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* Context.--The incidence of prostate cancer with Gleason scores 2 through 4 has been decreasing for decades, largely because of evolving criteria for Gleason scores, including the 2005 International Society of Urological Pathology recommendation that scores of 2 through 4 should rarely, if ever, be diagnosed based on needle biopsy. Whether trends in assigning Gleason scores 2 through 4 vary by facility type and patient characteristics is unknown. Objective.--To assess trends in prostate cancer grading among various categories of treatment facilities. Design.--Analyses of National Cancer Database records from 1990 through 2013 for 434 612 prostate cancers diagnosed by core needle biopsy, including multivariable regression for 106 331 patients with clinical T1c disease diagnosed from 2004 through 2013. Results.--The proportion of prostate core needle biopsies with Gleason scores 2 through 4 declined from 11 476 of 53 850 (21.3%) (1990-1994) to 96 of 43 566 (0.2%) (2010-2013). The proportions of American Joint Committee on Cancer category T1c needle biopsies assigned Gleason scores 2 through 4 were 416 of 12 796 (3.3%) and 9 of 7194 (0.1%) during 2004 and 2013, respectively. Declines occurred earliest at National Cancer Institute-designated programs and latest at community programs. A multivariable logistic model adjusting for patient demo- graphic and clinical variables and restricted to T1c cancers diagnosed in needle biopsies from 2004 through 2013 showed that facility type is independently associated with the likelihood of cancers in such specimens being assigned Gleason scores of 2 through 4, with community centers having a statistically significant odds ratio of 5.99 relative to National Cancer Institute-designated centers. Conclusions.--These results strongly suggest differences in Gleason grading by pathologists practicing in different facility categories and variations in their promptness of adopting International Society of Urological Pathology recommendations. [ABSTRACT FROM AUTHOR]

Context.--Image-guided, fine-needle aspiration--assisted core needle biopsy with an on-site evaluation by a pathologist (FNACBP) of osseous lesions is not a common practice in pediatric institutions. Objectives.--To evaluate the diagnostic adequacy and accuracy of FNACBP for pediatric osseous lesions and to compare the adequacy with procedures that do not use fine-needle aspiration. Design.--Six-year, retrospective review of 144 consecutive children biopsied for osseous lesions with and without fine-needle aspiration assistance. Results.--Pathologic diagnosis was achieved in 79% (57 of 72) of the core biopsies without an on-site evaluation, 78% (32 of 41) of the open biopsies (9 with intraoperative consultation), and 97% (30 of 31) of the FNACBPs as the initial diagnostic procedure. Three FNACBP cases were preceded by nondiagnostic open biopsies. Among 34 lesions sampled by FNACBP, 33 (97%) succeeded with diagnostic tissue, with most (30 of 33; 91%) being neoplasms, including 16 malignant (48%), 13 benign (39%), and 1 indeterminate (3%) lesions. The mostcommon diagnoses were osteosarcoma (9 of 33; 27%) and Langerhans cell histiocytosis (7 of 33; 21%). In cases with follow-up information available, 93% (28 of 30) of the FNACBP-rendered diagnoses were clinically useful, allowing initiation of appropriate therapy. The FNACBP procedure had 100% specificity, sensitivity, and positive predictive value for all 14 malignant lesions, with the sensitivity being 88% in benign lesions. Most FNACBP procedures (32 of 34; 94%) yielded adequate material for ancillary testing. A gradual upward trend was observed for the choice of FNACBP as an initial diagnostic procedure for osseous lesions. Conclusions.--The FNACBP procedure yields sufficient material for diagnosis and ancillary studies in pediatric, osseous lesions and may be considered an initial-diagnostic procedure of choice. [ABSTRACT FROM AUTHOR]

