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Context.--Urine cytology is used in the evaluation of hematuria or to follow patients with known urothelial neoplasia. Objective.--To investigate the performance characteristics of urinary cytology challenges in the College of American Pathologists Interlaboratory Comparison Program in Nongynecologic Cytopathology. Design.--Participant responses from 2000 to 2010 were evaluated for the reference diagnoses of high-grade urothelial carcinoma (HGUC), squamous cell carcinoma, adenocarcinoma, and benign diagnoses (including poly-omavirus infection and ileal loop urine). Responses were compared for differences in sample preparation (conventional, liquid based, and cytospin) and participant type (laboratory, pathologist, cytotechnologist). Results.--There were 96 093 responses (46 637 pathologists [48.5%], 29 976 cytotechnologists [31.2%], and 19 480 laboratories [20.3%]); 69 814 of 74 821 responses (93.3%) for the general category positive for malignancy and 18 698 of 21 272 responses (87.9%) for positive for malignancy were concordant. Of the malignant reference diagnoses, 83.3% (59 985 of 71 581), 43.9% (732 of 1667), and 49.1 % (370 of 756) were correctly identified as HGUC, adenocarcinoma, and squamous cell carcinoma, respectively. However, 802 of 1669 adenocarcinoma challenges (48.1%) and 275 of 755 squamous cell carcinoma challenges (36.4%) were misdiagnosed as HGUC. For the benign cases, the most common diagnostic pitfall was overinterpretation of ileal loop urines (330 of 5291; 6.2%) and Polyomavirus challenges (220 of 3535; 6.2%) as HGUC. For the general diagnosis of positive for malignancy, cytotechnologists performed slightly better that pathologists (94.5% [23 553 of 24 924] versus 92.3% [36 210 of 39 230]), whereas the reverse occurred for the negative category (85.6% [6423 of 7503] versus 88.8% [10 427 of 11 742]). Conclusions.--Although the participants performed well in accurately classifying cases as benign and malignant, there were difficulties with the correct identification of adenocarcinoma and squamous cell carcinoma cases and with overinterpretation of ileal loop and Polyomavirus challenges as HGUC. [ABSTRACT FROM AUTHOR]

Context.-Mucinous breast carcinoma has characteristic cytologic features, but few studies exist that analyze the reproducibility of this diagnosis. Objective.-To analyze participants' diagnosis of mucinous carcinoma in breast fine-needle aspiration (FNA) slides distributed in an educational interlaboratory peer comparison program. Design.-Participant responses for FNA slides with a reference diagnosis of mucinous carcinoma, distributed between 2001-2008 in the College of American Pathologists Interlaboratory Comparison Program in Nongynecologic Cytopathology, were evaluated for concordance with the general category and reference diagnosis of mucinous carcinoma. Results.-Of 8061 responses, 6353 (78.8%) were categorized as malignant; 775 (9.6%) as suspicious; and 933 (11.6%) as negative. The most frequent incorrect responses for the benign category included fibroadenoma (51.7%), nonspecified benign lesion (12%), fibrocystic changes (7.8%), and fat necrosis/granulomatosis/foreign body reaction (6.9%). Conventional Papanicolaou-stained preparations were reviewed for 58.7% (4732) of responses; of these, 39.4% (3177) were from modified Giemsa-stained smears and 1.9% (152) from ThinPrep slides. Papanicolaou-stained conventional smears had the lowest concordance (86.5%) when compared to modified Giemsa- stained smears (91.2%) and ThinPrep challenges (92.1%) (P < .001). Participants specifically diagnosed mucinous carcinoma 37.3% of the time, and modified Giemsa- stained challenges performed best (43.1%, P < .001). There was no significant difference between cytotechnologists' and pathologists' responses (87.9% versus 88.2%; P = .69). Conclusions.-Mucinous carcinoma in FNA was not accurately identified in a glass slide interlaboratory comparison program. We observed better performance with modified Giemsa-stained and ThinPrep slides than with Papanicolaou-stained preparations. The most common response for the benign category of mucinous carcinoma was fibroadenoma. Increased awareness of the cytologic features of mucinous carcinoma may improve accuracy in breast FNA. [ABSTRACT FROM AUTHOR]

The article discusses the history of the Texas Society of Pathologists (TSP), commemorating its 90th anniversary. It highlights the milestones of the Society, right from the meeting of the 16 founding members in 1921 to the recognition of pathology as a practice of medicine by the House of Delegates of the American Medical Association (AMA) in 1943. It also mentions how from the establishment of the House of Delegates (HOD) in the 1980s, it now has a membership of 705 clinicians and physicians.

