Perineural invasion is associated with increased relapse after external beam radiotherapy for men with low-risk prostate cancer and may be a marker for occult, high-grade cancer.

PURPOSE: To investigate the risk of postradiotherapy prostate-specific antigen (PSA) failure on the basis of pretreatment risk factors in prostate cancer patients with and without perineural invasion (PNI) in prostate biopsy specimens and to explain the observation that otherwise low-risk patients with PNI experience decreased freedom from PSA failure after external beam radiotherapy (RT). METHODS AND MATERIALS: The study cohort consisted of 381 patients who underwent RT between 1989 and 2000 for clinically localized prostate cancer. A single genitourinary pathologist scored the absence or presence of PNI on all prostate biopsy specimens. Patients were divided into low-, intermediate- and high-risk subgroups on the basis of their 1992 American Joint Committee on Cancer T-stage, pretreatment PSA level, and Gleason score. Cox regression uni- and multivariate analyses were performed to evaluate whether the presence or absence of PNI in the biopsy specimen was a predictor of the time to post-RT PSA failure for patients in each pretreatment risk group. PSA failure was defined using the American Society for Therapeutic Radiology and Oncology consensus definition. Actuarial PSA failure-free survival was estimated using the Kaplan-Meier method, and comparisons were performed using the log-rank test. RESULTS: Cox regression univariate analysis revealed that PNI was a significant predictor of the time to PSA failure in the low-risk (p = 0.04) and high-risk (p = 0.03) cohorts. The 5-year PSA failure-free survival rate was 50% vs. 80% (p = 0.04) in low-risk patients, 70% vs. 75% (p = 0.72) in intermediate-risk patients, and 29% vs. 53% (p = 0.03) in high-risk patients with and without PNI, respectively. Cox regression multivariate analysis within the high-risk group revealed that a PSA level > or =20 ng/mL (p = 0.01) and Gleason score > or =8 (p = 0.02), but not PNI, were the only significant predictors of the time to PSA failure after RT. However, an association was found between the presence of PNI in the needle biopsy specimen and a biopsy Gleason score of 8-10 (p = 0.06). The association was stronger between the presence of PNI in the needle biopsy specimen and a biopsy Gleason score of 7-10 (p = 0. 033). CONCLUSION: A decrement in PSA outcome after RT for low-risk patients with PNI-positive biopsy specimens was found. The association between PNI and high Gleason score provides a possible explanation for the loss of statistical significance of PNI in the Cox regression multivariate analysis of the high-risk cohort. The data suggest that PNI found in the biopsy specimen of an otherwise low-risk patient predicts for occult high-grade disease that is missed owing to the sampling error associated with prostate biopsy. The association between PNI and a high Gleason score argues for the use of more aggressive therapy, such as hormonal therapy with RT and/or dose escalation, in these select patients.

Subclassification of renal cell neoplasms: an update for the practising pathologist.

The classification of renal cell neoplasms has been extensively studied in the last decade, and a standardized nomenclature adopted. Although this system is based on a combination of genetic, histological and immunohistological features, in most cases accurate classification can be based on histological features alone. This review summarizes the key features of the tumours included in this system, and then focuses on diagnostic difficulties that can arise when using this system, as well as reviewing several recently characterized tumours that are not yet included.

Should atypical squamous cells of undetermined significance (ASCUS) be subcategorized? Accuracy analysis of Papanicolaou smears using receiver operating characteristic curves and implications for the ASCUS/squamous intraepithelial lesion ratio.

We correlated all Papanicolaou test diagnoses over a 6-month period with biopsy results and determined accuracy using receiver operating characteristic curves and biopsy as the "gold standard." Accuracies were calculated using all atypical squamous cells of undetermined significance (ASCUS) cases or by eliminating subsets thereof. Retaining the ASCUS category resulted in significantly greater accuracy for the diagnosis of squamous intraepithelial lesion (SIL) on biopsy compared with eliminating it by diagnosing all such cases as negative. Subcategorization significantly improved the accuracy of the test only when all cases were included. The highest accuracy without subcategorization was achieved when ASCUS, favor reactive, cases were diagnosed as negative, but this threshold was significantly less sensitive than including all ASCUS cases. Increasing or decreasing the estimated ASCUS/SIL ratio from 2.4 without subcategorization significantly reduced accuracy. Similar results were obtained when high-grade SIL on biopsy was used as the gold standard. Use of the ASCUS category significantly improves the accuracy of the Papanicolaou test. Eliminating any subset of ASCUS reduces the ASCUS/SIL ratio but also significantly diminishes the sensitivity of the Papanicolaou test.

