CAP Profiles

Bio

Bio

Dr. Allison is the Director of Breast Pathology at Stanford. Her research interests include prognostic/predictive markers in breast cancer, standards in HER2 and ER testing, management of risk lesions, diagnostic criteria and diagnostic agreement in breast pathology and patient communication. She is on the editorial board for the 5th edition of the WHO Classification of Tumours of the Breast, is co-chair of the ASCO/CAP ER/PR Testing in Breast Cancer committee, was on the steering committee for the 2018 ASCO/CAP HER2 Testing Guidelines Update, and serves on the NCCN Breast Cancer Treatment Guidelines committee. She is actively involved in resident/fellow training as Director of the Stanford Breast Pathology Fellowship and Residency Director for the Department of Pathology. Dr. Allison is also a breast cancer survivor and the author of “Red Sunshine; A Story of Strength and Inspiration from a Doctor Who Survived Stage 3 Breast Cancer.”

Clinical Focus

  • Breast Pathology
  • Anatomic and Clinical Pathology

Academic Appointments

  • Professor - Med Center Line, Pathology

Administrative Appointments

  • Director of Breast Pathology, Stanford Dept of Pathology (2014 - Present)
  • Fellowship Director, Breast Pathology, Stanford Dept of Pathology (2016 - Present)
  • Program Director of Anatomic and Clinical Pathology Residency, Stanford Dept of Pathology (2017 - Present)
  • Associate Residency Director, Anatomic Pathology (2013 - 2017)

Professional Education

  • Residency: University of Washington Pathology Residency (2006) WA
  • Fellowship: University of Washington Pathology Fellowships (2005) WA
  • Medical Education: New York Medical College Registrar (2001) NY
  • Board Certification: Anatomic and Clinical Pathology, American Board of Pathology (2006)
  • Board Certification, Amercian Board of Pathology, Anatomic and Clinical Pathology (2006)
  • Fellowship, University of Washington Medical Center, Surgical Pathology with focus of Breast/GYN Pathology (2005)
  • Residency, University of Washington Medical Center, Anatomic and Clinical Pathology (2006)
  • MD, New York Medical College (2001)
  • BA, Princeton University, Molecular Biology (1997)

Contact

  • Pathology Department 300 Pasteur Dr Rm L235 MC 5324 Stanford, CA 94305
    • Tel: (650) 723-7211
    Fax: (650) 723-1950

Links

Research & Scholarship

Current Research and Scholarly Interests

Dr. Allison’s clinical expertise is in breast pathology. Her research interests include how standards should be applied to breast cancer diagnostics (such as ER and HER2 testing), the utility of molecular panel-based testing in breast cancer, digital pathology applications and identifying the most appropriate management of specific pathologic diagnoses.

Teaching

2019-20 Courses

Publications

All Publications

  • Pretreatment Tattoo Marking of Suspicious Axillary Lymph Nodes: Reliability and Correlation with Sentinel Lymph Node. Annals of surgical oncology Patel, R., MacKerricher, W., Tsai, J., Choy, N., Lipson, J., Ikeda, D., Pal, S., De Martini, W., Allison, K. H., Wapnir, I. L. 2019

    Abstract

    BACKGROUND: Tattooing is an alternative method for marking biopsied axillary lymph nodes (ALNs) before initiation of treatments for newly diagnosed breast cancer. Detection of black ink-stained nodes is performed under direct visualization at surgery and is combined with sentinel node (SLN) mapping procedures.METHODS: Women with newly diagnosed breast cancer who underwent fine or core-needle biopsy of suspicious ALNs were recruited. The nodal cortex and perinodal soft tissue was injected with 0.1-1.0ml of Spot (GI Supply) black ink under ultrasound guidance. Intraoperatively, black stained nodes were removed along with SLNs, noting concordance between the two.RESULTS: Sixty-six evaluable patients were enrolled (2013-2017). Nineteen received surgery first (Group 1) and 47 neoadjuvant therapy (NAT, Group 2). The average number of nodes tattooed was 1.16 for Group 1 and 1.04 for Group 2. The average interval from tattoo to surgery was 21days (range 1-62) for Group 1 and 148days (range 71-257) for Group 2. The tattooed node(s) were visually identified at surgery and corresponded to the sentinel lymph node(s) in 98.5% of cases (18/19 in Group 1 and 47/47 in Group 2). Of the 14 patients in Group 2 whose nodes remained positive following NAT, the tattooed node was the SLN associated with carcinoma.CONCLUSIONS: Tattooing is an alternative method for marking biopsied ALNs. Tattooed nodes coincided with SLNs in 98.5% of cases. This technique is advantageous, because it allows for fewer procedures and lower costs compared with other methods.

    View details for PubMedID 31087176

  • Quantitative Image Analysis of Human Epidermal Growth Factor Receptor 2 Immunohistochemistry for Breast Cancer: Guideline From the College of American Pathologists. Archives of pathology & laboratory medicine Bui, M. M., Riben, M. W., Allison, K. H., Chlipala, E., Colasacco, C., Kahn, A. G., Lacchetti, C., Madabhushi, A., Pantanowitz, L., Salama, M. E., Stewart, R. L., Thomas, N. E., Tomaszewski, J. E., Hammond, M. E. 2019

    Abstract

    CONTEXT.: Advancements in genomic, computing, and imaging technology have spurred new opportunities to use quantitative image analysis (QIA) for diagnostic testing.OBJECTIVE.: To develop evidence-based recommendations to improve accuracy, precision, and reproducibility in the interpretation of human epidermal growth factor receptor 2 (HER2) immunohistochemistry (IHC) for breast cancer where QIA is used.DESIGN.: The College of American Pathologists (CAP) convened a panel of pathologists, histotechnologists, and computer scientists with expertise in image analysis, immunohistochemistry, quality management, and breast pathology to develop recommendations for QIA of HER2 IHC in breast cancer. A systematic review of the literature was conducted to address 5 key questions. Final recommendations were derived from strength of evidence, open comment feedback, expert panel consensus, and advisory panel review.RESULTS.: Eleven recommendations were drafted: 7 based on CAP laboratory accreditation requirements and 4 based on expert consensus opinions. A 3-week open comment period received 180 comments from more than 150 participants.CONCLUSIONS.: To improve accurate, precise, and reproducible interpretation of HER2 IHC results for breast cancer, QIA and procedures must be validated before implementation, followed by regular maintenance and ongoing evaluation of quality control and quality assurance. HER2 QIA performance, interpretation, and reporting should be supervised by pathologists with expertise in QIA.

    View details for PubMedID 30645156

  • In Reply. Archives of pathology & laboratory medicine Wolff, A. C., Hammond, M. E., Allison, K. H., Harvey, B. E., McShane, L. M., Dowsett, M. 2019

    View details for PubMedID 30605367

  • NCCN Guidelines Insights: Breast Cancer, Version 3.2018. Journal of the National Comprehensive Cancer Network : JNCCN Goetz, M. P., Gradishar, W. J., Anderson, B. O., Abraham, J., Aft, R., Allison, K. H., Blair, S. L., Burstein, H. J., Dang, C., Elias, A. D., Farrar, W. B., Giordano, S. H., Goldstein, L. J., Isakoff, S. J., Lyons, J., Marcom, P. K., Mayer, I. A., Moran, M. S., Mortimer, J., O'Regan, R. M., Patel, S. A., Pierce, L. J., Reed, E. C., Rugo, H. S., Sitapati, A., Smith, K. L., Smith, M. L., Soliman, H., Telli, M. L., Ward, J. H., Young, J. S., Shead, D. A., Kumar, R. 2019; 17 (2): 118–26

    Abstract

    These NCCN Guidelines Insights highlight the updated recommendations for use of multigene assays to guide decisions on adjuvant systemic chemotherapy therapy for women with hormone receptor-positive, HER2-negative early-stage invasive breast cancer. This report summarizes these updates and discusses the rationale behind them.

    View details for PubMedID 30787125

  • Breast Cancer Prognostic Factors in the Digital Era: Comparison of Nottingham Grade using Whole Slide Images and Glass Slides. Journal of pathology informatics Davidson, T. M., Rendi, M. H., Frederick, P. D., Onega, T., Allison, K. H., Mercan, E., Brunye, T. T., Shapiro, L. G., Weaver, D. L., Elmore, J. G. 2019; 10: 11

    Abstract

    Background: To assess reproducibility and accuracy of overall Nottingham grade and component scores using digital whole slide images (WSIs) compared to glass slides.Methods: Two hundred and eight pathologists were randomized to independently interpret 1 of 4 breast biopsy sets using either glass slides or digital WSI. Each set included 5 or 6 invasive carcinomas (22 total invasive cases). Participants interpreted the same biopsy set approximately 9 months later following a second randomization to WSI or glass slides. Nottingham grade, including component scores, was assessed on each interpretation, providing 2045 independent interpretations of grade. Overall grade and component scores were compared between pathologists (interobserver agreement) and for interpretations by the same pathologist (intraobserver agreement). Grade assessments were compared when the format (WSI vs. glass slides) changed or was the same for the two interpretations.Results: Nottingham grade intraobserver agreement was highest using glass slides for both interpretations (73%, 95% confidence interval [CI]: 68%, 78%) and slightly lower but not statistically different using digital WSI for both interpretations (68%, 95% CI: 61%, 75%; P= 0.22). The agreement was lowest when the format changed between interpretations (63%, 95% CI: 59%, 68%). Interobserver agreement was significantly higher (P < 0.001) using glass slides versus digital WSI (68%, 95% CI: 66%, 70% versus 60%, 95% CI: 57%, 62%, respectively). Nuclear pleomorphism scores had the lowest inter- and intra-observer agreement. Mitotic scores were higher on glass slides in inter- and intra-observer comparisons.Conclusions: Pathologists' intraobserver agreement (reproducibility) is similar for Nottingham grade using glass slides or WSI. However, slightly lower agreement between pathologists suggests that verification of grade using digital WSI may be more challenging.

    View details for PubMedID 31057980

  • Reply to C. Murray et al and V. Martin et al. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Wolff, A. C., Hammond, M. E., Allison, K. H., Harvey, B. E., McShane, L. M., Dowsett, M. 2018: JCO1801163

    View details for PubMedID 30346904

  • HER2 Testing in Breast Cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Focused Update Summary. Journal of oncology practice Wolff, A. C., Hammond, M. E., Allison, K. H., Harvey, B. E., McShane, L. M., Dowsett, M. 2018: JOP1800206

    View details for PubMedID 29920138

  • Pathological confirmation of pre-chemotherapy biopsied and tattooed axillary lymph nodes Patel, R., MacKerricher, W., Tsai, J., Wood, L., Allison, K., Wapnir, I. SPRINGER. 2018: 426–27

    View details for Web of Science ID 000433587300141

  • Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Focused Update. Archives of pathology & laboratory medicine Wolff, A. C., Hammond, M. E., Allison, K. H., Harvey, B. E., Mangu, P. B., Bartlett, J. M., Bilous, M., Ellis, I. O., Fitzgibbons, P., Hanna, W., Jenkins, R. B., Press, M. F., Spears, P. A., Vance, G. H., Viale, G., McShane, L. M., Dowsett, M. 2018

    Abstract

    PURPOSE: - To update key recommendations of the American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) human epidermal growth factor receptor 2 (HER2) testing in breast cancer guideline.METHODS: - Based on the signals approach, an Expert Panel reviewed published literature and research survey results on the observed frequency of less common in situ hybridization (ISH) patterns to update the recommendations.RECOMMENDATIONS: - Two recommendations addressed via correspondence in 2015 are included. First, immunohistochemistry (IHC) 2+ is defined as invasive breast cancer with weak to moderate complete membrane staining observed in >10% of tumor cells. Second, if the initial HER2 test result in a core needle biopsy specimen of a primary breast cancer is negative, a new HER2 test may (not "must") be ordered on the excision specimen based on specific clinical criteria. The HER2 testing algorithm for breast cancer is updated to address the recommended workup for less common clinical scenarios (approximately 5% of cases) observed when using a dual-probe ISH assay. These scenarios are described as ISH group 2 ( HER2/chromosome enumeration probe 17 [CEP17] ratio ≥2.0; average HER2 copy number <4.0 signals per cell), ISH group 3 ( HER2/CEP17 ratio <2.0; average HER2 copy number ≥6.0 signals per cell), and ISH group 4 ( HER2/CEP17 ratio <2.0; average HER2 copy number ≥4.0 and <6.0 signals per cell). The diagnostic approach includes more rigorous interpretation criteria for ISH and requires concomitant IHC review for dual-probe ISH groups 2 to 4 to arrive at the most accurate HER2 status designation (positive or negative) based on combined interpretation of the ISH and IHC assays. The Expert Panel recommends that laboratories using single-probe ISH assays include concomitant IHC review as part of the interpretation of all single-probe ISH assay results.