Context.-The cytomorphology of liquid-based preparations in urine cytology is different than classic slide preparations. Objectives.-To compare the performance of liquidbased preparation specimens to classically prepared urine specimens with a malignant diagnosis in the College of American Pathologists Interlaboratory Comparison Program in Nongynecologic Cytology. Design.-Participant responses between 2000 and 2007 for urine specimens with a reference diagnosis of highgrade urothelial carcinoma/carcinoma in situ/dysplasia (HGUCA), squamous cell carcinoma, or adenocarcinoma were evaluated. ThinPrep and SurePath challenges were compared with classic preparations (smears, cytospins) for discordant responses. Results.-There were 18 288 pathologist, 11 957 cytotechnologist, and 8086 ''laboratory'' responses available. Classic preparations comprised 90% (n = 34 551) of urine challenges; 9% (n = 3295) were ThinPrep and 1% (n = 485) were SurePath. Concordance to the general category of ''positive-malignant'' was seen in 92% of classic preparations, 96.5% of ThinPrep, and 94.6% of SurePath challenges (P < .001). These results were statistically different for the exact reference interpretation of HGUCA (P = .001) but not for adenocarcinoma (P = .22). Cytotechnologists demonstrate statistically better performance for the general category of ''positive-malignant'' compared with pathologists for all urinary slide types and for the exact reference interpretation of HGUCA (94% versus 91.1%; P < .001) but not adenocarcinoma (96.3% versus 95.8%; P < .77) or squamous cell carcinoma (93.6% versus 87.7%; P = .07). Conclusions.-Liquid-based preparations performed significantly better in urinary cytology challenges when evaluating malignant categories in the College of American Pathologists interlaboratory comparison program. The liquidbased preparation challenges also performed better for the exact reference interpretation of HGUCA, but no difference was observed for adenocarcinoma challenges. Cytotechnologists perform better than pathologists for all slide types, as well as those demonstrating HGUCA. These results suggest that liquid-based preparations facilitate a more accurate diagnosis than conventional preparations. [ABSTRACT FROM AUTHOR]

Context.—Cytologic examination of the respiratory tract has been a useful diagnostic tool when evaluating neoplastic lesions of the respiratory tract. However, we have limited experience in the application of this technique in the management of nonneoplastic occupational and environmental diseases of the lung and pleura. This review focuses on the cytologic characteristics of a variety of occupational lung diseases, grouping them into 2 broad diagnostic categories: reactive cellular changes and noncellular elements. The former includes entities such as reactive mesothelial proliferation, goblet cell metaplasia, Creola bodies, and reserve cell hyperplasia, and the latter encompasses Curschmann spirals, Charcot-Leyden crystals, and asbestos bodies. Objective.—To illustrate the cytologic features of several nonneoplastic occupational and environmental diseases and correlate the cytology with various etiologic agents. Data Sources.—Case-derived material and literature review. Conclusions.-The role of cytology in the diagnosis of nonneoplastic occupational and environmental lung diseases is limited. This may be because more than one agent can elicit a similar host reaction and/or the offending agent can be associated with more than one pathologic process. However, in the appropriate clinical and radiographic setting, the cytology can render valuable diagnostic information. Examples include pulmonary alveolar proteinosis in patients with acute silicoproteinosis and asbestos bodies in bronchoalveolar lavage samples of patients with asbestos exposure. [ABSTRACT FROM AUTHOR]

Context.-Intraoperative evaluation of breast tissue has changed as newer imaging techniques and surgical approaches to the treatment of breast cancer have placed the pathologist in a pivotal role in the management of this disease. Assessment of the index lesion and surgical margins are but two of the many tasks we face when the specimen arrives in the surgical pathology laboratory. We are also called on to correlate changes in the mammogram with the gross pathology, particularly in those cases in which the lesion is nonpalpable. More recently, pathologists have been asked to analyze 1 or more sentinel lymph nodes at the time of frozen section to look for metastatic disease. This review discusses many of these issues and also provides a simplified approach to the differential diagnosis of a variety of breast lesions one may encounter intraoperatively. Objective.-To provide guidelines for and address potential pitfalls in the intraoperative management of the breast. Data Sources.-Author's experience and pertinent literature. Conclusions.-Careful assessment of the gross specimen coupled with prudent utilization of frozen sections is pivotal to reducing intraoperative error rates and preventing needless anxiety for the patient. [ABSTRACT FROM AUTHOR]

Most types of invasive breast cancer are thought to evolve over long periods from specific preexisting benign lesions. Of the many types of benign entities found in the human breast, only a few have clinically significant premalignant potential. Currently, the best-characterized premalignant lesions are atypical ductal hyperplasia, atypical lobular hyperplasia, and lobular carcinoma in situ. Ductal carcinoma in situ is considered to be a preinvasive malignant lesion. Two additional lesions, unfolded lobules and usual ductal hyperplasia, are sometimes considered to be very early premalignant epithelial abnormalities. Premalignant lesions are currently defined by their histologic features, and not all necessarily progress to invasive cancer. This suggests that although lesions within specific categories look alike, they must possess underlying genetic differences that cause some to remain stable and others to advance. The development of modern molecular genetic techniques has allowed breast cancer researchers to clarify the multistep model of breast carcinogenesis. Recent studies indicate that cancer evolves by highly diverse genetic mechanisms, and research into these altered pathways may identify specific early defects that might be targeted to prevent progression of premalignant lesions to invasive cancer. Current clinical management is heterogeneous and depends on histologic examination and individual patient factors. Options for breast cancer risk reduction and prevention are available. [ABSTRACT FROM AUTHOR]