Accuracy of thyroid fine-needle aspiration using receiver operator characteristic curves.

Although many large series demonstrate the effectiveness of thyroid fine-needle aspiration (FNA), measuring its accuracy has been suboptimal owing to inappropriate statistical methods. All thyroid fine-needle aspirates were correlated with corresponding histologic and cytologic follow-up for a 4-year period, and the accuracy was determined using receiver operator characteristic curves, which allow inclusion of nondiagnostic and indeterminate cases. There were 1,085 cases, 291 with follow-up. The overall accuracy was 0.90 +/- 0.02 for a single aspiration session. A nondiagnostic aspirate was associated with a significant risk of malignancy (16%). However, 70% of patients who underwent reaspiration had adequate and negative results, and reaspiration significantly increased overall accuracy. Subcategorizing the nondiagnostic category did not affect accuracy, but did define categories with a significantly different change of a negative diagnosis on repeated aspiration. Although subcategories of papillary carcinoma were associated with significantly different risks of carcinoma (40% vs 81%), they did not significantly improve overall accuracy. Receiver operator characteristic curves can be used to define the accuracy of thyroid FNA. This method demonstrates significantly increased accuracy with repeated aspiration of nondiagnostic cases and demonstrates that subcategorization does not improve the overall accuracy of the test.

Estimating the impact on prostate cancer mortality of incorporating prostate-specific antigen testing into screening.

OBJECTIVES: Whether early detection using prostate-specific antigen (PSA) and digital rectal examination (DRE) compared with DRE alone will reduce prostate cancer mortality awaits the results of ongoing prospective randomized trials. However, the impact that early detection could have on prostate cancer-specific survival can be estimated by assuming that PSA failure after radical prostatectomy (RP) will translate into death from prostate cancer. METHODS: The study population consisted of 1274 men with clinically localized prostate cancer who underwent RP in Boston, Massachusetts or Philadelphia, Pennsylvania between 1989 and 2000 and had a preoperative PSA level greater than 4 but not more than 10 ng/mL. The primary endpoint was actuarial freedom from PSA failure (defined as PSA outcome). RESULTS: The relative risk of PSA failure after RP for patients diagnosed with a PSA of greater than 4 to 5, 5 to 6, 6 to 7, or 7 to 8 ng/mL compared with greater than 8 up to 10 ng/mL was 0.3 (95% confidence interval [CI] 0.2 to 0.5), 0.5 (95% CI 0.4 to 0.8), 0.6 (95% CI 0.4 to 0.9), or 0.9 (95% CI 0.6 to 1.3), respectively. On the basis of the estimates of the 5-year PSA outcome, patients with a biopsy Gleason score of 5 or 6 (781 of 1274; 61%) consistently benefited from RP performed when the PSA at diagnosis was greater than 4 to 7 ng/mL compared with greater than 8 to 10 ng/mL (93% versus 78%, P <0.0001). A benefit to early detection was not found for the vast majority (266 of 312; 88%) of patients who had a biopsy Gleason score of 7 or higher. CONCLUSIONS: Early detection using both PSA and DRE-based screening may benefit men who present with biopsy Gleason score 5 or 6 prostate cancer and a PSA level greater than 4 to 7 ng/mL compared with greater than 8 up to 10 ng/mL. This finding awaits validation from ongoing prospective randomized trials.

Estimating the percentage of Papanicolaou smears that can be reproducibly identified: modeling Papanicolaou smear interpretation based on multiple blinded rescreenings.