    View details for PubMedID 29846104

  • Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Focused Update. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Wolff, A. C., Hammond, M. E., Allison, K. H., Harvey, B. E., Mangu, P. B., Bartlett, J. M., Bilous, M., Ellis, I. O., Fitzgibbons, P., Hanna, W., Jenkins, R. B., Press, M. F., Spears, P. A., Vance, G. H., Viale, G., McShane, L. M., Dowsett, M. 2018: JCO2018778738

    Abstract

    Purpose To update key recommendations of the American Society of Clinical Oncology/College of American Pathologists human epidermal growth factor receptor 2 (HER2) testing in breast cancer guideline. Methods Based on the signals approach, an Expert Panel reviewed published literature and research survey results on the observed frequency of less common in situ hybridization (ISH) patterns to update the recommendations. Recommendations Two recommendations addressed via correspondence in 2015 are included. First, immunohistochemistry (IHC) 2+ is defined as invasive breast cancer with weak to moderate complete membrane staining observed in > 10% of tumor cells. Second, if the initial HER2 test result in a core needle biopsy specimen of a primary breast cancer is negative, a new HER2 test may (not "must") be ordered on the excision specimen based on specific clinical criteria. The HER2 testing algorithm for breast cancer is updated to address the recommended work-up for less common clinical scenarios (approximately 5% of cases) observed when using a dual-probe ISH assay. These scenarios are described as ISH group 2 ( HER2/chromosome enumeration probe 17 [CEP17] ratio ≥ 2.0; average HER2 copy number < 4.0 signals per cell), ISH group 3 ( HER2/CEP17 ratio < 2.0; average HER2 copy number ≥ 6.0 signals per cell), and ISH group 4 ( HER2/CEP17 ratio < 2.0; average HER2 copy number ≥ 4.0 and < 6.0 signals per cell). The diagnostic approach includes more rigorous interpretation criteria for ISH and requires concomitant IHC review for dual-probe ISH groups 2 to 4 to arrive at the most accurate HER2 status designation (positive or negative) based on combined interpretation of the ISH and IHC assays. The Expert Panel recommends that laboratories using single-probe ISH assays include concomitant IHC review as part of the interpretation of all single-probe ISH assay results. Find additional information at www.asco.org/breast-cancer-guidelines .

    View details for PubMedID 29846122

  • Clinicopathologic Features, Management and Outcomes of Breast Secretory Lesions with and without Atypia Mooney, K., Lin, C., Sibley, R., Rendi, M., Allison, K. NATURE PUBLISHING GROUP. 2018: 92

    View details for Web of Science ID 000429308600260

  • The clinicopathologic and genomic features of fibrotic foci in breast cancer - results from the TCGA cohort Beca, F., Tsang, J., Jensen, K. C., Allison, K., Tse, G. NATURE PUBLISHING GROUP. 2018: 50

    View details for Web of Science ID 000429308600145

  • Ancillary Prognostic and Predictive Testing in Breast Cancer: Focus on Discordant, Unusual, and Borderline Results. Surgical pathology clinics Allison, K. H. 2018; 11 (1): 147–76

    Abstract

    Ancillary testing in breast cancer has become standard of care to determine what therapies may be most effective for individual patients with breast cancer. Single-marker tests are required on all newly diagnosed and newly metastatic breast cancers. Markers of proliferation are also used, and include both single-marker tests like Ki67 as well as panel-based gene expression tests, which have made more recent contributions to prognostic and predictive testing in breast cancers. This review focuses on pathologist interpretation of these ancillary test results, with a focus on expected versus unexpected results and troubleshooting borderline, unusual, or discordant results.

    View details for PubMedID 29413654

  • Potential Impact of Proposed HER2 FISH Guideline Updates on FISH results; A Multi-Institutional Study Ballard, M., MacKerricher, W., Jalikis, F., Krings, G., Schmidt, R., Chen, Y., Rendi, M., Dintzis, S., Troxell, M., West, R., Sibley, R., Allison, K. NATURE PUBLISHING GROUP. 2018: 48

    View details for Web of Science ID 000429308600139

  • Pathologic Features and Clinical Outcomes of HER2 FISH Cases with HER2: CEP17 ratio > 2.0 but < 4 HER2 signals/cell; A Multi-Institutional Study Ballard, M., Toukatly, M., Bean, G., Jalikis, F., Krings, G., Schmidt, R., Chen, Y., Dintzis, S., Troxell, M., West, R., Sibley, R., Allison, K. NATURE PUBLISHING GROUP. 2018: 47–48

    View details for Web of Science ID 000429308600138

  • Pathologic Features and Clinical Outcomes of Breast Cancers with HER2/CEP17 ratio < 2.0 and mean HER2 signals /cell > 6.0 by FISH; A Multi-Institutional Study Ballard, M., Toukatly, M., Bean, G., Jalikis, F., Krings, G., Schmidt, R., Chen, Y., Rendi, M., Dintzis, S., Troxell, M., West, R., Sibley, R., Allison, K. NATURE PUBLISHING GROUP. 2018: 48

    View details for Web of Science ID 000429308600140

  • Characteristics and clinical outcomes of pleomorphic lobular carcinoma in situ of the breast BREAST JOURNAL Fasola, C. E., Chen, J., Jensen, K. C., Allison, K. H., Horst, K. C. 2018; 24 (1): 66–69

    Abstract

    Pleomorphic lobular carcinoma in situ (PLCIS) of the breast is a rare variant of lobular carcinoma in situ (LCIS). We reviewed 78 cases of PLCIS diagnosed at our institution from 1998 to 2012. Among all cases, 47 (60%) were associated with invasive carcinoma and/or ductal carcinoma in situ (DCIS) after final surgical excision. Of the 20 cases with PLCIS alone on core needle biopsy (CNB), 6 (30%) were upgraded to invasive carcinoma or DCIS after final surgical excision. Our findings support a recommendation for complete surgical excision of PLCIS when diagnosed on CNB.

    View details for PubMedID 28929550

  • Second opinion strategies in breast pathology: a decision analysis addressing over-treatment, under-treatment, and care costs BREAST CANCER RESEARCH AND TREATMENT Tosteson, A. A., Yang, Q., Nelson, H. D., Longton, G., Soneji, S. S., Pepe, M., Geller, B., Carney, P. A., Onega, T., Allison, K. H., Elmore, J. G., Weaver, D. L. 2018; 167 (1): 195–203

    Abstract

    To estimate the potential near-term population impact of alternative second opinion breast biopsy pathology interpretation strategies.Decision analysis examining 12-month outcomes of breast biopsy for nine breast pathology interpretation strategies in the U.S. health system. Diagnoses of 115 practicing pathologists in the Breast Pathology Study were compared to reference-standard-consensus diagnoses with and without second opinions. Interpretation strategies were defined by whether a second opinion was sought universally or selectively (e.g., 2nd opinion if invasive). Main outcomes were the expected proportion of concordant breast biopsy diagnoses, the proportion involving over- or under-interpretation, and cost of care in U.S. dollars within one-year of biopsy.Without a second opinion, 92.2% of biopsies received a concordant diagnosis. Concordance rates increased under all second opinion strategies, and the rate was highest (95.1%) and under-treatment lowest (2.6%) when all biopsies had second opinions. However, over-treatment was lowest when second opinions were sought selectively for initial diagnoses of invasive cancer, DCIS, or atypia (1.8 vs. 4.7% with no 2nd opinions). This strategy also had the lowest projected 12-month care costs ($5.907 billion vs. $6.049 billion with no 2nd opinions).Second opinion strategies could lower overall care costs while reducing both over- and under-treatment. The most accurate cost-saving strategy required second opinions for initial diagnoses of invasive cancer, DCIS, or atypia.

    View details for PubMedID 28879558

  • Assessing Tumor-Infiltrating Lymphocytes in Solid Tumors: A Practical Review for Pathologists and Proposal for a Standardized Method from the International Immuno-Oncology Biomarkers Working Group: Part 2: TILs in Melanoma, Gastrointestinal Tract Carcinomas, Non-Small Cell Lung Carcinoma and Mesothelioma, Endometrial and Ovarian Carcinomas, Squamous Cell Carcinoma of the Head and Neck, Genitourinary Carcinomas, and Primary Brain Tumors ADVANCES IN ANATOMIC PATHOLOGY Hendry, S., Salgado, R., Gevaert, T., Russell, P. A., John, T., Thapa, B., Christie, M., van de Vijver, K., Estrada, M. V., Gonzalez-Ericsson, P. I., Sanders, M., Solomon, B., Solinas, C., Van den Eynden, G. M., Allory, Y., Preusser, M., Hainfellner, J., Pruneri, G., Vingiani, A., Demaria, S., Symmans, F., Nuciforo, P., Comerma, L., Thompson, E. A., Lakhani, S., Kim, S., Schnitt, S., Colpaert, C., Sotiriou, C., Scherer, S. J., Ignatiadis, M., Badve, S., Pierce, R. H., Viale, G., Sirtaine, N., Penault-Llorca, F., Sugie, T., Fineberg, S., Paik, S., Srinivasan, A., Richardson, A., Wang, Y., Chmielik, E., Brock, J., Johnson, D. B., Balko, J., Wienert, S., Bossuyt, V., Michiels, S., Ternes, N., Burchardi, N., Luen, S. J., Savas, P., Klauschen, F., Watson, P. H., Nelson, B. H., Criscitiello, C., O'Toole, S., Larsimont, D., de Wind, R., Curigliano, G., Andre, F., Lacroix-Triki, M., van de Vijver, M., Rojo, F., Floris, G., Bedri, S., Sparano, J., Rimm, D., Nielsen, T., Kos, Z., Hewitt, S., Singh, B., Farshid, G., Loibl, S., Allison, K. H., Tung, N., Adams, S., Willard-Gallo, K., Horlings, H. M., Gandhi, L., Moreira, A., Hirsch, F., Dieci, M. V., Urbanowicz, M., Brcic, I., Korski, K., Gaire, F., Koeppen, H., Lo, A., Giltnane, J., Rebelatto, M. C., Steele, K. E., Zha, J., Emancipator, K., Juco, J. W., Denkert, C., Reis-Filho, J., Loi, S., Fox, S. B. 2017; 24 (6): 311–35

    Abstract

    Assessment of the immune response to tumors is growing in importance as the prognostic implications of this response are increasingly recognized, and as immunotherapies are evaluated and implemented in different tumor types. However, many different approaches can be used to assess and describe the immune response, which limits efforts at implementation as a routine clinical biomarker. In part 1 of this review, we have proposed a standardized methodology to assess tumor-infiltrating lymphocytes (TILs) in solid tumors, based on the International Immuno-Oncology Biomarkers Working Group guidelines for invasive breast carcinoma. In part 2 of this review, we discuss the available evidence for the prognostic and predictive value of TILs in common solid tumors, including carcinomas of the lung, gastrointestinal tract, genitourinary system, gynecologic system, and head and neck, as well as primary brain tumors, mesothelioma and melanoma. The particularities and different emphases in TIL assessment in different tumor types are discussed. The standardized methodology we propose can be adapted to different tumor types and may be used as a standard against which other approaches can be compared. Standardization of TIL assessment will help clinicians, researchers and pathologists to conclusively evaluate the utility of this simple biomarker in the current era of immunotherapy.