Context.—College of American Pathologists (CAP) surveys are used to establish national benchmarks for laboratory parameters. Objective.—To evaluate changes in laboratory human papillomavirus (HPV) testing patterns in laboratories incorporating HPV testing with Papanicolaou tests in 2012. Design.—Data were analyzed from the CAP HPV Supplemental Questionnaire distributed to 1771 laboratories participating in either CAP HPV or CAP Papanicolaou proficiency testing in 2013. Results.—A total of 1022 laboratories (58%) responded. There were more high-risk (HR) HPV tests performed per institution as compared to previous surveys. There were more HPV tests performed within an institution as compared to previous surveys. Hybrid Capture 2 (HC2) remains the most common method (42.4%, 239 of 564); Cervista and cobas methods are used in 37.2% (210 of 564) and 14.9% (84 of 564) of laboratories, respectively. Human papillomavirus testing is offered as a reflex test after a Papanicolaou test result of atypical squamous cells of undetermined significance (ASC-US) in 89.6% of laboratories (476 of 531); as a cotest for women aged 30 years and older in 60.3% (404 of 531); as reflex testing after atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion (ASC-H) in 42.7% (320 of 531); and as reflex testing after atypical glandular cells (AGC) in 27.3% (145 of 531). The HPV-positive rates for ASC-US and ASC-H were similar in 2012 and 2006. Cervista (49.2%, 88 of 179) and Roche cobas (27.4%, 49 of 179) are the most common methods used for genotyping. Most laboratories use the CAP Human Papillomavirus for Cytology Program for proficiency testing. Conclusions.—There was an increase in annual volume of HR-HPV testing with a shift toward in-house HR-HPV testing. Genotyping volumes also increased. HC2 and Cervista are most commonly used, with an increasing volume of Roche cobas testing. The most common indication for HPV testing among all laboratories was ASC-US reflex testing, but an increase in HPV cotesting was observed. The data provide an update into persisting and newer trends in HPV testing practices. [ABSTRACT FROM AUTHOR]

Context.--The deposition of extracellular matrix is a major pathogenic mechanism leading to fibrosis and progressive decline in renal function in patients with lupus nephritis (LN). Currently, available clinicopathologic features cannot predict renal outcome consistently. Objective.--To test that the expression of renal fibrogenic genes correlates with renal fibrosis at the time of biopsy and is predictive of renal outcomes. Design.--Renal gene expression levels of transforming growth factor β-1 (TGFB1), and collagen I (COL1) were studied by real-time multiplex quantitative polymerase chain reaction in a prospective cohort of patients with LN (n = 39). Extracellular matrix index (ECMI) and collagen I/ III matrix index were measured from Picro-Sirius Red--stained slides under normal and polarized light, respectively. Results.--After follow-up (median, 43.9 months), renal failure (50% reduction in glomerular filtration rate [GFR] or dialysis) had developed in 13 subjects. The expression levels of renal fibrogenic genes were increased as compared to controls without LN. COL1 correlated with collagen I/III matrix index at baseline. Both high expression of TGFB1 or COL1 tended to predict renal failure by univariate analysis. By multivariate analysis, high ECMI and low GFR were predictive of renal failure. In patients with baseline GFR of 60 mL/min/1.73 m2 or greater, high renal COL1 expression was an independent (hazard ratio = 4.4, P = .04) predictor of renal failure. Conclusions.--High renal COL1 expression is a strong predictor of adverse renal outcome in patients with LN and preserved baseline GFR. These findings support larger prospective studies to confirm the benefits of COL1 in identifying patients at high risk of progression to renal disease. [ABSTRACT FROM AUTHOR]