Context.-The usefulness of spontaneous nipple discharge analysis is controversial. Nipple discharge preparations are rare in clinical practice and malignant cases are exceptional. The College of American Pathologists Interlaboratory Comparison Program in Nongynecologic Cytopathology has included nipple discharge preparations since its inception. Objective.-To evaluate participant responses in the College of American Pathologists Interlaboratory Comparison Program in Nongynecologic Cytopathology to assess the accuracy of cytologic interpretation of nipple discharge preparation. Design.-General diagnostic category (benign, suspicious, malignant), participant type (pathologist, cytotechnologist), stain (Papanicolaou, modified Giemsa), and program year (2005-2009) were analyzed using χ2 and a nonlinear mixed model for slide factor correlation structure. Results.-Of 2506 responses, 1280 (51%) were malignant, 171 (7%) were papillary, and 1055 (42%) were benign. There were 222 discordant general category responses with a false-positive/suspicious rate of 12.8% and a false-negative rate of 3.4%. The most common falsenegative diagnosis was mastitis/abscess (125 of 1272 responses; 9.8%). The most common false-positive response was papillary lesion (26 of 457 responses; 5.7%). There were no differences between stains or years. Cytotechnologists performed better than pathologists; pathologists had a higher false-negative rate than cytotechnologists (15.3% versus 7.9%, P < .001). Conclusions.-There is poor accuracy in evaluating nipple discharge preparation in the College of American Pathologists Interlaboratory Comparison Program in Nongynecologic Cytopathology. If the findings in the program parallel clinical practice, nipple discharge preparations may adversely impact patient care. A benign nipple discharge cytologic diagnosis does not exclude malignancy, and the false-positive/suspicious rate requires confirmation of a malignant nipple discharge prior to definitive patient management. [ABSTRACT FROM AUTHOR]

Context.--The false-positive rate for fine-needle aspirates of the lung has been cited as less than 1% for granulomatous inflammation, comprising one of the known causes of false-positive diagnoses. Objective.--To determine the rate of false-positive diagnoses of granulomatous inflammation for lung fineneedle aspirates by assessing the false-positive response rate in the context of the College of American Pathologists Nongynecologic Cytopathology Interlaboratory Comparison Program. Design.--We performed a retrospective review of 1092 participant responses for lung fine-needle aspirate challenges with the reference diagnosis of specific infections/ granulomatous inflammation from 1998 to 2008 from the College of American Pathologists Nongynecologic Cytopathology Interlaboratory Comparison Program. False-positive rates by participant type (pathologist versus cytotechnologist), general diagnosis category, reference diagnosis, and preparation type were analyzed for the pathologists' responses. Results.--Of the 502 general category responses for pathologists, 428 (85.3%) were benign, 55 (11%) were malignant, and 19 (3.8%) were suspicious. There was no difference in the false-positive rate between preparations (P = .76) or participants (P = .39). Of those responses by pathologists that were benign, only 68.7% (292 of 425) were an exact match to granulomatous inflammation. Non-small cell carcinoma, adenocarcinoma, and squamous carcinoma represented 64% of false-positive/suspicious responses, while small cell carcinoma and carcinoid comprised 13%. Conclusion.--In an interlaboratory comparison program, granulomatous inflammation represents an important cause of false-positive/suspicious responses in lung fine-needle aspirates (14.8%) and is much higher than false-positive rates reported historically in clinical studies. These results highlight the importance of granulomatous inflammation as a mimic of carcinoma. [ABSTRACT FROM AUTHOR]

Missense mutations in the p53 tumor suppressor occur frequently in human breast cancer and influence both the prognosis and response to chemotherapy. Amino acid 175 (equivalent to murine 172) is the second most common site of missense mutations in p53 in human breast cancer. Over 95% of these mutations are arginine-to-histidine (R-H) substitutions resulting in a gain-of-function, and not merely a dominant-negative phenotype. Transgenic mice expressing a p53 172R–H construct targeted to the mammary gland by means of a whey acidic protein (WAP) promoter were characterized as a model system in order to determine the specific effects of this mutation on mammary tumorigenesis. Although transgene expression alone had no apparent effect on normal mammary development, transgenic mice treated with the chemical carcinogen dimethylbenz(a)anthracene developed tumors with much shorter latency than did control littermates and had a greater tumor burden. Tumors arising in transgenic mice did not exhibit either decreased apoptosis or increased cell proliferation relative to tumors arising in nontransgenic littermates, but did display increased genomic instability. Large pleiomorphic nuclei were visible in many tumors from transgenic mice, and DNA flow analysis confirmed the presence of significant aneuploid cell populations. Since these transgenic mice develop very few spontaneous tumors, while accelerating carcinogen-and oncogene-mediated tumorigenesis, this mouse model will, therefore, be useful in the investigation of early events in mammary tumorigenesis. It may also be used as a preclinical model to test newly developed chemotherapeutic strategies. [ABSTRACT FROM AUTHOR]

Background: When cells fail to maintain a balance between proliferation, terminal differentiation, and programmed cell death, cancer often results. The CCAAT/enhancer-binding protein (C/EBP) family of transcription factors regulates many genes involved in the processes of proliferation and terminal differentiation. The messenger RNA for C/EBPbeta is translated into two major isoforms, LAP (liver-enriched activating protein) and LIP (liver-enriched inhibitory protein). LIP levels appear to be elevated in mouse mammary tumors but not in hyperplastic mammary tissues. We tested whether LIP expression is elevated in human breast cancer and whether elevated expression is associated with biologic predictors of the aggressiveness of the disease.Methods: Homogenates of infiltrating ductal carcinoma specimens from 39 women were analyzed for C/EBPbeta protein content by western blot analysis, and the ratio of LAP to LIP in specimens containing high levels of LIP (i.e., levels approximately 15 times higher than those in tumor specimens that express little or no LIP) was also determined. Nonparametric statistical analyses were performed.Results: LIP was present at high levels in nine of 39 specimens of infiltrating ductal carcinoma. Eight of the nine specimens of infiltrating ductal carcinoma that contained high levels of LIP were negative for estrogen receptor and progesterone receptor (ER-/PR-); all nine tumors were aneuploid and poorly differentiated, and eight of nine were highly proliferative. Of the tumors that contained LIP at low or nondetectable levels, six of 30 were ER-/PR-, 17 of 29 were aneuploid, eight of 27 were highly proliferative, and 11 of 30 were poorly differentiated.Implication: LIP expression should be evaluated further as a prognostic marker for patients with breast cancer. [ABSTRACT FROM AUTHOR]