    View details for PubMedID 28777143

  • Assessing Tumor-infiltrating Lymphocytes in Solid Tumors: A Practical Review for Pathologists and Proposal for a Standardized Method From the International Immunooncology Biomarkers Working Group: Part 1: Assessing the Host Immune Response, TILs in Invasive Breast Carcinoma and Ductal Carcinoma In Situ, Metastatic Tumor Deposits and Areas for Further Research ADVANCES IN ANATOMIC PATHOLOGY Hendry, S., Salgado, R., Gevaert, T., Russell, P. A., John, T., Thapa, B., Christie, M., van de Vijver, K., Estrada, M. V., Gonzalez-Ericsson, P. I., Sanders, M., Solomon, B., Solinas, C., Van den Eynden, G. M., Allory, Y., Preusser, M., Hainfellner, J., Pruneri, G., Vingiani, A., Demaria, S., Symmans, F., Nuciforo, P., Comerma, L., Thompson, E. A., Lakhani, S., Kim, S., Schnitt, S., Colpaert, C., Sotiriou, C., Scherer, S. J., Ignatiadis, M., Badve, S., Pierce, R. H., Viale, G., Sirtaine, N., Penault-Llorca, F., Sugie, T., Fineberg, S., Paik, S., Srinivasan, A., Richardson, A., Wang, Y., Chmielik, E., Brock, J., Johnson, D. B., Balko, J., Wienert, S., Bossuyt, V., Michiels, S., Ternes, N., Burchardi, N., Luen, S. J., Savas, P., Klauschen, F., Watson, P. H., Nelson, B. H., Criscitiello, C., O'Toole, S., Larsimont, D., de Wind, R., Curigliano, G., Andre, F., Lacroix-Triki, M., van de Vijver, M., Rojo, F., Floris, G., Bedri, S., Sparano, J., Rimm, D., Nielsen, T., Kos, Z., Hewitt, S., Singh, B., Farshid, G., Loibl, S., Allison, K. H., Tung, N., Adams, S., Willard-Gallo, K., Horlings, H. M., Gandhi, L., Moreira, A., Hirsch, F., Dieci, M. V., Urbanowicz, M., Brcic, I., Korski, K., Gaire, F., Koeppen, H., Lo, A., Giltnane, J., Rebelatto, M. C., Steele, K. E., Zha, J., Emancipator, K., Juco, J. W., Denkert, C., Reis-Filho, J., Loi, S., Fox, S. B. 2017; 24 (5): 235–51

    Abstract

    Assessment of tumor-infiltrating lymphocytes (TILs) in histopathologic specimens can provide important prognostic information in diverse solid tumor types, and may also be of value in predicting response to treatments. However, implementation as a routine clinical biomarker has not yet been achieved. As successful use of immune checkpoint inhibitors and other forms of immunotherapy become a clinical reality, the need for widely applicable, accessible, and reliable immunooncology biomarkers is clear. In part 1 of this review we briefly discuss the host immune response to tumors and different approaches to TIL assessment. We propose a standardized methodology to assess TILs in solid tumors on hematoxylin and eosin sections, in both primary and metastatic settings, based on the International Immuno-Oncology Biomarker Working Group guidelines for TIL assessment in invasive breast carcinoma. A review of the literature regarding the value of TIL assessment in different solid tumor types follows in part 2. The method we propose is reproducible, affordable, easily applied, and has demonstrated prognostic and predictive significance in invasive breast carcinoma. This standardized methodology may be used as a reference against which other methods are compared, and should be evaluated for clinical validity and utility. Standardization of TIL assessment will help to improve consistency and reproducibility in this field, enrich both the quality and quantity of comparable evidence, and help to thoroughly evaluate the utility of TILs assessment in this era of immunotherapy.

    View details for PubMedID 28777142

  • The diagnostic challenge of low-grade ductal carcinoma in situ. European journal of cancer Onega, T., Weaver, D. L., Frederick, P. D., Allison, K. H., Tosteson, A. N., Carney, P. A., Geller, B. M., Longton, G. M., Nelson, H. D., Oster, N. V., Pepe, M. S., Elmore, J. G. 2017; 80: 39-47

    Abstract

    Diagnostic agreement among pathologists is 84% for ductal carcinoma in situ (DCIS). Studies of interpretive variation according to grade are limited.A national sample of 115 pathologists interpreted 240 breast pathology test set cases in the Breast Pathology Study and their interpretations were compared to expert consensus interpretations. We assessed agreement of pathologists' interpretations with a consensus reference diagnosis of DCIS dichotomised into low- and high-grade lesions. Generalised estimating equations were used in logistic regression models of rates of under- and over-interpretation of DCIS by grade.We evaluated 2097 independent interpretations of DCIS (512 low-grade DCIS and 1585 high-grade DCIS). Agreement with reference diagnoses was 46% (95% confidence interval [CI] 42-51) for low-grade DCIS and 83% (95% CI 81-86) for high-grade DCIS. The proportion of reference low-grade DCIS interpretations over-interpreted by pathologists (i.e. categorised as either high-grade DCIS or invasive cancer) was 23% (95% CI 19-28); 30% (95% CI 26-34) were interpreted as a lower diagnostic category (atypia or benign proliferative). Reference high-grade DCIS was under-interpreted in 14% (95% CI 12-16) of observations and only over-interpreted 3% (95% CI 2-4).Grade is a major factor when examining pathologists' variability in diagnosing DCIS, with much lower agreement for low-grade DCIS cases compared to high-grade. These findings support the hypothesis that low-grade DCIS poses a greater interpretive challenge than high-grade DCIS, which should be considered when developing DCIS management strategies.

    View details for DOI 10.1016/j.ejca.2017.04.013

    View details for PubMedID 28535496

  • Surgical implications and variability in the use of the flat epithelial atypia diagnosis on breast biopsy specimens. Breast Samples, L. S., Rendi, M. H., Frederick, P. D., Allison, K. H., Nelson, H. D., Morgan, T. R., Weaver, D. L., Elmore, J. G. 2017; 34: 34-43

    Abstract

    Flat epithelial atypia (FEA) is a relatively new diagnostic term with uncertain clinical significance for surgical management. Any implied risk of invasive breast cancer associated with FEA is contingent upon diagnostic reproducibility, yet little is known regarding its use.Pathologists in the Breast Pathology Study interpreted one of four 60-case test sets, one slide per case, constructed from 240 breast biopsy specimens. An electronic data form with standardized diagnostic categories was used; participants were instructed to indicate all diagnoses present. We assessed participants' use of FEA as a diagnostic term within: 1) each test set; 2) 72 cases classified by reference as benign without FEA; and 3) six cases classified by reference as FEA. 115 pathologists participated, providing 6900 total independent assessments.Notation of FEA ranged from 0% to 35% of the cases interpreted, with most pathologists noting FEA on 4 or more test cases. At least one participant noted FEA in 34 of the 72 benign non-FEA cases. For the 6 reference FEA cases, participant agreement with the case reference FEA diagnosis ranged from 17% to 52%; diagnoses noted by participating pathologists for these FEA cases included columnar cell hyperplasia, usual ductal hyperplasia, atypical lobular hyperplasia, and atypical ductal hyperplasia.We observed wide variation in the diagnosis of FEA among U.S. pathologists. This suggests that perceptions of diagnostic criteria and any implied risk associated with FEA may also vary. Surgical excision following a core biopsy diagnosis of FEA should be reconsidered and studied further.

    View details for DOI 10.1016/j.breast.2017.04.004

    View details for PubMedID 28475933

  • Characteristics associated with requests by pathologists for second opinions on breast biopsies. Journal of clinical pathology Geller, B. M., Nelson, H. D., Weaver, D. L., Frederick, P. D., Allison, K. H., Onega, T., Carney, P. A., Tosteson, A. N., Elmore, J. G. 2017

    Abstract

    Second opinions in pathology improve patient safety by reducing diagnostic errors, leading to more appropriate clinical treatment decisions. Little objective data are available regarding the factors triggering a request for second opinion despite second opinion consultations being part of the diagnostic system of pathology. Therefore we sought to assess breast biopsy cases and interpreting pathologists characteristics associated with second opinion requests.Collected pathologist surveys and their interpretations of 60 test set cases were used to explore the relationships between case characteristics, pathologist characteristics and case perceptions, and requests for second opinions. Data were evaluated by logistic regression and generalised estimating equations.115 pathologists provided 6900 assessments; pathologists requested second opinions on 70% (4827/6900) of their assessments 36% (1731/4827) of these would not have been required by policy. All associations between case characteristics and requesting second opinions were statistically significant, including diagnostic category, breast density, biopsy type, and number of diagnoses noted per case. Exclusive of institutional policies, pathologists wanted second opinions most frequently for atypia (66%) and least frequently for invasive cancer (20%). Second opinion rates were higher when the pathologist had lower assessment confidence, in cases with higher perceived difficulty, and cases with borderline diagnoses.Pathologists request second opinions for challenging cases, particularly those with atypia, high breast density, core needle biopsies, or many co-existing diagnoses. Further studies should evaluate whether the case characteristics identified in this study could be used as clinical criteria to prompt system-level strategies for mandating second opinions.