Context.-Previous studies have shown that there are disagreements in interlaboratory consultation, including false-negative and false-positive diagnoses. To date, methods to reduce false-negative and false-positive diagnoses have been poorly documented. Objective.-To identify features associated with falsenegative and false-positive diagnoses in anatomic pathology. Design.-We reviewed the results of interlaboratory consultation in our institution during a 9-year period. For false-negative and false-positive diagnoses, methods that might have prevented the error were identified. Results.-Disagreements were identified in 810 of 8082 consults (10%). Fifty-four false-negative cases (0.7% of all consults) and 27 false-positive cases (0.3%) were identified. False-negative cases were more common in breast (20 of 1131; 1.8%), genitourinary (16 of 970; 1.7%), hematologic (3 of 242; 1.3%), and cytology (3 of 404; 0.8%) than in all other sites combined (P < .001); no significant difference in sites were identified for falsepositive cases. Overall, there was no difference in the percentage of cases that were reviewed by more than one pathologist in either false-negative cases (109 of 810; 13.5%) or false-positive cases (135 of 810; 16.7%), compared with all other consults (858 of 7272; 11.8%) (P = .74 and .59, respectively). However, on review, 12 of all 27 false-positive cases (44%) might have been prevented by the use of immunohistochemistry alone, and 36 of all 54 false-negative cases (67%) might have been prevented by the use of a second review; special stains, including immunohistochemistry; additional levels; changes in processing; and hedges. Conclusion.-Approximately one-half of false-negative and false-positive cases (48 of 81; 59%) might be preventable by the use of a combination of pathologic methods. [ABSTRACT FROM AUTHOR]

Context.-Breast cancer treatment has greatly evolved from radical mastectomy to more cosmetically acceptable and less-debilitating surgeries. Nipple-sparing mastectomy is increasingly done for both cancer treatment and risk reduction. The frequency of terminal duct lobular units (TDLUs) and occult neoplastic epithelial proliferation in grossly/clinically unremarkable nipples (GUNs) is not well investigated. Objective.-To describe frequency of TDLUs and occult and overt neoplastic nipple involvement. Design.-Nipples from 105 consecutive specimens (90 therapeutic, 15 prophylactic) were studied. Sixty-five nipples were entirely submitted to evaluate frequency of TDLUs; the rest had 1 vertical section submitted. Results.-Terminal duct lobular unit was seen in 17 GUNs (26%). Six had TDLU in the base, 6 had it in the papilla, and 5 in both. Four GUNs showed lobular carcinoma in situ (1), Paget disease (1), and pagetoid extension of underlying malignancy (2). Grossly/clinically abnormal nipples had Paget disease (2), lymphovascular invasion (2), invasive carcinoma (4), and pagetoid extension (5). Involved nipples were closer to tumor (mean, 1.1 versus 3.2 cm, P < 001), had larger underlying tumors (mean, 4.3 versus 2.6 cm, P =.03) and of higher grade (P = .04), and more often had lymph node metastases (91% versus 44%, P = .007). No pathologic abnormalities were found in prophylactic mastectomy nipples. Conclusions.-Terminal duct lobular units were seen in 26% of nipples. They were frequently seen in the nipple papilla. Occult neoplastic epithelial proliferation was seen in 5% of grossly/clinically unremarkable therapeutic mastectomy nipples. Pagetoid extension was the dominant spread of underlying malignancy. Overall, the nipple was more often involved by larger and higher-grade tumors located closer to the nipple. All prophylactic mastectomies had unremarkable nipples. These findings should be considered while selecting patients for nipple-sparing mastectomy. [ABSTRACT FROM AUTHOR]