BACKGROUND: Multiple blinded rescreenings of Papanicolaou (Pap) smears for litigation purposes is based on the assumption that a subset of Pap smears can be reproducibly identified. The size of this subset is not known. METHODS: To estimate the size of the subset of Pap smears that can be reproducibly identified, a model was constructed based on the results of repeated blinded screenings in the AutoPap Primary Screening System Trial. Additional analysis came from data in the literature. RESULTS: Routine and AutoPap-assisted screening both have a detection rate for all detected abnormal cases of < 50%. Models with only two subsets or types of slides each with a different detection rate correlated well with the available data. Data from multiple rapid reviews strongly supported the existence of additional definable subsets. Although the percentage of cases with an expected detection rate of 100% in a three-subset model might have been as high as 30% of the abnormal cases detected in a single review, all estimates that included a second subset of slides with at least a 50% detection rate limited the percentage of slides in the 100% sensitive subset of slides to < 2% of all abnormal slides and < 6% of all abnormal slides detected by a single screening. CONCLUSIONS: Repeated screenings of Pap smears allowed more accurate models of the sensitivity of Pap-smear screening and the overall incidence of abnormal cases. The data strongly supported the existence of multiple subsets of Pap smears, which can be defined by repeated blinded rescreenings. The percentage of slides that can be reproducibly identified was small.

Adequate histologic sampling of breast core needle biopsies.

OBJECTIVE: To determine the degree of histologic sampling necessary for adequate examination of breast core needle biopsy specimens. DESIGN: The results of all breast core needle biopsies (11 and 14 gauge) with a diagnosis of atypical small acinar proliferation or atypical ductal hyperplasia and subsequent excisional biopsies, for a 50-month period were reviewed. Blocks of all cores were sectioned entirely in 8 slides to determine the amount of sectioning needed to detect these foci, and the results were correlated with those from the excision specimen. SETTING: Large community hospital practice. RESULTS: Of 3026 cases, 216 (7.1%) were diagnosed as atypical ductal hyperplasia or atypia not otherwise specified. Subsequent resections were available in 105 (49%) cases, and after review, 95 (92%) qualified as atypical ductal hyperplasia and 2 were determined to be atypical small acinar proliferations. The 2 small acinar proliferations were first detected on the second and fourth slides. Of the atypical ductal hyperplasia cases, 43% were detected on the first slide, 17% on the second, 23% on the third, 8% on the fourth, and 8% on the fifth. No lesions were initially detected after this level. Ductal carcinoma in situ was detected in the excision specimens from 1 case each of those detected initially on the fourth and fifth slides. CONCLUSION: Five sections of breast core needle biopsy specimens are necessary to ensure that all atypical small acinar proliferations and atypical ductal hyperplasia lesions are sampled.

Helicobacter pylori infection in patients undergoing gastric bypass surgery for morbid obesity.

BACKGROUND: Studies suggest that the incidence of Helicobacter pylori infection in obese patients, including those undergoing gastric reduction surgery, may be increased. METHODS: We examined the histologic findings at the time of surgery in a series of patients who were undergoing Roux-en-Y gastric bypass (RYGBP) for morbid obesity and compared these results with patients in our institution undergoing endoscopy. RESULTS: Of 60 patients undergoing RYGBP, material for histologic examination was available in 56 cases, and in 40 cases gastric fundic mucosa from the anastomotic site was sampled at the time of surgery. Active chronic gastritis was present in 6 (15%), and chronic gastritis was present in 27 (68%). H. pylori was present in all 6 cases of active chronic gastritis and in 9 cases of chronic gastritis (total 38%). This incidence of H. pylori infection was higher than that found in the series of gastric biopsies (107/500, 21%, p = 0.03) and fundic biopsies (10/80, 13%, p = 0.003), but was not different when compared with age-matched gastric biopsies (44/177, 25%, p = 0.12). CONCLUSIONS: The incidence of H. pylori in patients undergoing RYGBP was higher than that found in all patients undergoing endoscopy and biopsy and than those undergoing fundic biopsies, but not higher when age-matched controls were considered.

Improved reporting methods for atypia and atypical ductal hyperplasia in breast core needle biopsy specimens. Potential for interlaboratory comparisons.

The incidence of atypia and atypical ductal hyperplasia (ADH) in breast core needle biopsies varies widely (900%). I sought to identify methods to reduce the dependence of this measure on variability in the patient population. The results of all breast core needle biopsies with a diagnosis of ADH or atypia not otherwise specified for a 50-month period were reviewed. These were separated into different groups by age, and the variability of different reporting methods was compared. Of 3,026 cases, 216 were diagnosed as ADH or atypia not otherwise specified. The overall incidence of atypia by age group varied significantly from 0.029 to 0.10. The variability was reduced when atypia was expressed in relation to ductal carcinoma in situ (range, 1.0-2.1) or fibrocystic changes (range, 0.15-0.28). However, variability by age was the least when atypia was expressed in relation to the number of cases performed for calcifications (range, 0.13-0.17). Variability in atypia rates associated with age is reduced significantly when atypia is expressed in relation to the number of biopsies done for calcifications. This method of reporting atypia may allow interlaboratory comparisons with less dependence on the characteristics of the patient population.