    View details for DOI 10.1136/jclinpath-2016-204231

    View details for PubMedID 28465449

  • Diagnostic Reproducibility: What Happens When the Same Pathologist Interprets the Same Breast Biopsy Specimen at Two Points in Time? ANNALS OF SURGICAL ONCOLOGY Jackson, S. L., Frederick, P. D., Pepe, M. S., Nelson, H. D., Weaver, D. L., Allison, K. H., Carney, P. A., Geller, B. M., Tosteson, A. N., Onega, T., Elmore, J. G. 2017; 24 (5): 1234-1241

    View details for DOI 10.1245/s10434-016-5695-0

    View details for Web of Science ID 000399013200015

  • A Standard Set of Value-Based Patient-Centered Outcomes for Breast Cancer: The International Consortium for Health Outcomes Measurement (ICHOM) Initiative. JAMA oncology Ong, W. L., Schouwenburg, M. G., van Bommel, A. C., Stowell, C., Allison, K. H., Benn, K. E., Browne, J. P., Cooter, R. D., Delaney, G. P., Duhoux, F. P., Ganz, P. A., Hancock, P., Jagsi, R., Knaul, F. M., Knip, A. M., Koppert, L. B., Kuerer, H. M., McLaughin, S., Mureau, M. A., Partridge, A. H., Reid, D. P., Sheeran, L., Smith, T. J., Stoutjesdijk, M. J., Vrancken Peeters, M. J., Wengström, Y., Yip, C., Saunders, C. 2017; 3 (5): 677-685

    Abstract

    A major challenge in value-based health care is the lack of standardized health outcomes measurements, hindering optimal monitoring and comparison of the quality of health care across different settings globally. The International Consortium for Health Outcomes Measurement (ICHOM) assembled a multidisciplinary international working group, comprised of 26 health care providers and patient advocates, to develop a standard set of value-based patient-centered outcomes for breast cancer (BC). The working group convened via 8 teleconferences and completed a follow-up survey after each meeting. A modified 2-round Delphi method was used to achieve consensus on the outcomes and case-mix variables to be included. Patient focus group meetings (8 early or metastatic BC patients) and online anonymized surveys of 1225 multinational BC patients and survivors were also conducted to obtain patients' input. The standard set encompasses survival and cancer control, and disutility of care (eg, acute treatment complications) outcomes, to be collected through administrative data and/or clinical records. A combination of multiple patient-reported outcomes measurement (PROM) tools is recommended to capture long-term degree of health outcomes. Selected case-mix factors were recommended to be collected at baseline. The ICHOM will endeavor to achieve wide buy-in of this set and facilitate its implementation in routine clinical practice in various settings and institutions worldwide.

    View details for DOI 10.1001/jamaoncol.2016.4851

    View details for PubMedID 28033439

  • 'Non-classical' HER2 FISH results in breast cancer: a multi-institutional study MODERN PATHOLOGY Ballard, M., Jalikis, F., Krings, G., Schmidt, R. A., Chen, Y., Rendi, M. H., Dintzis, S. M., Jensen, K. C., West, R. B., Sibley, R. K., Troxell, M. L., Allison, K. H. 2017; 30 (2): 227-235

    Abstract

    The 2013 CAP/ASCO HER2 Testing Guidelines Update modified HER2 FISH categories such that some cases with 'monosomy', 'co-amplification/polysomy', low-level increased HER2 signals or clustered heterogeneity now are considered amplified or equivocal. This study examines the frequency and clinico-pathologic characteristics of breast cancers with equivocal or 'non-classical' HER2 FISH results. Breast cancers (2001-2014) with HER2 FISH results, HER2 immunohistochemistry, ER, grade, and age from three institutions (Stanford, UCSF, UWMC) were collected. HER2 FISH was interpreted using the updated recommendations. Amplified cases with non-classical results were grouped into the following categories: (1) 'monosomy' (ratio ≥2.0, mean HER2/cell<4.0); (2) 'co-amplified' (ratio<2.0, mean HER2/cell ≥6.0); (3) 'low amplified' (ratio ≥2.0, mean HER2/cell 4.0-5.9). Heterogeneous cases with clustered HER2-positive cells were also included. Of 8068 cases, 5.2% were equivocal and 4.6% had a 'non-classical' HER2 amplified result; 1.4% 'monosomy', 0.8% 'co-amplified', 2.1% 'low amplified', and 0.3% clustered heterogeneity. These cancers had a high frequency of ER positive (80.4%), Nottingham grade 3 (52.1%) results. The highest percentage of grade 3 cancers (66.7%) and positive HER2 immunohistochemistry (31.7%) was in the 'co-amplified' group. The 'monosomy' group had the highest percent grade 1 cancers (13.3%) and was most frequently HER2 immunohistochemistry negative (30.1%). Equivocal cases had very similar characteristics to the 'low-amplified' category. Cases with non-classical HER2 amplification or equivocal results are typically ER positive, higher grade cancers. 'Co-amplified' cases have the highest frequencies of aggressive characteristics and 'monosomy' cases the highest frequencies of lower risk features. With little clinical outcomes data currently available on these non-classical HER2 results, these results support the current classification scheme for HER2 FISH, with case-by-case correlation with additional clinical-pathologic factors when evaluating whether to offer HER2-targeted therapies in these non-classical cases.Modern Pathology advance online publication, 14 October 2016; doi:10.1038/modpathol.2016.175.

    View details for DOI 10.1038/modpathol.2016.175

    View details for Web of Science ID 000393257400007

  • The molecular basis of breast cancer pathological phenotypes. journal of pathology Heng, Y. J., Lester, S. C., Tse, G. M., Factor, R. E., Allison, K. H., Collins, L. C., Chen, Y., Jensen, K. C., Johnson, N. B., Jeong, J. C., Punjabi, R., Shin, S. J., Singh, K., Krings, G., Eberhard, D. A., Tan, P. H., Korski, K., Waldman, F. M., Gutman, D. A., Sanders, M., Reis-Filho, J. S., Flanagan, S. R., Gendoo, D. M., Chen, G. M., Haibe-Kains, B., Ciriello, G., Hoadley, K. A., Perou, C. M., Beck, A. H. 2017; 241 (3): 375-391

    Abstract

    The histopathological evaluation of morphological features in breast tumours provides prognostic information to guide therapy. Adjunct molecular analyses provide further diagnostic, prognostic and predictive information. However, there is limited knowledge of the molecular basis of morphological phenotypes in invasive breast cancer. This study integrated genomic, transcriptomic and protein data to provide a comprehensive molecular profiling of morphological features in breast cancer. Fifteen pathologists assessed 850 invasive breast cancer cases from The Cancer Genome Atlas (TCGA). Morphological features were significantly associated with genomic alteration, DNA methylation subtype, PAM50 and microRNA subtypes, proliferation scores, gene expression and/or reverse-phase protein assay subtype. Marked nuclear pleomorphism, necrosis, inflammation and a high mitotic count were associated with the basal-like subtype, and had a similar molecular basis. Omics-based signatures were constructed to predict morphological features. The association of morphology transcriptome signatures with overall survival in oestrogen receptor (ER)-positive and ER-negative breast cancer was first assessed by use of the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) dataset; signatures that remained prognostic in the METABRIC multivariate analysis were further evaluated in five additional datasets. The transcriptomic signature of poorly differentiated epithelial tubules was prognostic in ER-positive breast cancer. No signature was prognostic in ER-negative breast cancer. This study provided new insights into the molecular basis of breast cancer morphological phenotypes. The integration of morphological with molecular data has the potential to refine breast cancer classification, predict response to therapy, enhance our understanding of breast cancer biology, and improve clinical management. This work is publicly accessible at www.dx.ai/tcga_breast. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

    View details for DOI 10.1002/path.4847

    View details for PubMedID 27861902

  • The Influence of Disease Severity of Preceding Clinical Cases on Pathologists' Medical Decision Making MEDICAL DECISION MAKING Frederick, P. D., Nelson, H. D., Carney, P. A., Brunye, T. T., Allison, K. H., Weaver, D. L., Elmore, J. G. 2017; 37 (1): 91-100

    View details for DOI 10.1177/0272989X16638326

    View details for Web of Science ID 000389609900012

  • Regional Variability in Percentage of Breast Cancers Reported as Positive for HER2 in California: Implications of Patient Demographics on Laboratory Benchmarks. American journal of clinical pathology Lin, C. Y., Carneal, E. E., Lichtensztajn, D. Y., Gomez, S. L., Clarke, C. A., Jensen, K. C., Kurian, A. W., Allison, K. H. 2017; 148 (3): 199–207

    Abstract

    The expected regional variability in percent human epidermal growth factor receptor 2 (HER2)-positive breast cancers is not currently clear.Data from the 2006 to 2011 California Cancer Registry were examined by county and health service area. The influence of demographic and pathologic features was used in a multivariable logistic regression model to compare expected with observed HER2-positive percentages by region.There was significant geographic variation by California counties (11.6%-26%). The reported HER2-positive percentage was higher when the population had higher stage, tumor size, grade, percent estrogen receptor negative, younger age, or lower socioeconomic status. Ethnic distribution of the population also influenced HER2-positive percentages. Using a multivariable logistic regression model, most regions had expected values based on their population characteristics; however, "outlier" regions were identified.These results deepen our understanding of population characteristics' influence on the distribution of HER2-positive breast cancers. Taking these factors into account can be useful when setting laboratory benchmarks and assessing test quality.

    View details for PubMedID 28821197

  • Topical Imiquimod Plus Nab-paclitaxel for Breast Cancer Cutaneous Metastases: A Phase 2 Clinical Trial. JAMA oncology Salazar, L. G., Lu, H., Reichow, J. L., Childs, J. S., Coveler, A. L., Higgins, D. M., Waisman, J., Allison, K. H., Dang, Y., Disis, M. L. 2017; 3 (7): 969–73

    Abstract

    Salvage chemotherapy for recurrent chest wall lesions in breast cancer results in response rates of 20% to 30%. Preclinical studies showed significant disease regression could be induced in murine chest wall mammary cancers with a topical toll-like receptor (TLR)-7 agonist, imiquimod.To evaluate the safety and objective response rate (ORR) of imiquimod in combination with systemic albumin bound paclitaxel in treatment-refractory breast cancer of the chest wall.A single arm phase 2 clinical trial of 15 patients with breast cancer previously treated in an academic medical center setting between 2009 and 2012 for chest wall disease that had recurred.Imiquimod cream, 5%, was applied topically to a designated target lesion once per day for 4 consecutive days on days 1 through 4, 8 through 11, 15 through 18, and 22 through 25 of a 28-day cycle, for 12 weeks. Albumin bound paclitaxel, 100 mg/m2, was given intravenously on days 1, 8, and 15, and repeated every 28 days over the 12-week period.The primary endpoint was safety and ORR. Secondary endpoints included the generation of tumor-infiltrating lymphocytes and modulation of immune cell populations.The median age at baseline of the 15 study participants was 54 years (range, 46-92 years). Fourteen patients were evaluable. Combination therapy was associated with low-grade toxic effects. Of 358 adverse events 330 (92%) were grades 1 and 2. Five (36%) patients achieved a compete response and another 5 (36%) were partial responders for an overall response rate of 72% (10 of 14). The response duration was limited. Pretreatment levels of programmed death-1 (PD-1)+ peripheral blood T cells (PD-1+ cluster of differentiation [CD]4+; 95% CI, 2.68-6.63; P < .001 and PD-1+CD8+; 95% CI, 1.13-8.35; P = .01) and monocytic myeloid derived suppressor cells (mMDSC) (95% CI, 3.62-12.74; P = .001) greater than controls predicted suboptimal clinical response.Chemoimmunomodulation with a TLR-7 agonist and albumin bound paclitaxel is effective in inducing disease regression in treatment-refractory breast cancer chest wall metastases but responses are short-lived. Preexisting levels of cells indicating either T-cell exhaustion or systemic immunosuppression may be markers of selection for responsive patients.clinicaltrials.gov Identifier: NCT00821964.