Context.--The National Cancer Care Network and the combined College of American Pathologists/International Association for the Study of Lung Cancer/Association for Molecular Pathology guidelines indicate that all lung adenocarcinomas (ADCs) should be tested for epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements. As the majority of patients present at a later stage, the subclassification and molecular analysis must be done on cytologic material. Objective.--To evaluate the accuracy and interobserver variability among cytopathologists in subtyping non-small cell lung carcinoma using cytologic preparations. Design.--Nine cytopathologists from different institutions submitted cases of non-small cell lung carcinoma with surgical follow-up. Cases were independently, blindly reviewed by each cytopathologist. A diagnosis of ADC or squamous cell carcinoma was rendered based on the Diff-Quik, Papanicolaou, and hematoxylin-eosin stains. The specimen types included fine-needle aspiration from lung, lymph node, and bone; touch preparations from lung core biopsies; bronchial washings; and bronchial brushes. A major disagreement was defined as a case being misclassified 3 or more times. Results.--Ninety-three cases (69 ADC, 24 squamous cell carcinoma) were examined. Of 818 chances (93 cases 3 9 cytopathologists) to correctly identify all the cases, 753 correct diagnoses were made (92% overall accuracy). Twenty-five of 69 cases of ADC (36%) and 7 of 24 cases of squamous cell carcinoma (29%) had disagreement (P = .16). Touch preparations were more frequently misdiag-nosed compared with other specimens. Diagnostic accuracy of each cytopathologist varied from 78.4% to 98.7% (mean, 91.7%). Conclusion.--Lung ADC can accurately be distinguished from squamous cell carcinoma by morphology in cytologic specimens with excellent interobserver concordance across multiple institutions and levels of cytology experience. [ABSTRACT FROM AUTHOR]

Context.--Nongynecologic cytology (NGC) practices are expanding in relationship to historical gynecologic cytology screening programs. Bronchopulmonary cytology is experiencing an evolution regarding new procedural types. The College of American Pathologists (CAP) tracks practice patterns in NGC by developing questionnaires, surveying participants, and analyzing respondent data. Objective.--To analyze responses to a 2013 CAP supplemental survey from the Interlaboratoy Comparison Program on bronchopulmonary NGC. Design.--The "NGC 2013 Supplemental Questionnaire: Demographics in Performance and Reporting of Respiratory Cytology" was mailed to 2074 laboratories. Results.--The survey response rate was 42% (880 of 2074) with 90% of respondents (788 of 880) indicating that their laboratories evaluated cytology bronchopulmonary specimens. More than 95% of respondents indicated interpreting bronchial washings (765 of 787) and bronchial brushings (757 of 787). A minority of laboratories (43%, 340 of 787) dealt with endobronchial ultrasound-guided samples, and an even smaller fraction of laboratories (14%, 110 of 787) saw cases from electromagnetic navigational bronchoscopy. Intraprocedural adequacy assessments by pathologists (and less often by cytotechnologists or pathologists-in-training) were routinely performed in percutaneous transthoracic aspiration cases (74%, 413 of 560) with less involvement for other case types. Most laboratories reported that newly diagnosed primary pulmonary adenocarcinomas were triaged for molecular testing of epidermal growth factor receptor and anaplastic lymphoma kinase. Conclusions.--The parameters examined in this 2013 survey provide a snapshot of current pulmonary cytopathology practice and may be used as benchmarks in the future. [ABSTRACT FROM AUTHOR]