Atypical ductal hyperplasia in breast core needle biopsies. Correlation of size of the lesion, complete removal of the lesion, and the incidence of carcinoma in follow-up biopsies.

We reviewed the results of all breast core needle biopsies with a diagnosis of atypical ductal hyperplasia (ADH) or atypia not otherwise specified and subsequent excisional biopsies for a 50-month period and correlated the results. Of 3,026 biopsies, 216 were diagnosed as ADH or atypia not otherwise specified, and subsequent resection was available for 105. After review, 95 qualified as ADH. Subsequent resection showed ductal carcinoma in situ (DCIS) in 13 excisions, ADH in 31, lobular carcinoma in situ in 6, and benign proliferative lesions in the remaining 45. In none of the 8 biopsies in which DCIS was found and radiographs were available for review was the radiographic lesion entirely removed. For comparison, the incidence of carcinoma in resections done for a diagnosis of DCIS, low or intermediate grade (solid, cribriform, or micropapillary type), on core needle biopsy was significantly greater (8 of 10 cases). However, the size of the lesions diagnosed as carcinoma also was significantly greater than that of the lesions diagnosed as ADH, and in none of the 8 biopsies with DCIS at excision was the lesion entirely removed at the time of biopsy. The incidence of carcinoma in excisional biopsies done for a diagnosis of ADH in core needle biopsies in our institution is relatively low, while the incidence of ADH is relatively high. Possible reasons for this include total removal of small lesions at the time of biopsy and use of the diagnostic term ADH for lesions that are not associated with coexistent DCIS.

Transition from in situ to invasive testicular germ cell neoplasia is associated with the loss of p21 and gain of mdm-2 expression.

INTRODUCTION: The tumor suppressor gene p53 has been shown to transcriptionally regulate expression of the cell cycle dependent kinase inhibitor p21. p53 is in turn regulated by the ubiquitin ligase mouse double minute-2 (mdm-2). We have set out to examine p21 expression in testicular germ cell tumors and its relationship with p53 and mdm-2 expression. METHODS: Immunohistochemical analysis was performed on formalin-fixed paraffin-embedded tissue for p53, p21, and mdm-2 in 31 testicular germ cell tumors, which included 17 pure seminomas and 14 mixed germ cell tumors composed predominantly of embryonal carcinoma. Twenty-seven cases contained adjacent areas of intratubular germ cell neoplasia (ITGCN). RESULTS: 17 out of 17 seminomas and 14 out of 14 embryonal carcinomas expressed p53 in both ITGCN and the invasive tumor. In contrast, none of the 17 seminomas and only 2 of 14 embryonal carcinomas revealed positive staining for p21 protein. p21 expression was noted in 18 of 27 cases (67%) of ITGCN, and in 16 of these cases (89%) the corresponding invasive tumor had lost p21 expression. In nine additional cases p21 expression was absent in both the invasive and intratubular tumor. mdm-2 expression was present in 8 out of 17 (47%) seminomas and 13 out of 14 (93%) embryonal carcinomas but was present in only 2 out of 27 (7%) cases of ITGCN. Statistically significant associations for loss of p21 and gain of mdm-2 expression in invasive tumors were present (P < .0001). CONCLUSIONS: The co-expression of p53 and p21 in ITGCN is consistent with preservation of p53-directed induction of p21. The loss of p21 expression in invasive tumors suggests a disruption of the p53 regulatory pathway. The inverse correlation of p21 and mdm-2 expression in both ITGCN and invasive tumors could indicate that loss of the functional p53 regulatory pathway may be correlated with the onset of mdm-2 expression. These results raise the possibility that the loss of p21 expression may be associated with the development of invasive germ cell tumors from ITGCN. Persistent p53 expression in the presence of mdm-2 suggests that in testicular germ cell tumors, while mdm-2 can block the transactivation potential of p53, it can no longer target p53 for degradation.

An accurate and precise methodology for routine determination of the false-negative rate of Papanicolaou smear screening.