    View details for PubMedID 28114604

    View details for PubMedCentralID PMC5824239

  • COMPARISON OF BREAST CARCINOMA NOTTINGHAM GRADING BY GLASS SLIDES VERSUS DIGITAL WHOLE SLIDE IMAGES: VARIABILITY INCREASES USING DIGITAL FORMAT Davidson, T. M., Rendi, M. H., Allison, K. H., Weaver, D. L., Elmore, J. G. BMJ PUBLISHING GROUP. 2017: 284

    View details for DOI 10.1136/jim-2016-000365.437

    View details for Web of Science ID 000433055100430

  • Will oncotype DX DCIS testing guide therapy? A single-institution correlation of oncotype DX DCIS results with histopathologic findings and clinical management decisions. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc Lin, C. Y., Mooney, K., Choy, W., Yang, S. R., Barry-Holson, K., Horst, K., Wapnir, I., Allison, K. 2017

    Abstract

    Given the increased detection rates of ductal carcinoma in situ (DCIS) and the limited overall survival benefit from adjuvant breast irradiation after breast-conserving surgery, there is interest in identifying subsets of patients who have low rates of ipsilateral breast tumor recurrence such that they might safely forgo radiation. The Oncotype DCIS score is a reverse transcription-PCR (RT-PCR)-based assay that was validated to predict which DCIS cases are most likely to recur. Clinically, these results may be used to assist in selecting which patients with DCIS might safely forgo radiation therapy after breast-conserving surgery; however, little is currently published on how this test is being used in practice. Our study examines traditional histopathologic features used in predicting DCIS risk with Oncotype DCIS results and how these results affect clinical decision-making at our academic institution. Histopathologic features and management decisions for 37 cases with Oncotype DCIS results over the past 4 years were collected. Necrosis, high nuclear grade, biopsy site change, estrogen receptor and progesterone receptor positivity <90% on immunohistochemistry, and Van Nuys Prognostic Index score of 8 or greater were significant predictors of an intermediate-high recurrence score on multivariate regression analysis (P<0.02). Low Oncotype DCIS scores and low nuclear grade were associated with lower rate of radiation therapy (P<0.008). There were seven cases (19%) with Oncotype DCIS results that we considered unexpected in relation to the histopathologic findings (ie, high nuclear grade with comedonecrosis and a low Oncotype score, or hormone receptor discrepancies). Overall, pathologic features correlate with Oncotype DCIS scores but unexpected results do occur, making individual recommendations sometimes challenging.Modern Pathology advance online publication, 15 December 2017; doi:10.1038/modpathol.2017.172.

    View details for PubMedID 29243740

  • A Randomized Study Comparing Digital Imaging to Traditional Glass Slide Microscopy for Breast Biopsy and Cancer Diagnosis. Journal of pathology informatics Elmore, J. G., Longton, G. M., Pepe, M. S., Carney, P. A., Nelson, H. D., Allison, K. H., Geller, B. M., Onega, T., Tosteson, A. N., Mercan, E., Shapiro, L. G., Brunyé, T. T., Morgan, T. R., Weaver, D. L. 2017; 8: 12-?

    Abstract

    Digital whole slide imaging may be useful for obtaining second opinions and is used in many countries. However, the U.S. Food and Drug Administration requires verification studies.Pathologists were randomized to interpret one of four sets of breast biopsy cases during two phases, separated by ≥9 months, using glass slides or digital format (sixty cases per set, one slide per case, n = 240 cases). Accuracy was assessed by comparing interpretations to a consensus reference standard. Intraobserver reproducibility was assessed by comparing the agreement of interpretations on the same cases between two phases. Estimated probabilities of confirmation by a reference panel (i.e., predictive values) were obtained by incorporating data on the population prevalence of diagnoses.Sixty-five percent of responding pathologists were eligible, and 252 consented to randomization; 208 completed Phase I (115 glass, 93 digital); and 172 completed Phase II (86 glass, 86 digital). Accuracy was slightly higher using glass compared to digital format and varied by category: invasive carcinoma, 96% versus 93% (P = 0.04); ductal carcinoma in situ (DCIS), 84% versus 79% (P < 0.01); atypia, 48% versus 43% (P = 0.08); and benign without atypia, 87% versus 82% (P < 0.01). There was a small decrease in intraobserver agreement when the format changed compared to when glass slides were used in both phases (P = 0.08). Predictive values for confirmation by a reference panel using glass versus digital were: invasive carcinoma, 98% and 97% (not significant [NS]); DCIS, 70% and 57% (P = 0.007); atypia, 38% and 28% (P = 0.002); and benign without atypia, 97% and 96% (NS).In this large randomized study, digital format interpretations were similar to glass slide interpretations of benign and invasive cancer cases. However, cases in the middle of the spectrum, where more inherent variability exists, may be more problematic in digital format. Future studies evaluating the effect these findings exert on clinical practice and patient outcomes are required.

    View details for DOI 10.4103/2153-3539.201920

    View details for PubMedID 28382226

  • Diagnostic Reproducibility: What Happens When the Same Pathologist Interprets the Same Breast Biopsy Specimen at Two Points in Time? Annals of surgical oncology Jackson, S. L., Frederick, P. D., Pepe, M. S., Nelson, H. D., Weaver, D. L., Allison, K. H., Carney, P. A., Geller, B. M., Tosteson, A. N., Onega, T., Elmore, J. G. 2016: -?

    Abstract

    Surgeons may receive a different diagnosis when a breast biopsy is interpreted by a second pathologist. The extent to which diagnostic agreement by the same pathologist varies at two time points is unknown.Pathologists from eight U.S. states independently interpreted 60 breast specimens, one glass slide per case, on two occasions separated by ≥9 months. Reproducibility was assessed by comparing interpretations between the two time points; associations between reproducibility (intraobserver agreement rates); and characteristics of pathologists and cases were determined and also compared with interobserver agreement of baseline interpretations.Sixty-five percent of invited, responding pathologists were eligible and consented; 49 interpreted glass slides in both study phases, resulting in 2940 interpretations. Intraobserver agreement rates between the two phases were 92% [95% confidence interval (CI) 88-95] for invasive breast cancer, 84% (95% CI 81-87) for ductal carcinoma-in-situ, 53% (95% CI 47-59) for atypia, and 84% (95% CI 81-86) for benign without atypia. When comparing all study participants' case interpretations at baseline, interobserver agreement rates were 89% (95% CI 84-92) for invasive cancer, 79% (95% CI 76-81) for ductal carcinoma-in-situ, 43% (95% CI 41-45) for atypia, and 77% (95% CI 74-79) for benign without atypia.Interpretive agreement between two time points by the same individual pathologist was low for atypia and was similar to observed rates of agreement for atypia between different pathologists. Physicians and patients should be aware of the diagnostic challenges associated with a breast biopsy diagnosis of atypia when considering treatment and surveillance decisions.

    View details for PubMedID 27913946

  • 'Non-classical' HER2 FISH results in breast cancer: a multi-institutional study. Modern pathology Ballard, M., Jalikis, F., Krings, G., Schmidt, R. A., Chen, Y., Rendi, M. H., Dintzis, S. M., Jensen, K. C., West, R. B., Sibley, R. K., Troxell, M. L., Allison, K. H. 2016

    Abstract

    The 2013 CAP/ASCO HER2 Testing Guidelines Update modified HER2 FISH categories such that some cases with 'monosomy', 'co-amplification/polysomy', low-level increased HER2 signals or clustered heterogeneity now are considered amplified or equivocal. This study examines the frequency and clinico-pathologic characteristics of breast cancers with equivocal or 'non-classical' HER2 FISH results. Breast cancers (2001-2014) with HER2 FISH results, HER2 immunohistochemistry, ER, grade, and age from three institutions (Stanford, UCSF, UWMC) were collected. HER2 FISH was interpreted using the updated recommendations. Amplified cases with non-classical results were grouped into the following categories: (1) 'monosomy' (ratio ≥2.0, mean HER2/cell<4.0); (2) 'co-amplified' (ratio<2.0, mean HER2/cell ≥6.0); (3) 'low amplified' (ratio ≥2.0, mean HER2/cell 4.0-5.9). Heterogeneous cases with clustered HER2-positive cells were also included. Of 8068 cases, 5.2% were equivocal and 4.6% had a 'non-classical' HER2 amplified result; 1.4% 'monosomy', 0.8% 'co-amplified', 2.1% 'low amplified', and 0.3% clustered heterogeneity. These cancers had a high frequency of ER positive (80.4%), Nottingham grade 3 (52.1%) results. The highest percentage of grade 3 cancers (66.7%) and positive HER2 immunohistochemistry (31.7%) was in the 'co-amplified' group. The 'monosomy' group had the highest percent grade 1 cancers (13.3%) and was most frequently HER2 immunohistochemistry negative (30.1%). Equivocal cases had very similar characteristics to the 'low-amplified' category. Cases with non-classical HER2 amplification or equivocal results are typically ER positive, higher grade cancers. 'Co-amplified' cases have the highest frequencies of aggressive characteristics and 'monosomy' cases the highest frequencies of lower risk features. With little clinical outcomes data currently available on these non-classical HER2 results, these results support the current classification scheme for HER2 FISH, with case-by-case correlation with additional clinical-pathologic factors when evaluating whether to offer HER2-targeted therapies in these non-classical cases.Modern Pathology advance online publication, 14 October 2016; doi:10.1038/modpathol.2016.175.

    View details for DOI 10.1038/modpathol.2016.175

    View details for PubMedID 27739440

  • Histological features associated with diagnostic agreement in atypical ductal hyperplasia of the breast: illustrative cases from the B-Path study. Histopathology Allison, K. H., Rendi, M. H., Peacock, S., Morgan, T., Elmore, J. G., Weaver, D. L. 2016

    Abstract

    This study examined the case-specific characteristics associated with interobserver diagnostic agreement in atypical ductal hyperplasia (ADH) of the breast.Seventy-two test set cases with a consensus diagnosis of ADH from the B-Path study were evaluated. Cases were scored for 17 histological features, which were then correlated with the participant agreement with the consensus ADH diagnosis. Participating pathologists' perceptions of case difficulty, borderline features or whether they would obtain a second opinion were also examined for associations with agreement. Of the 2070 participant interpretations of the 72 consensus ADH cases, 48% were scored by participants as difficult and 45% as borderline between two diagnoses; the presence of both of these features was significantly associated with increased agreement (P < 0.001). A second opinion would have been obtained in 80% of interpretations, and this was associated with increased agreement (P < 0.001). Diagnostic agreement ranged from 10% to 89% on a case-by-case basis. Cases with papillary lesions, cribriform architecture and obvious cytological monotony were associated with higher agreement. Lower agreement rates were associated with solid or micropapillary architecture, borderline cytological monotony, or cases without a diagnostic area that was obvious on low power.The results of this study suggest that pathologists frequently recognize the challenge of ADH cases, with some cases being more prone to diagnostic variability. In addition, there are specific histological features associated with diagnostic agreement on ADH cases. Multiple example images from cases in this test set are provided to serve as educational illustrations of these challenges.

    View details for DOI 10.1111/his.13035

    View details for PubMedID 27398812

    View details for PubMedCentralID PMC5115948

  • Pupil diameter changes reflect difficulty and diagnostic accuracy during medical image interpretation BMC MEDICAL INFORMATICS AND DECISION MAKING Brunye, T. T., Eddy, M. D., Mercan, E., Allison, K. H., Weaver, D. L., Elmore, J. G. 2016; 16

    Abstract

    No automated methods exist to objectively monitor and evaluate the diagnostic process while physicians review computerized medical images. The present study tested whether using eye tracking to monitor tonic and phasic pupil dynamics may prove valuable in tracking interpretive difficulty and predicting diagnostic accuracy.Pathologists interpreted digitized breast biopsies varying in diagnosis and rated difficulty, while pupil diameter was monitored. Tonic diameter was recorded during the entire duration of interpretation, and phasic diameter was examined when the eyes fixated on a pre-determined diagnostic region during inspection.Tonic pupil diameter was higher with increasing rated difficulty levels of cases. Phasic diameter was interactively influenced by case difficulty and the eventual agreement with consensus diagnosis. More difficult cases produced increases in pupil diameter, but only when the pathologists' diagnoses were ultimately correct. All results were robust after adjusting for the potential impact of screen brightness on pupil diameter.Results contribute new understandings of the diagnostic process, theoretical positions regarding locus coeruleus-norepinephrine system function, and suggest novel approaches to monitoring, evaluating, and guiding medical image interpretation.