Context.--Although the cytomorphology of adenoid cystic carcinoma (ACC) has been well described, the accuracy of this diagnosis in fine-needle aspirates (FNAs) of the salivary glands has not been extensively evaluated. Objective.--To assess participants' responses in the College of American Pathologists (CAP) Nongynecologic Cytology (NGC) Program to determine the accuracy and false-negative rate of ACC cases in salivary gland FNAs. Design.--A retrospective review of the CAP NGC Program's cumulative data from 2000-2010 was performed for the general and the specific reference diagnosis categories for ACC in salivary gland FNAs according to preparation and participant types. Results.--Of 5156 responses, the overall concordance rates for both the general category of malignancy and the specific category of ACC were 63.6% (3279 of 5156) and 38.6% (1966 of 5088), respectively, with a false-negative rate of 36.4% (1877 of 5156). The most frequent false-negative responses were pleomorphic (1080) and monomorphic (526) adenoma (1614 of 5088, 31.5%), while lymphoma was the most frequent malignant misinterpretation. There was a significant statistical difference in concordance to the reference interpretation between the reader types: 39.9% (1006 of 2521) concordance rate for pathologists compared to 33.8% (503 of 1488) for cytotechnologists. However, there was no significant statistical difference for concordance to the general category or reference interpretation, based on preparation type (Papanicolaou versus modified Giemsa stained). Conclusions.--In this interlaboratory comparison educational program, accurate identification of ACC has shown to be problematic, with ACC representing an important cause of false-negative responses. The most common diagnostic pitfall is distinguishing this entity from pleomorphic and monomorphic adenoma in the benign category and from lymphoma and adenocarcinoma in the malignant one. [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.—Pulmonary bronchial brushing specimens can be processed by liquid-based or conventional methods. The ability to accurately diagnose a pulmonary malignancy with a liquid-based preparation (LBP) versus a conventional preparation may differ. Objective.—To compare the performance of LBPs of malignant pulmonary bronchial brushing specimens with the performance of conventional preparations. Design.—Participant responses from 553 malignant pulmonary bronchial brushing samples were evaluated for concordance with the general diagnosis. The performance of LBPs was compared with that of classic preparations. A nonlinear mixed model was used to analyze the performance by reference diagnosis, preparation type, program years, participant type, and the interaction terms between these 4 factors. Results.—Concordance with the general category of malignant disease was observed in 95.2% of conventional Papanicolaou-stained, 90.9% of modified Giemsa-stained, and 96.9% of LBP (P < .001) samples. The results were significantly different between individual reference diagnoses (P < .001). The performance of LBPs was consistently higher for most diagnoses and was significantly better for squamous cell carcinoma (P ¼ .005), small cell carcinoma (P < .001), and metastatic carcinoma not otherwise specified (P < .001). All participant types performed significantly better with LBPs of small cell carcinoma. Pathologists and cytotechnologists performed significantly better with LBPs of squamous cell carcinoma. A significantly higher concordance was observed between the general diagnosis and program years 2007–2011 versus 2001–2006 (P = .006). Conclusions.—Liquid-based preparations performed better than conventional methods, with significantly higher performance in squamous cell, small cell, and metastatic carcinomas. Improved performance over time may reflect more frequent use of LBP methods and increased familiarity with interpreting the morphologic findings. [ABSTRACT FROM AUTHOR]

Context.—Nongynecologic cytology (NGC) practices are expected to expand relative to gynecologic cytology. The College of American Pathologists attempts to track practice patterns in NGC using a self-reported questionnaire. Objective.—To analyze self-reported laboratory staffing and practices from a 2010 survey relating to NGC specimens, stains, preparation, procedures, and ancillary testing. Design.—The ‘‘NGC 2010 Demographics and Supplemental Questionnaire: Current Nongynecologic Practices in Cytopathology Laboratories’’ was mailed to 2059 laboratories. Results.—Survey response rate was 51% (1048 of 2059), predominantly from voluntary, nonprofit hospitals, where NGC samples were reviewed in nontraining settings by pathologists without American Board of Pathology Added Qualification in Cytopathology. Cytotechnologists reviewed NGC cases in 67.4% (675 of 1002) of laboratories. The annual mean and median volumes of NGC cases were 1927 and 858, respectively. Laboratories used more than one method to process NGCs; cell-blocks were most frequently used (930 of 1029; 90.4%) and were created with centrifugation to pellet (538 of 961; 56%). Direct smears were second in preparation frequency; discrete staining was preferred to batch staining. Nongynecologic cytology was used for molecular studies in 34.9% (350 of 1002) of laboratories, most commonly for fluorescent in situ hybridization of urine specimens. Flow cytometric immunophenotyping was performed by 55.9% (554 of 991) and immunohistochemistry by 91.9% (911 of 991) of the responding laboratories. Most laboratories (911 of 993; 91.7%) report specimen completion in 2 or fewer days. Cytohistologic correlation was performed by 71.6% (722 of 1008) of the laboratories both concurrently and retrospectively. Conclusion.—The various parameters examined in the 2010 survey provide a benchmark for future efforts in quality assurance and process improvement in NGC. [ABSTRACT FROM AUTHOR]

Context.-Subtyping of non-small cell lung carcinomas (NSCLCs) is necessary for optimal patient management with specific diagnoses triggering specific molecular tests and affecting therapy. Objective.-To assess the accuracy of the participants of the College of American Pathologists Interlaboratory Comparison Program in diagnosing and subtyping NSCLC fine-needle aspiration (FNA) slides, based on morphology alone, considering preparation and participant type and trends over time. Design.-The performance of program participants was reviewed for the 5-year period spanning 2007-2011. Lung FNA challenges with reference diagnoses of adenocarcinoma and squamous cell carcinoma (SCC) were evaluated for diagnostic concordance by using a nonlinear mixed model analysis. Results.-There were 10 493 pathologist and 6378 cytotechnologist responses with concordance rates of 97.4% and 97.9% for malignancy, respectively. Overall concordance rates for subcategorization were 54.6% for adenocarcinoma and 74.9% for SCC. For the exact reference diagnoses, pathologists performed better for adenocarcinoma and cytotechnologists performed better for SCC. Accurate subcategorization of adenocarcinomas significantly increased over time with 31.5% of adenocarcinomas classified as NSCLC in 2007 and 25.5% of adenocarcinomas classified as NSCLC in 2011 (P < .001). In comparing preparation types, modified Giemsa-stained smears showed the lowest overall concordance (46.8%). Modified Giemsa-stained smears with SCCs were the least likely to be accurately subcategorized (36.4%). Conclusions.-Participants are proficient at interpreting NSCLCs as malignant by FNA but are less successful at subcategorization with cytomorphology alone. During the study period, a statistically significant trend was confirmed toward greater accuracy of subcategorization of adenocarcinomas, suggesting that participants are cognizant of the impact that more specific cytomorphologic interpretations have in directing molecular triage and therapy. [ABSTRACT FROM AUTHOR]