BACKGROUND: Although the false-negative rate (FNR) is the most important quality control measure for Papanicolaou smear screening, accurate, precise, and feasible methods for determining this value are lacking. METHODS: The author undertook an analysis and review of the literature. RESULTS: The best estimates of the FNR using atypical squamous cells of undetermined significance (ASCUS) as a threshold range from 17% to 61%. Sources of error in the accuracy of this measure that must be accounted for include the FNR of the review method, differences in diagnostic thresholds between the original diagnostic method and the review method, and differences in diagnostic accuracy between the original diagnostic method and the review method. Statistically precise (valid to within 10%) measurement of this value in laboratories with an ASCUS+ rate of 7% can be made from interlaboratory rescreening of approximately 1200-1500 randomly selected normal and abnormal slides along with both laboratories rediagnosing without rescreening 300-400 benign cellular change and ASCUS slides to determine the difference in diagnostic threshold. Consensus for each slide is not required with this method. Changing the threshold to low grade squamous intraepithelial lesion (best estimate FNR, 14-58%) requires review of significantly more slides to achieve the same statistical level of precision. CONCLUSIONS: Detailed analysis of the sources of error in determining the FNR allow creation of methods that are relatively unbiased, feasible, and testable and whose accuracy and precision can be determined.

The human false-negative rate of rescreening Pap tests. Measured in a two-arm prospective clinical trial.

BACKGROUND: Routine quality control rescreening often is used to calculate the false-negative rate (FNR) of gynecologic cytology. Theoretic analysis suggests that this is not appropriate, due to the high FNR of rescreening and the inability to actually measure it. The authors sought to determine the FNR of manual rescreening in a large, prospective, two-arm clinical trial using an analytic instrument in the evaluation. METHODS: The results of the Autopap System Clinical Trial, encompassing 25,124 analyzed slides, were reviewed. The false-negative and false-positive rates at various thresholds were determined for routine primary screening, routine rescreening, Autopap primary screening, and Autopap rescreening by using a simple, standard methodology. RESULTS: The FNR of routine manual rescreening at the level of atypical squamous cells of undetermined significance (ASCUS) was 73%, more than 3 times the FNR of primary screening; 11 cases were detected. The FNR of Autopap rescreening was 34%; 80 cases were detected. Routine manual rescreening decreased the laboratory FNR by less than 1%; Autopap rescreening reduced the overall laboratory FNR by 5.7%. At the same time, the false-positive rate for Autopap screening was significantly less than that of routine manual screening at the ASCUS level (4.7% vs. 5.6%; P < 0.0001). Rescreening with the Autopap system remained more sensitive than manual rescreening at the low grade squamous intraepithelial lesions threshold (FNR of 58.8% vs. 100%, respectively), although the number of cases rescreened was low. CONCLUSIONS: Routine manual rescreening cannot be used to calculate the FNR of primary screening. Routine rescreening is an extremely ineffective method to detect error and thereby decrease a laboratory's FNR. The Autopap system is a much more effective way of detecting errors within a laboratory and reduces the laboratory's FNR by greater than 25%.

Measuring and reporting errors in surgical pathology. Lessons from gynecologic cytology.

Substantial improvements in measuring and reporting errors in gynecologic cytology have been made during the last decade. Measuring and reporting errors in surgical pathology recently has gained renewed interest. However, review of current literature demonstrates mistakes in how these data are measured and reported. Error rates have been reported from review of consecutive material, biopsy material, and consultation material and range from 0.25% to 43%. Errors have been divided into anatomic regions and specimen types and separated according to their clinical significance. However, to be comparable, errors must be reported in reference to the incidence of disease and not to overall caseload. Blinding and reviewer error have been addressed only rarely, and the true incidence of errors is almost certainly higher than reported. "Gold standards" are not well defined. In addition, available data strongly suggest that the greatest source of error is with false-negative diagnoses, which are detected only rarely by review of consultation material. Most of these issues have been addressed in the gynecologic cytology literature. Errors in surgical pathology are more common than generally believed, and efforts should be made to define methods that allow appropriate interlaboratory comparisons.

Optimizing patient selection for prostate monotherapy.