    View details for DOI 10.1186/s12911-016-0322-3

    View details for Web of Science ID 000379208900001

    View details for PubMedID 27378371

    View details for PubMedCentralID PMC4932753

  • Identifying and processing the gap between perceived and actual agreement in breast pathology interpretation MODERN PATHOLOGY Carney, P. A., Allison, K. H., Oster, N. V., Frederick, P. D., Morgan, T. R., Geller, B. M., Weaver, D. L., Elmore, J. G. 2016; 29 (7): 717-726

    Abstract

    We examined how pathologists' process their perceptions of how their interpretations on diagnoses for breast pathology cases agree with a reference standard. To accomplish this, we created an individualized self-directed continuing medical education program that showed pathologists interpreting breast specimens how their interpretations on a test set compared with a reference diagnosis developed by a consensus panel of experienced breast pathologists. After interpreting a test set of 60 cases, 92 participating pathologists were asked to estimate how their interpretations compared with the standard for benign without atypia, atypia, ductal carcinoma in situ and invasive cancer. We then asked pathologists their thoughts about learning about differences in their perceptions compared with actual agreement. Overall, participants tended to overestimate their agreement with the reference standard, with a mean difference of 5.5% (75.9% actual agreement; 81.4% estimated agreement), especially for atypia and were least likely to overestimate it for invasive breast cancer. Non-academic affiliated pathologists were more likely to more closely estimate their performance relative to academic affiliated pathologists (77.6 vs 48%; P=0.001), whereas participants affiliated with an academic medical center were more likely to underestimate agreement with their diagnoses compared with non-academic affiliated pathologists (40 vs 6%). Before the continuing medical education program, nearly 55% (54.9%) of participants could not estimate whether they would overinterpret the cases or underinterpret them relative to the reference diagnosis. Nearly 80% (79.8%) reported learning new information from this individualized web-based continuing medical education program, and 23.9% of pathologists identified strategies they would change their practice to improve. In conclusion, when evaluating breast pathology specimens, pathologists do a good job of estimating their diagnostic agreement with a reference standard, but for atypia cases, pathologists tend to overestimate diagnostic agreement. Many participants were able to identify ways to improve.

    View details for DOI 10.1038/modpathol.2016.62

    View details for Web of Science ID 000378933500006

    View details for PubMedID 27056072

    View details for PubMedCentralID PMC4925256

  • Evaluation of 12 strategies for obtaining second opinions to improve interpretation of breast histopathology: simulation study BMJ-BRITISH MEDICAL JOURNAL Elmore, J. G., Tosteson, A. N., Pepe, M. S., Longton, G. M., Nelson, H. D., Geller, B., Carney, P. A., Onega, T., Allison, K. H., Jackson, S. L., Weaver, D. L. 2016; 353

    Abstract

     To evaluate the potential effect of second opinions on improving the accuracy of diagnostic interpretation of breast histopathology. Simulation study. 12 different strategies for acquiring independent second opinions. Interpretations of 240 breast biopsy specimens by 115 pathologists, one slide for each case, compared with reference diagnoses derived by expert consensus. Misclassification rates for individual pathologists and for 12 simulated strategies for second opinions. Simulations compared accuracy of diagnoses from single pathologists with that of diagnoses based on pairing interpretations from first and second independent pathologists, where resolution of disagreements was by an independent third pathologist. 12 strategies were evaluated in which acquisition of second opinions depended on initial diagnoses, assessment of case difficulty or borderline characteristics, pathologists' clinical volumes, or whether a second opinion was required by policy or desired by the pathologists. The 240 cases included benign without atypia (10% non-proliferative, 20% proliferative without atypia), atypia (30%), ductal carcinoma in situ (DCIS, 30%), and invasive cancer (10%). Overall misclassification rates and agreement statistics depended on the composition of the test set, which included a higher prevalence of difficult cases than in typical practice. Misclassification rates significantly decreased (P<0.001) with all second opinion strategies except for the strategy limiting second opinions only to cases of invasive cancer. The overall misclassification rate decreased from 24.7% to 18.1% when all cases received second opinions (P<0.001). Obtaining both first and second opinions from pathologists with a high volume (≥10 breast biopsy specimens weekly) resulted in the lowest misclassification rate in this test set (14.3%, 95% confidence interval 10.9% to 18.0%). Obtaining second opinions only for cases with initial interpretations of atypia, DCIS, or invasive cancer decreased the over-interpretation of benign cases without atypia from 12.9% to 6.0%. Atypia cases had the highest misclassification rate after single interpretation (52.2%), remaining at more than 34% in all second opinion scenarios. Second opinions can statistically significantly improve diagnostic agreement for pathologists' interpretations of breast biopsy specimens; however, variability in diagnosis will not be completely eliminated, especially for breast specimens with atypia.

    View details for DOI 10.1136/bmj.i3069

    View details for Web of Science ID 000378723500004

    View details for PubMedID 27334105

    View details for PubMedCentralID PMC4916777

  • Variability in Pathologists' Interpretations of Individual Breast Biopsy Slides: A Population Perspective ANNALS OF INTERNAL MEDICINE Elmore, J. G., Nelson, H. D., Pepe, M. S., Longton, G. M., Tosteson, A. N., Geller, B., Onega, T., Carney, P. A., Jackson, S. L., Allison, K. H., Weaver, D. L. 2016; 164 (10): 649-?

    Abstract

    The effect of physician diagnostic variability on accuracy at a population level depends on the prevalence of diagnoses.To estimate how diagnostic variability affects accuracy from the perspective of a U.S. woman aged 50 to 59 years having a breast biopsy.Applied probability using Bayes' theorem.B-Path (Breast Pathology) Study comparing pathologists' interpretations of a single biopsy slide versus a reference consensus interpretation from 3 experts.115 practicing pathologists (6900 total interpretations from 240 distinct cases).A single representative slide from each of the 240 cases was used to estimate the proportion of biopsies with a diagnosis that would be verified if the same slide were interpreted by a reference group of 3 expert pathologists. Probabilities of confirmation (predictive values) were estimated using B-Path Study results and prevalence of biopsy diagnoses for women aged 50 to 59 years in the Breast Cancer Surveillance Consortium.Overall, if 1 representative slide were used per case, 92.3% (95% CI, 91.4% to 93.1%) of breast biopsy diagnoses would be verified by reference consensus diagnoses, with 4.6% (CI, 3.9% to 5.3%) overinterpreted and 3.2% (CI, 2.7% to 3.6%) underinterpreted. Verification of invasive breast cancer and benign without atypia diagnoses is highly probable; estimated predictive values were 97.7% (CI, 96.5% to 98.7%) and 97.1% (CI, 96.7% to 97.4%), respectively. Verification is less probable for atypia (53.6% overinterpreted and 8.6% underinterpreted) and ductal carcinoma in situ (DCIS) (18.5% overinterpreted and 11.8% underinterpreted).Estimates are based on a testing situation with 1 slide used per case and without access to second opinions. Population-adjusted estimates may differ for women from other age groups, unscreened women, or women in different practice settings.This analysis, based on interpretation of a single breast biopsy slide per case, predicts a low likelihood that a diagnosis of atypia or DCIS would be verified by a reference consensus diagnosis. This diagnostic grey zone should be considered in clinical management decisions in patients with these diagnoses.National Cancer Institute.

    View details for DOI 10.7326/M15-0964

    View details for Web of Science ID 000375878500012

    View details for PubMedID 26999810

  • The Milky Way Sign: A New Diagnostic Finding of Ductal Carcinoma in situ on Digital Breast Tomosynthesis BREAST JOURNAL Xu, Y., Miyake, K. K., Liu, Y. I., Downey, J. R., Lipson, J. A., Allison, K. H., Ikeda, D. M. 2016; 22 (3): 349-351

    View details for DOI 10.1111/tbj.12583

    View details for PubMedID 26932582

  • The Influence of Disease Severity of Preceding Clinical Cases on Pathologists' Medical Decision Making. Medical decision making Frederick, P. D., Nelson, H. D., Carney, P. A., Brunyé, T. T., Allison, K. H., Weaver, D. L., Elmore, J. G. 2016: -?

    Abstract

    Medical decision making may be influenced by contextual factors. We evaluated whether pathologists are influenced by disease severity of recently observed cases.Pathologists independently interpreted 60 breast biopsy specimens (one slide per case; 240 total cases in the study) in a prospective randomized observational study. Pathologists interpreted the same cases in 2 phases, separated by a washout period of >6 months. Participants were not informed that the cases were identical in each phase, and the sequence was reordered randomly for each pathologist and between phases. A consensus reference diagnosis was established for each case by 3 experienced breast pathologists. Ordered logit models examined the effect the pathologists' diagnoses on the preceding case or the 5 preceding cases had on their diagnosis for the subsequent index case.Among 152 pathologists, 49 provided interpretive data in both phases I and II, 66 from only phase I, and 37 from phase II only. In phase I, pathologists were more likely to indicate a more severe diagnosis than the reference diagnosis when the preceding case was diagnosed as ductal carcinoma in situ (DCIS) or invasive cancer (proportional odds ratio [POR], 1.28; 95% confidence interval [CI], 1.15-1.42). Results were similar when considering the preceding 5 cases and for the pathologists in phase II who interpreted the same cases in a different order compared with phase I (POR, 1.17; 95% CI, 1.05-1.31).Physicians appear to be influenced by the severity of previously interpreted test cases. Understanding types and sources of diagnostic bias may lead to improved assessment of accuracy and better patient care.

    View details for PubMedID 27037007

  • Breast cancer stem cells: are we ready to go from bench to bedside? HISTOPATHOLOGY Lin, C., Barry-Holson, K. Q., Allison, K. H. 2016; 68 (1): 119-137

    Abstract

    Since the discovery of breast cancer stem cells (BCSCs) more than 10 years ago, a body of exciting research has developed. The intrinsic properties of BCSCs, including self-renewal and the ability to give rise to heterogeneous progeny, make BCSCs a likely source of tumour initiation, heterogeneity, progression and metastasis. BCSCs are also inherently resistant to conventional therapies and are therefore thought to contribute to disease recurrence. In this review, we will focus on both the challenges and recent advances in the characterization of BCSCs with respect to phenotype, molecular signature and their role in the behaviour of the different molecular subtypes of breast cancer. Of most importance is our ability to translate our growing knowledge base into the development of targeted therapies with the goal of reducing adverse outcomes in breast cancer patients.

    View details for DOI 10.1111/his.12868

    View details for Web of Science ID 000367822200011

  • Breast cancer stem cells: are we ready to go from bench to bedside? Histopathology Lin, C. Y., Barry-Holson, K. Q., Allison, K. H. 2016; 68 (1): 119–37

    Abstract

    Since the discovery of breast cancer stem cells (BCSCs) more than 10 years ago, a body of exciting research has developed. The intrinsic properties of BCSCs, including self-renewal and the ability to give rise to heterogeneous progeny, make BCSCs a likely source of tumour initiation, heterogeneity, progression and metastasis. BCSCs are also inherently resistant to conventional therapies and are therefore thought to contribute to disease recurrence. In this review, we will focus on both the challenges and recent advances in the characterization of BCSCs with respect to phenotype, molecular signature and their role in the behaviour of the different molecular subtypes of breast cancer. Of most importance is our ability to translate our growing knowledge base into the development of targeted therapies with the goal of reducing adverse outcomes in breast cancer patients.