Context.- Anal cytology is being used more frequently for anal cancer screening, yet many cytologists are unfamiliar with it. Objective.- To describe the performance of anal cytology in the College of American Pathologists' Interlaboratory Comparison Program in Non-Gynecologic Cytology (CAP NGC) educational slide program during a 6-year time span, from 2006 to 2011, using participant responses (pathologist, cytotechnologist, and laboratory). Design.- Concordance rates for the target diagnosis and general category for each slide challenge were analyzed. Four main factors were included in the analysis: (1) general category or specific responses, (2) program year from 2006 to 2011, (3) participant type (pathologist, cytotechnologist, or overall laboratory), and (4) preparation type (liquid-based or conventional). Results.- Participants most frequently correctly classified negative for intraepithelial lesion or malignancy, lowgrade squamous intraepithelial lesion, and herpes simplex virus infection, with concordance rates of 78.8%, 85%, and 80.2%, respectively. Performance on challenges with target diagnoses of high-grade squamous intraepithelial lesion (HSIL), squamous cell carcinoma, and ameba was poor, with concordance rates of 57.1%, 56.2%, and 41.5%, respectively. Significant improvement during the 6 years was seen in the concordance rates of participants' responses for low-grade squamous intraepithelial lesion challenges but not for HSIL. There was no significant difference in performance by slide preparation type. Conclusions.- The poor performance on anal cytology in the CAP NGC program, especially with regard to correct identification of HSIL and squamous cell carcinoma, indicates that there is a need for continued education about anal cytology. [ABSTRACT FROM AUTHOR]

Background: Thyroid nodules are exceedingly common, and the cytologic interpretation of fine needle aspiration (FNA) findings has been the reference standard for diagnosing nodules as benign, atypia or a follicular lesion of undetermined significance, suspicious for follicular or Hürthle cell neoplasm, suspicious for malignancy, or malignant. Many patients undergo thyroid lobectomy for indeterminate FNA findings (atypia or a follicular lesion of undetermined significance or suspicious for follicular or Hürthle cell neoplasm), although the risk of malignancy is low. The general data have quoted a 20% risk of hypothyroidism after lobectomy. The purpose of the present study was to determine the risk of hypothyroidism after lobectomy in our diverse population. Methods: The pathology records from a large county hospital were reviewed to identify patients with indeterminate FNA findings. The incidence of hypothyroidism was determined by the need for thyroid hormone replacement therapy. Categorical variables were compared using the chi-square and continuous variables using the Mann-Whitney U test. Results: A total of 655 FNAs were performed during the study period, and 60 resulted in indeterminate cases. Of these 60 patients, 17 subsequently underwent diagnostic lobectomy. The mean age was 52.8 ± 16.5 years, 88% were women, and 67% were Hispanic and 22% were African American. Only 6% had a final diagnosis of cancer, and eight patients (47%) became hypothyroid postoperatively. Conclusions: The incidence of hypothyroidism after diagnostic thyroid lobectomy in our patient population was much higher than previously reported. It is necessary to preoperatively counsel patients about this increased risk, in addition to the usual risks of nerve palsy and bleeding, with thyroid lobectomy. As testing of thyroid nodules evolves, the expense of preoperative testing should be weighed against the increased incidence for lifelong thyroid hormone replacement. [ABSTRACT FROM AUTHOR]

Context.-The College of American Pathologists (CAP) Human Papillomavirus (High-Risk) Survey for Cytopathology and Other Laboratories (CHPV) meets the Clinical Laboratory Improvement Amendments of 1988 (CLIA '88) requirements for 5 proficiency testing challenges analyzed 3 times per year. This study reports laboratory performance for CHPV from 2008 through 2010. Objective.-To identify trends in proficiency testing performance for subscribers to the CAP CHPV. Design.-CHPV responses were evaluated by using a nonlinear mixed model (significance level of .05) with a 2- factor interaction term and repeated measures component, comparing year, media, method, and intended response. Media types included Digene transport, SurePath, Thin- Prep media, or a mixture of media types. Proficiency testing challenges validated at 80% consensus. Results.-All challenges validated; 476 laboratories submitted 14 911 responses with 14 620 correct responses (98%). There were no differences between positive or negative challenges, or rate of correct responses; significant differences existed between media types by year and methods. Digene and ThinPrep media performed better than SurePath (P < .001; P =.03). There was a statistically significant difference between methods (P < .001); ''other commercial kits,'' ''other (noncommercial)'' tests, and Third Wave performed more poorly than others. Conclusions.-Laboratories performed well when testing for human papillomavirus in CHPV during a period of 3 years. All challenges performed to the 80% threshold. Significant differences were found between methods and media. The CAP CHPV survey provides useful information for laboratories choosing human papillomavirus testing methods. [ABSTRACT FROM AUTHOR]