Context.-Prostate cancer (PC) with lymph node metastases (LN+) is relatively rare, whereas it is relatively common in disease with a Gleason score (GS) 8 to 10 and virtually never seen in PC with GS 6 or less. It is most variable in GS 7 PC. Objective.-To determine clinicopathologic features associated with GS 7 PC with LN+ compared with a control group without lymph node metastases (LN-). Design.-We analyzed 184 GS 7 radical prostatectomies with LN+ and the same number of LN- Gleasonmatched controls. The LN+ cases were GS 3+4=7 (n=64; 34.8%), GS 4 + 3 = 7 (n ¼ 66; 35.9%), GS 3 + 4 = 7 with tertiary 5 (n = 10; 5.4%), and GS 4 + 3 = 7 with tertiary 5 (n = 44; 23.9%). Results.-The LN+ cases demonstrated higher average values in preoperative prostate-specific antigen (12.2 versus 8.1 ng/mL), percentage of positive biopsy cores (59.1% versus 42.9%), prostate weight (54.4 versus 49.4 g), number of LNs submitted (12.7 versus 9.4), incidence of nonfocal extraprostatic extension (82.6% versus 63.6%), tumor volume (28.9% versus 14.8%), frequency of lymphovascular invasion (78.3% versus 38.6%), intraductal spread of carcinoma (42.4% versus 20.7%), incidence of satellite tumor foci (16.4% versus 4.3%), incidence of pT3b disease (49.5% versus 14.7%), and lymphovascular invasion in the seminal vesicles (52% versus 30%). There were differences in GS 4 patterns and cytology between LN+ and LN- cases, with the former having higher volumes of cribriform and poorly formed patterns, larger nuclei and nucleoli, and more-frequent macronucleoli. All P ≤ .05. Conclusion.-Gleason score 7 PC with LN+ has features highlighting a more-aggressive phenotype. These features can be assessed as prognostic markers in GS 7 disease on biopsy (eg, GS 4 pattern, intraductal spread, cytology) or at radical prostatectomies (all variables), even in men without LN dissection or LN- disease. [ABSTRACT FROM AUTHOR]

Context.--Human telomerase reverse transcriptase (hTERT), an enzyme that enables cells to overcome replicative senescence and to divide indefinitely, is overexpressed in many cancers and their precursor lesions. Objective.--To test whether hTERT expression is related to neoplastic progression and resistance to apoptosis in vulvar epithelia. Design.--Immunoexpression of hTERT was evaluated in 101 formalin-fixed, paraffin-embedded archival vulvar epithelia consisting of normal squamous vulvar epithelia (n = 25), lichen sclerosus (n = 10), high-grade classic vulvar intraepithelial neoplasia (n = 16), differentiated vulvar intraepithelial neoplasia (n = 18), and vulvar invasive keratinizing squamous cell carcinoma (n = 32) and related to survivin and p53 expression. Immunostaining for all factors was scored for moderate and strong intensities with regard to quantity to determine upregulation and overexpression (score 0, 0% immunoreactive cells; score 1+, <5% immunoreactive cells; score 2+, 5% to 50% immunoreactive cells; score 3+, >50% immunoreactive cells). Score 3+ was considered as overexpression. Results.--Nuclear hTERT immunoexpression was closely related to survivin reactivity, increased from normal vulvar squamous epithelia to lichen sclerosus and to high-grade classic vulvar intraepithelial neoplasia, differentiated vulvar intraepithelial neoplasia, and invasive keratinizing squamous cell carcinoma (P < .001), and followed the morphologic distribution of atypical squamous epithelial cells. Overexpression of hTERT was comparable to that seen for p53 in invasive keratinizing squamous cell carcinoma (P = .62); significant differences were calculated for differentiated vulvar intraepithelial neoplasia (P = .003) and high-grade classic vulvar intraepithelial neoplasia (P = .001). Conclusion.--Human telomerase reverse transcriptase is upregulated in vulvar intraepithelial neoplasia and invasive keratinizing squamous cell carcinoma compared with nonneoplastic squamous epithelia of the vulva as an apparently early and preinvasive event in the neoplastic transformation, with development of cellular longevity and resistance to apoptosis by survivin activation as associated features, independent of the etiology of vulvar intraepithelial neoplasia. [ABSTRACT FROM AUTHOR]