PURPOSE: Patients at low risk for prostate-specific antigen (PSA) failure following definitive local therapy are those with PSA of 10 or less, biopsy Gleason Score of 6 or less, and 1992 American Joint Committee on Cancer (AJCC) clinical Stage T1c or T2a. However, low-risk patients managed with radical prostatectomy and found to have prostatectomy Gleason score > or = 3+4 have a less favorable PSA outcome when compared to patients with prostatectomy Gleason score < or = 3+3. This study was performed to determine whether the percentage of positive prostate biopsy cores could predict upgrading from a biopsy Gleason score of 6 or less to a prostatectomy Gleason score > or = 3+4 in low-risk patients to optimize selection for prostate only radiation therapy. METHODS AND MATERIALS: Concordance testing of the biopsy Gleason score and the primary and secondary prostatectomy Gleason grades was performed in 427 prostate cancer patients treated with radical prostatectomy and at low risk for PSA failure. Logistic regression multivariable analysis was performed to test the ability of the established prognostic factors and the percentage of positive prostate biopsies (<34%, 34-50%, >50%) to predict for upgrading from biopsy Gleason score of 6 or less prostatectomy Gleason score > or = 3+4. PSA failure-free survival was reported using the actuarial method of Kaplan and Meier and comparisons were made using a log-rank test. RESULTS: Twenty-nine percent of the 427 study patients were upgraded from a biopsy Gleason score of 6 or less to a prostatectomy Gleason score > or = 3+4. The presence of greater than 50% positive biopsies was the only significant factor for predicting the upgrading from biopsy Gleason score of 6 or less to prostatectomy Gleason score > or = 3+4 on logistic regression multivariable analysis with the variables treated as continuous and categorical. Specifically, upgrading occurred in 26% vs. 59% of patients with 50% or less vs. greater than 50% positive biopsies, respectively. This translated into a 5-year PSA failure-free survival which was significantly higher (92% vs. 62%, p = 0.00001) for men with 50% or less vs. greater than 50% positive prostate biopsies, respectively. CONCLUSION: The presence of greater than 50% positive biopsies was associated with higher rates of pathologic upgrading which translated into lower 5-year PSA failure-free survival following radical prostatectomy (RP). Therefore, the percentage of positive biopsies may be useful in optimizing the selection of low-risk patients for prostate only radiation therapy such as external beam radiation or implant monotherapy.

The clinical utility of the percent of positive prostate biopsies in predicting biochemical outcome following external-beam radiation therapy for patients with clinically localized prostate cancer.

PURPOSE: An investigation was performed of the clinical utility of the percent of positive prostate biopsies in predicting prostate-specific antigen (PSA) outcome following external-beam radiation therapy (RT) for men with PSA-detected or clinically palpable prostate cancer. METHODS AND MATERIALS: A Cox regression multivariable analysis was used to determine whether the percent of positive prostate biopsies provided clinically relevant information about PSA outcome following external beam RT in 473 men while accounting for the previously established risk groups based on the pretreatment PSA level, biopsy Gleason score, and the 1992 American Joint Commission on Cancer (AJCC) clinical T stage. RESULTS: Controlling for the known prognostic factors, the percent of positive prostate biopsies added clinically significant information (p = 0.02) regarding time to PSA failure following RT. Specifically, 76% of the patients in the intermediate risk group (1992 AJCC T(2b) or biopsy Gleason 7 or PSA > 10 ng/mL and < or = 20 ng/mL) could be classified into either an 30% or 85% 5-year PSA control cohort using the preoperative prostate biopsy data. CONCLUSION: The previously validated stratification of PSA outcome following radical prostatectomy (RP) using the percent of positive prostate biopsies in intermediate-risk patients is also clinically significant for men treated with external beam RT. The percent positive prostate biopsies should be considered in conjunction with the PSA level, biopsy Gleason score, and 1992 AJCC clinical T stage when counseling patients with newly diagnosed and clinically localized prostate cancer about PSA outcome following RP or external beam RT.

Extensively keratinized squamous intraepithelial lesions of the cervix are difficult to grade.

We tested the hypothesis that extensively keratinized squamous intraepithelial lesions (SILs) are difficult to grade precisely by identifying 100 Papanicolaou smears with a keratinizing SIL that had been originally judged difficult to grade. Of these, 65 were confirmed as low-grade SIL (LSIL) or high-grade SIL (HSIL) on subsequent biopsy. The 65 smears were reviewed independently by 3 cytopathologists who graded each case as LSIL or HSIL (by Bethesda System criteria). The accuracy of the grade was determined by the subsequent biopsy results; accuracy was compared with that of a historic control group of SILs with biopsy follow-up. In the study group, biopsies showed LSIL in 41 cases and HSIL in 24. The mean accuracy for a smear diagnosis of LSIL was 60% for the study group and 92% for the control group. For a smear diagnosis of HSIL, the accuracy was 60% for the study group and 95% for the control group. The overall kappa value for the study group confirmed poor interobserver agreement. Some keratinizing SILs are difficult if not impossible to grade precisely using standard criteria. For such lesions, the diagnosis "SIL, grade cannot be determined due to extensive keratinization" is justified.

