern 4/5 elements as clinically insignificant. The objective of this study was to characterize the anatomic distribution and pathologic features of small tumors (aggregate volume of 0.5 ml or less) in whole-mount prostatectomy specimens. Between 1999 and 2003, 371 consecutive patients underwent radical prostatectomy at the Indiana University Hospitals for localized prostate cancer. Patients who received hormonal or radiation therapy prior to the surgery were excluded from the study. A total of 62 specimens with total tumor volume of 0.5 ml or less were identified and included in this study. All specimens were embedded and whole-mounted. Tumor volume was measured using the grid method. The mean age at the time of surgery was 59 years (median, 61 years; range, 37-72 years). The mean preoperative prostate-specific antigen (PSA) was 6.5 ng/ml (range: 0.3-18 ng/ml). The mean prostate weight was 53 g (range: 16-132 g). The mean tumor volume was 0.29 ml (median, 0.35 ml; range, 0.02-0.48 ml). Tumor multifocality and bilaterality were present in 69 and 37% of cases, respectively. Three (5%) had positive surgical margins. The largest tumor was located in the peripheral zone, transitional zone, and central zone in 79, 16, and 5% of cases, respectively. The largest tumor was located in the anterior prostate in 10 cases (16%) and in the posterior prostate in 52 cases (84%). The distribution of Gleason scores was 5 (12 cases, 19 %), 6 (40 cases, 65 %), and 7 (10 cases, 16 %). One case had a primary Gleason pattern 4. None had extraprostatic extension, seminal vesicle invasion, or lymph node metastasis. Small-volume prostate cancers are often multifocal and bilateral, with predilection for the peripheral zone. Of these small-volume cases, 16% had Gleason pattern 4 and might, therefore, be clinically significant.     

Neutrophil gelatinase-associated lipocalin (NGAL) and matrix metalloproteinase-9 (MMP-9) prognostic value in stage I colorectal carcinoma

The expression of neutrophil gelatinase-associated lipocalin (NGAL) has been suggested to behave like a negative prognostic marker in stage I colorectal carcinoma. In the aim of clarifying whether its association with adverse outcome may descend from NGAL's ability to regulate matrix metallo-proteinase-9 (MMP-9), we analyzed the correlation, prognostic value, and association with neo-angiogenesis of NGAL and MMP-9 immunohistochemical expression in a series of stage I colorectal carcinomas. A variable NGAL immunoexpression was demonstrated in 17 of the 48 analyzed cases with a significantly higher frequency of positive cases among patients showing disease progression. NGAL expression was also positively correlated with VEGF expression detected in the same cases. MMP-9 immunostaining was present in the cytoplasm of the neoplastic cells in 30 cases; no significant correlations were evidenced with NGAL expression, as well as with the various clinico-pathological parameters or with progression of the colorectal carcinomas. By contrast, NGAL expression was confirmed as a significant independent negative prognostic marker related to a shorter disease-free survival in stage I colorectal carcinoma. Our preliminary results suggest that the association of NGAL with poor outcome might be independent from MMP-9 regulation, thus highlighting its prognostic value in this neoplasia. If our findings are confirmed in further analyses, NGAL assessment might be used in order to select those patients with a higher progression risk and to submit them to adjuvant therapies useful to prevent adverse outcome.     

HER2 status in gastric cancer: A comparison of two novel in situ hybridization methods (IQ FISH and dual color SISH) and two immunohistochemistry methods (A0485 and HercepTest™)

In contrast to breast HER2 testing, the optimal ISH method and antibody for gastric HER2 testing are unclear. The aim of this study was to find out gastric HER2 positivity rates in our institutional data, and to compare the two novel ISH methods with A0485 antibody and HercepTest™. IHC and ISH were carried out on gastrectomy specimens of 88 patients up to the standardly advised procedure protocols, and interpretations were also carried out up to widely accepted international protocols., HER2 expression was (−) in 65, (+) in 5, (++) in 6, and (+++) in 12 cases by A0485 IHC. IHC (+) 4 cases and (++) 3 cases were (−) by HercepTest™. One IHC (−) amplified case was (++) by HercepTest™. All A0485 and HercepTest™ (+++) 12 cases were amplified by ISH. HER2 amplification was detected in 18 (20.4%) and in 15 (17.2%) cases by SISH and FISH, respectively. Of the 18 cases, 4 showed focal heterogeneous low level amplification by SISH. Focal amplification was noted in only 2 cases by FISH. The HER2 status of our gastric cancer file is 17.2% by FISH, 20.4% by SISH. The concordance between HercepTest™/A0485 IHC and ISH is perfect in (+++) cases. Equivocal results (++) with any IHC method should be clarified by one of the molecular methods (SISH and FISH). Probably up to the higher level of heterogeneity of gastric carcinomas, there is a 4.5% dilemma of cases that are negative or weakly positive by conventional IHC methods. Therefore, regarding HER2 status in gastric carcinoma, the reliability of IHC methods should be checked.     

The prognostic role of tumor associated glycoprotein 72 (TAG-72) in stage II and III colorectal adenocarcinoma

Tumor associated glycoprotein 72 (TAG-72) is a membrane-bound glycoprotein complex that is overexpressed in many adenocarcinomas. Recently, monoclonal antibody targeting TAG72, minretumomab, have been introduced as a potential therapeutic target in colorectal cancers (CRC) as well as breast and lung cancers. However, the detailed expression profile of TAG72 and its prognostic effect in CRC are not clear yet. We investigated the relationship between tumor associated glycoprotein 72 (TAG-72) expression and clinicopathologic characteristics in CRC using 3E8 antibody, a fully humanized antibody with the highest affinity to TAG-72. Immunohistochemical staining for TAG-72 was performed in 578 CRC patients, and the results were analyzed using a modified Remmele scoring system (score: 0–12). Of the 578 patients, 144 (24.9%) composed the TAG-72 overexpression (TAG-72^high) group. TAG-72^high was significantly associated with microsatellite stable tumor (P?=?.002), lymphatic invasion (P?=?.001), venous invasion (P?=?.005), and high pN status (P?<?.001). In survival analyses, TAG-72^high group showed shorter disease-free survival in univariate analysis (P?=?.001), and TAG-72^high was found to be an independent prognostic factor in multivariate analysis (P?=?.028), in addition to TNM stage. In conclusion, TAG-72 is thought to be the factors involved in the progression of CRC and may be considered as one of the potential therapeutic target.     

VEGFR-2 as a novel predictor of survival in gastric cancer: A systematic review and meta-analysis

Background

Expression of VEGFRs may affect cancer prognosis. The aim of this work is to evaluate the prognostic significance of VEGFRs of patients with gastric cancer.