Context.--In 2006, the first gynecologic cytology proficiency tests were offered by the College of American Pathologists. Four years of data are now available using field-validated slides, including conventional and liquid-based Papanicolaou tests. Objective.--To characterize the pattern of error types that resulted in initial proficiency-test failure for cytotechnologists, primary screening pathologists, and secondary pathologists (those whose slides are prescreened by cytotechnologists). Design.--The results of 37 029 initial College of American Pathologists Papanicolaou proficiency tests were reviewed from 4 slide-set modules: conventional, Thin-Prep, SurePath, or a module containing all 3 slide types. Results.--During this 4-year period, cytotechnologists were least likely to fail the initial test (3.4%; 614 of 18 264), followed by secondary pathologists (ie, those reviewing slides already screened by a cytotechnologist) with a failure rate of 4.2% (728 of 17 346), and primary pathologists (ie, those screening their own slides) having the highest level of failure (13.7%; 194 of 1419). Failure rates have fallen for all 3 groups over time. Pathologists are graded more stringently on proficiency tests, and more primary pathologists would have passed if they had been graded as cytotechnologists. There were no significant differences among performances using different types of slide sets. False-positive errors were common for both primary (63.9%; 124 of 194 errors) and secondary (55.6%; 405 of 728 errors) pathologists, whereas automatic failures were most common for cytotechnologists (75.7%; 465 of 614 errors). Conclusions.--The failure rate is decreasing for all participants. The failures for primary pathologist screeners are due to false-positive responses. Primary screening cytotechnologists and secondary pathologists have automatic failures more often than do primary screening pathologists. [ABSTRACT FROM AUTHOR]

Context.--Traditionally, lung cancer has been viewed as an aggressive, relentlessly progressive disease with few treatment options and poor survival. The traditional role of the pathologist has been primarily to differentiate small cell carcinoma from non-small cell carcinoma on biopsy and cytology specimens and to stage non-small cell carcinomas that underwent resection. In recent years, our concepts of lung cancer have undergone a revolution, including (1) the advent of successful, new, molecular-targeted therapies for lung cancer, many of which are associated with specific histologic cell types and subtypes; (2) new observations on the natural history of lung cancer derived from ongoing high-resolution computed tomography screening studies and recent histologic findings; and (3) proposals to revise the classification of lung cancers, particularly adenocarcinomas, in part because of the first 2 developments. Objective.--To summarize the important, new developments in lung cancer, emphasizing the role of the surgical pathologist in personalized care for patients with lung cancer. Data Sources.--Information about the new developments in lung cancer was obtained from the peer-review medical literature and the authors' experiences. Conclusions.--For decades, we have perceived lung cancer as a relentlessly aggressive and mostly incurable disease for which the surgical pathologist had a limited role. Today, surgical pathologists have an important and expanding role in the diagnosis and treatment of lung cancer, and it is essential to keep informed of new advances. [ABSTRACT FROM AUTHOR]

Context.--Differences in participant responses for Thin- Prep (TP) and non-ThinPrep (NTP) preparations for gastrointestinal cytology challenges, which circulated in the College of American Pathologists Interlaboratory Comparison Program in Nongynecologic Cytology (CAP NGC), may help to identify performance variations between preparation types. Objective.--To compare the performance of TP-prepared slides of gastrointestinal exfoliative cytology specimens to that of NTP preparations in the CAP NGC program. Design.--Participant responses between 2000 and 2007 were evaluated for esophageal wash/brush, gastric wash/ brush, and biliary tract brush specimens with a reference diagnosis of adenocarcinoma, squamous cell carcinoma, carcinoid, or spindle cell neoplasm. ThinPrep challenges were compared with NTP preparations (conventional smears, cytospins) for discordant responses. Results.--In all, 6023 pathologist responses and 3825 cytotechnologist responses were reviewed. Non-ThinPrep preparations comprised 93% (n = 11 588) of the challenges, while 7% (n = 912) were TP material. A match for a ''positive/suspicious'' diagnosis was seen in 88.5% of NTP and 95.9% of TP preparations (P < .001). These results were statistically significant when the specific reference diagnosis was adenocarcinoma (P < .001). Overall performance of cytotechnologists was not different from that of pathologists (89.2% versus 89.0%; P = .75). Cytotechnologists had better performance for detecting squamous cell carcinoma (96.3% versus 92.6%; P < .001), while pathologists had better performance for detecting spindle cell neoplasm (79.7% versus 42.9%; P < .001). Conclusions.--ThinPrep preparations performed significantly better than NTP preparations in gastrointestinal cytology specimens circulated in an interlaboratory comparison program. Performance varied by reference interpretation, with the best performance for the interpretation of adenocarcinoma. Cytotechnologists and pathologists performed at the same level overall, but with differences for the diagnosis of spindle cell neoplasm and squamous carcinoma. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Extracellular matrix changes occur in many heart valve pathologies. For example, myxomatous mitral valves are reported to contain excess proteoglycans and hyaluronan. However, it is unknown which specific proteoglycans are altered in myxomatous valves. Because proteoglycans perform varied functions in connective tissues, this study was designed to identify and localize three matrix-associated proteoglycans, as well as hyaluronan and the hyaluronan receptor for endocytosis, within myxomatous and normal mitral valves. Methods: Human mitral posterior leaflets (control, n=6–9; myxomatous, n=14–21; mean age, 61 years for all groups) were histochemically stained for proteoglycan core proteins, hyaluronan, and the hyaluronan receptor for endocytosis. Stain intensity was semiquantitatively graded to determine differences in marker abundance between normal and myxomatous valves. The proteoglycans were localized to different regions of the leaflet by correspondence to parallel Movat-stained sections. Results: The proteoglycans decorin, biglycan, and versican were more abundant in myxomatous valves than in normal controls (P<.03). There was a gender effect on proteoglycan presence, but no age-related trends were observed. Hyaluronan and the hyaluronan receptor for endocytosis were distributed throughout all valves. There was no significant difference in hyaluronan between groups, but expression of the hyaluronan receptor for endocytosis was reduced in myxomatous valves compared to normal controls (P<.002). Conclusion: Excess decorin, biglycan, and versican may be associated with the remodeling of other matrix components in myxomatous mitral valves. Decreased expression of the hyaluronan receptor for endocytosis in myxomatous valves suggests that hyaluronan metabolism could be altered in myxomatous mitral valve disease. These findings contribute towards elucidating the pathogenesis of myxomatous mitral valve disease and developing potential new therapies. [Copyright &y& Elsevier]