    View details for PubMedID 26768034

  • Role of Patient and Disease Factors in Adjuvant Systemic Therapy Decision Making for Early-Stage, Operable Breast Cancer: American Society of Clinical Oncology Endorsement of Cancer Care Ontario Guideline Recommendations. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Henry, N. L., Somerfield, M. R., Abramson, V. G., Allison, K. H., Anders, C. K., Chingos, D. T., Hurria, A., Openshaw, T. H., Krop, I. E. 2016; 34 (19): 2303–11

    Abstract

    An American Society of Clinical Oncology (ASCO) panel considered the Cancer Care Ontario (CCO) recommendations on the role of patient and disease factors in selecting adjuvant therapy for women with early-stage breast cancer for endorsement.ASCO staff reviewed the CCO guideline for methodologic rigor, and an ASCO panel of content experts reviewed the content of the recommendations.For making decisions regarding adjuvant therapy, nodal status, tumor size, estrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor 2 (HER2) status, tumor grade, and lymphovascular invasion are relevant; Oncotype DX score and Adjuvant! Online may be used as risk stratification tools; and age, menopausal status, and medical comorbidities should be considered. Chemotherapy should be considered for patients with positive lymph nodes, ER-negative disease, HER2-positive disease, Adjuvant! Online mortality greater than 10%, grade 3 lymph node-negative tumors (T > 5 mm), triple-negative (ER-negative, PgR-negative, HER2-negative) tumors, lymphovascular invasion positivity, or estimated distant relapse risk of greater than 15% at 10 years based on Oncotype DX recurrence score (RS). Chemotherapy may not be beneficial or required for small node-negative tumors (T < 5 mm) without high-risk features or for patients with HER2-negative, strongly ER-positive, and PgR-positive cancer with micrometastatic nodal disease, T less than 5 mm, or Oncotype DX RS with an estimated distant relapse risk of less than 15% at 10 years.The ASCO panel endorses the recommendations with minor suggested revisions and highlights three areas that warrant further consideration: tumor histology and adjuvant therapy recommendations, risk stratification tools and proposed Oncotype DX RS thresholds to guide decisions about chemotherapy, and patient factors in decision making.

    View details for PubMedID 27001586

  • DNA defects, epigenetics, and gene expression in cancer-adjacent breast: a study from The Cancer Genome Atlas. NPJ breast cancer Troester, M. A., Hoadley, K. A., D'Arcy, M., Cherniack, A. D., Stewart, C., Koboldt, D. C., Robertson, A. G., Mahurkar, S., Shen, H., Wilkerson, M. D., Sandhu, R., Johnson, N. B., Allison, K. H., Beck, A. H., Yau, C., Bowen, J., Sheth, M., Hwang, E. S., Perou, C. M., Laird, P. W., Ding, L., Benz, C. C. 2016; 2: 16007

    Abstract

    Recurrence rates after breast-conserving therapy may depend on genomic characteristics of cancer-adjacent, benign-appearing tissue. Studies have not evaluated recurrence in association with multiple genomic characteristics of cancer-adjacent breast tissue. To estimate the prevalence of DNA defects and RNA expression subtypes in cancer-adjacent, benign-appearing breast tissue at least 2 cm from the tumor margin, cancer-adjacent, pathologically well-characterized, benign-appearing breast tissue specimens from The Cancer Genome Atlas project were analyzed for DNA sequence, copy-number variation, DNA methylation, messenger RNA (mRNA) sequence, and mRNA/microRNA expression. Additional samples were also analyzed by at least one of these genomic data types and associations between genomic characteristics of normal tissue and overall survival were assessed. Approximately 40% of cancer-adjacent, benign-appearing tissues harbored genomic defects in DNA copy number, sequence, methylation, or in RNA sequence, although these defects did not significantly predict 10-year overall survival. Two mRNA/microRNA expression phenotypes were observed, including an active mRNA subtype that was identified in 40% of samples. Controlling for tumor characteristics and the presence of genomic defects, this active subtype was associated with significantly worse 10-year survival among estrogen receptor (ER)-positive cases. This multi-platform analysis of breast cancer-adjacent samples produced genomic findings consistent with current surgical margin guidelines, and provides evidence that extratumoral RNA expression patterns in cancer-adjacent tissue predict overall survival among patients with ER-positive disease.

    View details for PubMedID 28721375

    View details for PubMedCentralID PMC5515343

  • Optimized Protocol for Quantitative Multiple Reaction Monitoring-Based Proteomic Analysis of Formalin-Fixed, Paraffin-Embedded Tissues. Journal of proteome research Kennedy, J. J., Whiteaker, J. R., Schoenherr, R. M., Yan, P., Allison, K., Shipley, M., Lerch, M., Hoofnagle, A. N., Baird, G. S., Paulovich, A. G. 2016; 15 (8): 2717–28

    Abstract

    Despite a clinical, economic, and regulatory imperative to develop companion diagnostics, precious few new biomarkers have been successfully translated into clinical use, due in part to inadequate protein assay technologies to support large-scale testing of hundreds of candidate biomarkers in formalin-fixed paraffin-embedded (FFPE) tissues. Although the feasibility of using targeted, multiple reaction monitoring mass spectrometry (MRM-MS) for quantitative analyses of FFPE tissues has been demonstrated, protocols have not been systematically optimized for robust quantification across a large number of analytes, nor has the performance of peptide immuno-MRM been evaluated. To address this gap, we used a test battery approach coupled to MRM-MS with the addition of stable isotope-labeled standard peptides (targeting 512 analytes) to quantitatively evaluate the performance of three extraction protocols in combination with three trypsin digestion protocols (i.e., nine processes). A process based on RapiGest buffer extraction and urea-based digestion was identified to enable similar quantitation results from FFPE and frozen tissues. Using the optimized protocols for MRM-based analysis of FFPE tissues, median precision was 11.4% (across 249 analytes). There was excellent correlation between measurements made on matched FFPE and frozen tissues, both for direct MRM analysis (R(2) = 0.94) and immuno-MRM (R(2) = 0.89). The optimized process enables highly reproducible, multiplex, standardizable, quantitative MRM in archival tissue specimens.

    View details for PubMedID 27462933

    View details for PubMedCentralID PMC5017241

  • Comprehensive Molecular Portraits of Invasive Lobular Breast Cancer CELL Ciriello, G., Gatza, M. L., Beck, A. H., Wilkerson, M. D., Rhie, S. K., Pastore, A., Zhang, H., McLellan, M., Yau, C., Kandoth, C., Bowlby, R., Shen, H., Hayat, S., Fieldhouse, R., Lester, S. C., Tse, G. M., Factor, R. E., Collins, L. C., Allison, K. H., Chen, Y., Jensen, K., Johnson, N. B., Oesterreich, S., Mills, G. B., Cherniack, A. D., Robertson, G., Benz, C., Sander, C., Laird, P. W., Hoadley, K. A., King, T. A., Perou, C. M. 2015; 163 (2): 506-519

    Abstract

    Invasive lobular carcinoma (ILC) is the second most prevalent histologic subtype of invasive breast cancer. Here, we comprehensively profiled 817 breast tumors, including 127 ILC, 490 ductal (IDC), and 88 mixed IDC/ILC. Besides E-cadherin loss, the best known ILC genetic hallmark, we identified mutations targeting PTEN, TBX3, and FOXA1 as ILC enriched features. PTEN loss associated with increased AKT phosphorylation, which was highest in ILC among all breast cancer subtypes. Spatially clustered FOXA1 mutations correlated with increased FOXA1 expression and activity. Conversely, GATA3 mutations and high expression characterized luminal A IDC, suggesting differential modulation of ER activity in ILC and IDC. Proliferation and immune-related signatures determined three ILC transcriptional subtypes associated with survival differences. Mixed IDC/ILC cases were molecularly classified as ILC-like and IDC-like revealing no true hybrid features. This multidimensional molecular atlas sheds new light on the genetic bases of ILC and provides potential clinical options.

    View details for DOI 10.1016/j.cell.2015.09.033

    View details for Web of Science ID 000362952700023

    View details for PubMedID 26451490

    View details for PubMedCentralID PMC4603750

  • Trends in Breast Biopsy Pathology Diagnoses Among Women Undergoing Mammography in the United States: A Report From the Breast Cancer Surveillance Consortium CANCER Allison, K. H., Abraham, L. A., Weaver, D. L., Tosteson, A. N., Nelson, H. D., Onega, T., Geller, B. M., Kerlikowske, K., Carney, P. A., Ichikawa, L. E., Buist, D. S., Elmore, J. G. 2015; 121 (9): 1369-1378

    Abstract

    Current data on the pathologic diagnoses of breast biopsy after mammography can inform patients, clinicians, and researchers about important population trends.Breast Cancer Surveillance Consortium data on 4,020,140 mammograms between 1996 and 2008 were linked to 76,567 pathology specimens. Trends in diagnoses in biopsies by time and risk factors (patient age, breast density, and family history of breast cancer) were examined for screening and diagnostic mammography (performed for a breast symptom or short-interval follow-up).Of the total mammograms, 88.5% were screening and 11.5% diagnostic; 1.2% of screening and 6.8% of diagnostic mammograms were followed by biopsies. The frequency of biopsies over time was stable after screening mammograms, but increased after diagnostic mammograms. For biopsies obtained after screening, frequencies of invasive carcinoma increased over time for women ages 40-49 and 60-69, Ductal carcinoma in situ (DCIS) increased for those ages 40-69, whereas benign diagnoses decreased for all ages. No trends in pathology diagnoses were found following diagnostic mammograms. Dense breast tissue was associated with high-risk lesions and DCIS relative to nondense breast tissue. Family history of breast cancer was associated with DCIS and invasive cancer.Although the frequency of breast biopsy after screening mammography has not changed over time, the percentages of biopsies with DCIS and invasive cancer diagnoses have increased. Among biopsies following mammography, women with dense breasts or family history of breast cancer were more likely to have high-risk lesions or invasive cancer. These findings are relevant to breast cancer screening and diagnostic practices.