Context.--Insulin-like growth factor II mRNA-binding protein 3 (IMP3) is an oncofetal protein highly expressed in fetal tissue and malignant tumors but only rarely within adult benign tissues. The expression of IMP3 in esophageal adenocarcinoma (EAC) and its precursor lesions including distinctive type Barrett mucosa (BM, intestinal metaplasia) and esophageal columnar dysplasia (ECD) is largely unknown. Objective.--To characterize the patterns of IMP3 expression in EAC and its precursor lesions. Design.--Samples from 132 cases of EAC, 28 cases of ECD (16 high-grade dysplasia and 12 low-grade dysplasia cases), 28 cases of BM without dysplasia, and 138 cases of nonneoplastic esophageal mucosa without dysplasia or BM within formalin-fixed, paraffin-embedded tissue microarray blocks were examined. Tissues were stained with mouse monoclonal anti-IMP3 antibody. The intensity (1-3+) and percent (0%-100%) of positive cytoplasmic and/or membranous IMP3 staining cells were determined. Results.--Most of EAC cases (93 of 132; 70%) showed cytoplasmic and membranous IMP3 staining. Poorly and moderately differentiated EAC showed statistically significant higher IMP3 expression compared with well-differentiated EAC (P < .001). A subset of ECD cases (7 of 28; 25%) was positive for IMP3, including 3 low-grade dysplasia cases (focal 1+ IMP3 staining) and 4 high-grade dysplasia cases (more diffuse 1-2+ IMP3 staining). No IMP3 staining was observed in any nonneoplastic esophageal mucosa and BM tissues without dysplasia. Conclusions.--This study suggests that IMP3 may play a role in the carcinogenesis of EAC and has diagnostic utility in differentiating neoplastic and nonneoplastic lesions of the esophagus. [ABSTRACT FROM AUTHOR]

Context.- The Bethesda System for thyroid fine-needle aspirates does not account for the size of the lesion that is aspirated. Objective.- To determine whether the size of the lesion would be helpful in order to reduce indeterminate thyroid aspirations. Design.- We correlated the results of all thyroid aspirations and surgical resection for the last 16 years at our institutions. Results.- A total of 9080 cases were aspirated and 1393 resections were performed. Of those resected, a total of 236 (17%) were classified as atypical follicular cells of undetermined significance, and 256 (18%) were classified as suspicious for a follicular/Hürthle cell neoplasm. A total of 52 incidental papillary carcinomas were identified in these indeterminate cases at resection (52 of 492; 11%). Thirty-seven (16%) atypical follicular cells of undetermined significance cases and 21 (8%) suspicious for a follicular/Hürthle cell neoplasm cases were for nodules smaller than 1 cm in diameter. When cases subtyped as atypical, a papillary carcinoma cannot be ruled out, were removed (13 cases), the remaining 24 and 21 aspirates identified 3 tumors each (13% and 14%), all papillary carcinomas. Together, the incidence of identified carcinomas was not significantly different than that of incidental carcinomas (13% versus 11%, P = .48). The rate of identified carcinomas was significantly less than for similar indeterminate cases smaller than 1 cm (excluding cases of atypical, papillary carcinoma cannot be ruled out) (88 of 330 cases; 27%; P = .05). Conclusions.- For nodules smaller than 1 cm in our series, indeterminate aspirates without features of papillary carcinomas have the same risk of malignancy as benign aspirates. [ABSTRACT FROM AUTHOR]

Context.--The degree to which critical values in anatomic pathology are understood in the nonpathology community is not know. Objective.--To measure the degree of agreement between pathologists and nonpathologists regarding critical values in anatomic pathology. Design.--A survey containing 15 anatomic pathologic diagnoses was given to a group of pathologists and nonpathologists who were then asked to state whether they should be regarded as critical values. Results.--Nonpathologists thought that a significantly greater percentage of diagnoses were critical than did pathologists, (49% versus 12%, P < .001). If the term critical value was changed to treatable immediately, life threatening, there was no significant difference between the responses of nonpathologists and pathologists (20% versus 12%, P = .06). Conclusions.--There is considerable disagreement between pathologists and nonpathologists concerning which diagnoses are critical values in anatomic pathology. Use of the term treatable immediately, life threatening significantly improves agreement. [ABSTRACT FROM AUTHOR]