Understanding the process of carcinogenesis is key to developing therapies which might interrupt or reverse tumor onset and progression. Cell growth and death signals are dependent not only upon molecular mechanisms within a cell but also upon external stimuli such as hormones, cell–cell signaling, and extracellular matrix. Mouse models can be used to dissect these complex processes, to identify key signaling pathways operating at different stages of tumorigenesis, and to test the strength of specific interventions. In the WAP-TAg mouse model, carcinogenesis is initiated by expression of the Simian Virus 40 T antigen (TAg). TAg expression is triggered by hormonal stimulation, either during estrus or pregnancy. Breast adenocarcinomas (ranging from well to poorly differentiated) develop in 100% of the female mice by approximately 8–9 months of age. Three distinct stages of tumorigenesis are easily identified: an initial proliferation, hyperplasia, and adenocarcinoma. The mean time to first palpable tumor in mice which undergo at least one pregnancy is 6 months. The tumorigenic process is marked by a competition between proliferation and apoptosis and is characterized by cellular acquisition of genetic mutations and increased stromal fibrosis. Protein levels of cell cycle control genes cyclin D1, cdk2, and E2F-1 are increased in these adenocarcinomas. c-Fos protein levels are slightly increased in these cancers, while c-Jun levels do not change. Hormonal exposure alters progression. Estrogen plays a role during the early stages of oncogenesis although the growth of the resulting adenocarcinomas is estrogen-independent. Transient hormonal stimulation by glucocorticoids that temporarily increases the rate of cell proliferation results in tetraploidy, premature appearance of irreversible hyperplasia, and early tumor development. Tumor appearance also can be accelerated through over expression of the cell survival protein, Bcl-2. Bcl-2 over expression... [ABSTRACT FROM AUTHOR]

Mammary tumorigenesis was analysed in transgenic mice which overexpress des(1-3)hIGF-I (WAP-DES) and/or a mutant form of p53 (p53172R-H). Nonlactating, multiparous WAP-DES mice exhibited hyperplastic lesions termed mammary interepithelial neoplasia (MIN) which constitutively expressed WAP-DES. By 23 months of age, 53% of the WAP-DES mice developed mammary adenocarcinomas. A 75% reduction in both apoptosis and proliferation was observed in the normal mammary glands of WAP-DES mice. Mammary tumor incidence in WAP-DES/p53 bitransgenic mice was similar to that of WAP-DES and 2–3-fold greater than that of nontransgenic and p53172R-H females. Tumor latency, however, was reduced by 8 months in bitransgenic mice as compared to mice of the other three genotypes. Aneuploidy was frequently observed in tumors from bitransgenic and p53172R-H mice, but not from mice expressing only the WAP-DES transgene. Expression of IGFBP3 was elevated in tumors from WAP-DES, but not bitransgenic mice, indicating an alteration in the p53/IGF-I axis. These studies indicate that overexpression of des(1-3)hIGF-I increases the frequency of MIN and stochastic mammary tumors and that the appearance of tumors displaying genomic instability is accelerated by mutant p53172R-H. Oncogene (2000) 19, 889–898. [ABSTRACT FROM AUTHOR]

Bcl-2 is an anti-apoptotic and anti-proliferative protein over-expressed in several different human cancers including breast. Gain of Bcl-2 function in mammary epithelial cells was superimposed on the WAP-TAg transgenic mouse model of breast cancer progression to determine its effect on epithelial cell survival and proliferation at three key stages in oncogenesis: the initial proliferative process, hyperplasia, and cancer. During the initial proliferative process, Bcl-2 strongly inhibited both apoptosis and mitotic activity. However as tumorigenesis progressed to hyperplasia and adenocarcinoma, the inhibitory effects on mitotic activity were lost. In contrast, anti-apoptotic activity persisted in both hyperplasias and adenocarcinomas. These results demonstrate that the inhibitory effect of Bcl-2 on epithelial cell proliferation and apoptosis can separate during cancer progression. In this model, retention of anti-apoptotic activity with loss of anti-proliferative action resulted in earlier tumor presentation. [ABSTRACT FROM AUTHOR]

Ectopic pregnancies that fail methotrexate therapy are predominantly euploid by comparative genomic hybridization (CGH). This feasibility study also confirms that formalin-fixed paraffin-embedded gestational tissue can successfully undergo CGH. [Copyright &y& Elsevier]

A letter to the editor is presented in response to the article "Performance Characteristics of Adenoid Cystic Carcinoma of the Salivary Glands in Fine-needle Aspirates: results from the College of American Pathologists Nongynecologic Cytology Program," published in the 2015;139(12) issue.

Explores the nature of environmental lung and pleural disease. Controversies surrounding the perceived connection between asbestos and lung cancer; Interactive effect between tobacco smoke and asbestos for the different histological types of lung cancer; Refutation factors for the asbestos-cancer model; Pathogenetic mechanisms that are supposed to be involved in lung cancer associated with polyvinyl chloride; Patterns of disease caused by inhalational injury; Agents producing adult respiratory distress syndrome.