Perineural invasion as a predictor of biochemical outcome following radical prostatectomy for select men with clinically localized prostate cancer.

PURPOSE: The presence of perineural invasion on the prostate needle biopsy specimen has been suggested to be an independent predictor of prostate specific antigen (PSA) outcome following radical prostatectomy. We evaluated the clinical use of perineural invasion at biopsy for predicting time to PSA failure following radical prostatectomy after controlling for established prognostic factors. MATERIALS AND METHODS: A prospective evaluation using a Cox regression multivariate analysis of 750 men with clinically localized or PSA detected prostate cancer was performed to evaluate the ability of PSA, biopsy Gleason score, perineural invasion on the needle biopsy specimen and the percent of positive prostate biopsies to predict PSA outcome following radical prostatectomy. RESULTS: Multivariate analysis demonstrated that the presence of perineural invasion on the needle biopsy specimen provided additional information regarding 5-year PSA outcome (82% versus 95%, p = 0.04) for patients who were in the low risk group. This difference in PSA outcome could be explained by higher rates of positive surgical margins (25% versus 17%, p = 0.07). Patients whose prostate needle biopsy contained perineural invasion and who had the corresponding neurovascular bundle resected had a significantly lower positive margin rate (11% versus 100%, p = 0.001) compared to those who had the neurovascular bundle spared. The presence of perineural invasion on biopsy was not a significant predictor of PSA outcome following radical prostatectomy for patients in the intermediate or high risk group. CONCLUSIONS: Resection of the neurovascular bundle on the side corresponding to location of perineural invasion on the biopsy may decrease the positive surgical margin rate and improve outcome for low risk patients.

Isochromosome 7q in adult Wilms' tumors: diagnostic and pathogenetic implications.

Wilms' tumors affecting adults are rare and are thought to have a worse prognosis than similar stage tumors in the pediatric population. To understand these tumors better, the authors reviewed their multi-institutional experience in a series of nine lesions diagnosed as Wilms' tumors in adults. In addition to histologic and immunohistochemical examination, they performed cytogenetic analysis and fluorescence in situ hybridization. On review, four cases were reclassified: two "blastema only" as Ewing's sarcoma/primitive neuroectodermal tumor and the other two as clear cell sarcoma of soft parts and sarcoma not otherwise specified (NOS). Of the remaining five cases, three exhibited biphasic histology and two were triphasic. In this group, there were three women and two men, and patient age ranged from 17 to 37 years (median age, 26 years). Tumor size was large and ranged from 10 to 31 cm (median tumor size, 12.5 cm). Histologically, the tumors showed the typical features of Wilms' tumors with varying amounts of blastema (n = 5), epithelium (n = 5), and stroma (n = 2). No tumors contained anaplasia, and persistent renal blastema was not identified in the non-neoplastic kidney in any specimen. All tumors were positive for cytokeratins (CK7, n = 3; pankeratin, n = 5), and one tumor was weakly positive for CD99 (0-13). Molecular analysis including dual color fluorescence in situ hybridization (all tumors), and cytogenetic analysis (n = 2) disclosed the presence of isochromosome 7q in three of five tumors whereas all tumors were diploid with respect to chromosome 12. Follow-up data ranged from 6 to 133 months (median follow-up, 82 months) with progression in only one patient who had stage IV disease with lymph node and lung metastases at presentation. The authors conclude that adult Wilms' tumor has been overdiagnosed. Most "blastema-only" tumors in adults are not Wilms' tumors, and in an adult, biphasic morphology should be the minimum criteria for their diagnosis. Using strict diagnostic criteria, adult Wilms' tumors have a relatively favorable prognosis. The characteristic findings of isochromosome 7q, lack of trisomy or tetrasomy for chromosome 12, and absence of persistent renal blastema suggest that the pathogenesis of Wilms' tumors in adults may be different than in the pediatric population. These genetic features may be helpful in distinguishing adult Wilms' tumors from other primary renal tumors.