    View details for DOI 10.1002/cncr.29199

    View details for Web of Science ID 000353357000006

    View details for PubMedID 25603785

    View details for PubMedCentralID PMC4419038

  • Reply to e.a. Rakha et Al. Journal of clinical oncology Wolff, A. C., Hammond, M. E., Hicks, D. G., Allison, K. H., Bartlett, J. M., Bilous, M., Fitzgibbons, P., Hanna, W., Jenkins, R. B., Mangu, P. B., Paik, S., Perez, E. A., Press, M. F., Spears, P. A., Vance, G. H., Viale, G., Dowsett, M., McShane, L. M., Hayes, D. F. 2015; 33 (11): 1302-1304

    View details for DOI 10.1200/JCO.2014.59.7559

    View details for PubMedID 25753441

  • Diagnostic Concordance Among Pathologists interpreting Breast Biopsy Specimens JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Elmore, J. G., Longton, G. M., Carney, P. A., Geller, B. M., Onega, T., Tosteson, A. N., Nelson, H. D., Pepe, M. S., Allison, K. H., Schnitt, S. J., O'Malley, F. P., Weaver, D. L. 2015; 313 (11): 1122-1132

    Abstract

    A breast pathology diagnosis provides the basis for clinical treatment and management decisions; however, its accuracy is inadequately understood.To quantify the magnitude of diagnostic disagreement among pathologists compared with a consensus panel reference diagnosis and to evaluate associated patient and pathologist characteristics.Study of pathologists who interpret breast biopsies in clinical practices in 8 US states.Participants independently interpreted slides between November 2011 and May 2014 from test sets of 60 breast biopsies (240 total cases, 1 slide per case), including 23 cases of invasive breast cancer, 73 ductal carcinoma in situ (DCIS), 72 with atypical hyperplasia (atypia), and 72 benign cases without atypia. Participants were blinded to the interpretations of other study pathologists and consensus panel members. Among the 3 consensus panel members, unanimous agreement of their independent diagnoses was 75%, and concordance with the consensus-derived reference diagnoses was 90.3%.The proportions of diagnoses overinterpreted and underinterpreted relative to the consensus-derived reference diagnoses were assessed.Sixty-five percent of invited, responding pathologists were eligible and consented to participate. Of these, 91% (N = 115) completed the study, providing 6900 individual case diagnoses. Compared with the consensus-derived reference diagnosis, the overall concordance rate of diagnostic interpretations of participating pathologists was 75.3% (95% CI, 73.4%-77.0%; 5194 of 6900 interpretations). Among invasive carcinoma cases (663 interpretations), 96% (95% CI, 94%-97%) were concordant, and 4% (95% CI, 3%-6%) were underinterpreted; among DCIS cases (2097 interpretations), 84% (95% CI, 82%-86%) were concordant, 3% (95% CI, 2%-4%) were overinterpreted, and 13% (95% CI, 12%-15%) were underinterpreted; among atypia cases (2070 interpretations), 48% (95% CI, 44%-52%) were concordant, 17% (95% CI, 15%-21%) were overinterpreted, and 35% (95% CI, 31%-39%) were underinterpreted; and among benign cases without atypia (2070 interpretations), 87% (95% CI, 85%-89%) were concordant and 13% (95% CI, 11%-15%) were overinterpreted. Disagreement with the reference diagnosis was statistically significantly higher among biopsies from women with higher (n = 122) vs lower (n = 118) breast density on prior mammograms (overall concordance rate, 73% [95% CI, 71%-75%] for higher vs 77% [95% CI, 75%-80%] for lower, P < .001), and among pathologists who interpreted lower weekly case volumes (P < .001) or worked in smaller practices (P = .034) or nonacademic settings (P = .007).In this study of pathologists, in which diagnostic interpretation was based on a single breast biopsy slide, overall agreement between the individual pathologists' interpretations and the expert consensus-derived reference diagnoses was 75.3%, with the highest level of concordance for invasive carcinoma and lower levels of concordance for DCIS and atypia. Further research is needed to understand the relationship of these findings with patient management.

    View details for DOI 10.1001/jama.2015.1405

    View details for Web of Science ID 000351102500014

    View details for PubMedID 25781441

  • Initial results with preoperative tattooing of biopsied axillary lymph nodes and correlation to sentinel lymph nodes in breast cancer patients. Annals of surgical oncology Choy, N., Lipson, J., Porter, C., Ozawa, M., Kieryn, A., Pal, S., Kao, J., Trinh, L., Wheeler, A., Ikeda, D., Jensen, K., Allison, K., Wapnir, I. 2015; 22 (2): 377-382

    Abstract

    Pretreatment evaluation of axillary lymph nodes (ALNs) and marking of biopsied nodes in patients with newly diagnosed breast cancer is becoming routine practice. We sought to test tattooing of biopsied ALNs with a sterile black carbon suspension (Spot™). The intraoperative success of identifying tattooed ALNs and their concordance to sentinel nodes was determined.Women with suspicious ALNs and newly diagnosed breast cancer underwent palpation and/or ultrasound-guided fine needle aspiration or core needle biopsy, followed by injection of 0.1 to 0.5 ml of Spot™ ink into the cortex of ALNs and adjacent soft tissue. Group I underwent surgery first, and group II underwent neoadjuvant therapy followed by surgery. Identification of black pigment and concordance between sentinel and tattooed nodes was evaluated.Twenty-eight patients were tattooed, 16 in group I and 12 in group II. Seventeen cases had evidence of atypia or metastases, 8 (50 %) in group I and 9 (75 %) in group II. Average number of days from tattooing to surgery was 22.9 (group I) and 130 (group II). Black tattoo ink was visualized intraoperatively in all cases, except one case with microscopic black pigment only. Fourteen group I and 10 group II patients had black pigment on histological examination of ALNs. Sentinel nodes corresponded to tattooed nodes in all except one group I patient with a tattooed non-sentinel node.Tattooed nodes are visible intraoperatively, even months later. This approach obviates the need for additional localization procedures during axillary staging.

    View details for DOI 10.1245/s10434-014-4034-6

    View details for PubMedID 25164040

  • The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014 ANNALS OF ONCOLOGY Salgado, R., Denkert, C., Demaria, S., Sirtaine, N., Klauschen, F., Pruneri, G., Wienert, S., Van den Eynden, G., Baehner, F. L., Penault-Llorca, F., Perez, E. A., Thompson, E. A., Symmans, W. F., Richardson, A. L., Brock, J., Criscitiello, C., Bailey, H., Ignatiadis, M., Floris, G., Sparano, J., KOS, Z., Nielsen, T., Rimm, D. L., Allison, K. H., Reis-Filho, J. S., Loibl, S., Sotiriou, C., Viale, G., Badve, S., Adams, S., Willard-Gallo, K., Loi, S. 2015; 26 (2): 259-271

    Abstract

    The morphological evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer (BC) is gaining momentum as evidence strengthens for the clinical relevance of this immunological biomarker. Accumulating evidence suggests that the extent of lymphocytic infiltration in tumor tissue can be assessed as a major parameter by evaluation of hematoxylin and eosin (H&E)-stained tumor sections. TILs have been shown to provide prognostic and potentially predictive value, particularly in triple-negative and human epidermal growth factor receptor 2-overexpressing BC.A standardized methodology for evaluating TILs is now needed as a prerequisite for integrating this parameter in standard histopathological practice, in a research setting as well as in clinical trials. This article reviews current data on the clinical validity and utility of TILs in BC in an effort to foster better knowledge and insight in this rapidly evolving field, and to develop a standardized methodology for visual assessment on H&E sections, acknowledging the future potential of molecular/multiplexed approaches.The methodology provided is sufficiently detailed to offer a uniformly applied, pragmatic starting point and improve consistency and reproducibility in the measurement of TILs for future studies.

    View details for DOI 10.1093/annonc/mdu450

    View details for Web of Science ID 000349609600003

    View details for PubMedID 25214542

  • Impact of histological subtype on long-term outcomes of neuroendocrine carcinoma of the breast BREAST CANCER RESEARCH AND TREATMENT Cloyd, J. M., Yang, R. L., Allison, K. H., Norton, J. A., Hernandez-Boussard, T., Wapnir, I. L. 2014; 148 (3): 637-644

    Abstract

    Although rare, neuroendocrine carcinoma of the breast (NECB) is becoming an increasingly recognized entity. The current literature is limited to case reports and small series and therefore a comprehensive population-based analysis was conducted to investigate the clinicopathologic features and long-term outcomes associated with NECB. We included all patients in the SEER Database from 2003 to 2010 with a diagnosis of NECB. The 2012 WHO classification system was used to categorize patients based on histopathologic diagnosis: well-differentiated neuroendocrine tumors, small/oat cell or poorly differentiated neuroendocrine tumors, adenocarcinoma with neuroendocrine features (ANF), large cell neuroendocrine and carcinoid tumors. Survival analysis was performed for disease specific (DSS) and overall (OS) survival. Of the 284 cases identified, 52.1% were classified as well-differentiated, 25.7% small cell, 14.8% ANF, 4.9% large cell, and 2.5% carcinoid. In general, patients presented with advanced disease: 36.2% had positive lymph node metastases and 20.4% presented with systemic metastases. Five-year DSS rates for stage I-IV NECB were 88.1, 67.8, 60.5, and 12.4%, respectively, while five-year OS rates were 77.9, 57.3, 52.9, and 8.9%, respectively. DSS and OS were significantly different for well-differentiated neuroendocrine tumors and ANFs compared to small cell and carcinoid tumors. On univariate Cox proportional hazards regression, small cell carcinoma was significantly associated with worse DSS (OR 1.97, 95% CI 1.05-3.67) and OS (OR 2.66, 95% CI 1.49-4.72) compared to other neuroendocrine tumors. NECB is associated with advanced stage disease at presentation and an unfavorable prognosis for stage II-IV disease and small cell, large cell, and carcinoid histologic subtypes.

    View details for DOI 10.1007/s10549-014-3207-0

    View details for Web of Science ID 000345370600018

  • Impact of histological subtype on long-term outcomes of neuroendocrine carcinoma of the breast. Breast cancer research and treatment Cloyd, J. M., Yang, R. L., Allison, K. H., Norton, J. A., Hernandez-Boussard, T., Wapnir, I. L. 2014; 148 (3): 637-644

    Abstract

    Although rare, neuroendocrine carcinoma of the breast (NECB) is becoming an increasingly recognized entity. The current literature is limited to case reports and small series and therefore a comprehensive population-based analysis was conducted to investigate the clinicopathologic features and long-term outcomes associated with NECB. We included all patients in the SEER Database from 2003 to 2010 with a diagnosis of NECB. The 2012 WHO classification system was used to categorize patients based on histopathologic diagnosis: well-differentiated neuroendocrine tumors, small/oat cell or poorly differentiated neuroendocrine tumors, adenocarcinoma with neuroendocrine features (ANF), large cell neuroendocrine and carcinoid tumors. Survival analysis was performed for disease specific (DSS) and overall (OS) survival. Of the 284 cases identified, 52.1% were classified as well-differentiated, 25.7% small cell, 14.8% ANF, 4.9% large cell, and 2.5% carcinoid. In general, patients presented with advanced disease: 36.2% had positive lymph node metastases and 20.4% presented with systemic metastases. Five-year DSS rates for stage I-IV NECB were 88.1, 67.8, 60.5, and 12.4%, respectively, while five-year OS rates were 77.9, 57.3, 52.9, and 8.9%, respectively. DSS and OS were significantly different for well-differentiated neuroendocrine tumors and ANFs compared to small cell and carcinoid tumors. On univariate Cox proportional hazards regression, small cell carcinoma was significantly associated with worse DSS (OR 1.97, 95% CI 1.05-3.67) and OS (OR 2.66, 95% CI 1.49-4.72) compared to other neuroendocrine tumors. NECB is associated with advanced stage disease at presentation and an unfavorable prognosis for stage II-IV disease and small cell, large cell, and carcinoid histologic subtypes.

    View details for DOI 10.1007/s10549-014-3207-0

    View details for PubMedID 25399232

  • Risk of Secondary Malignancy (Including Breast) in Patients With Mismatch-repair Protein Deficiency AMERICAN JOURNAL OF SURGICAL PATHOLOGY Clay, M. R., Allison, K. H., Folkins, A. K., Longacre, T. A. 2014; 38 (11): 1494-1500

    Abstract

    Lynch syndrome (LS) is an autosomal dominant inherited disease that is associated with an increased risk for colorectal and endometrial cancer due to germline mutations in mismatch-repair (MMR) genes. Whereas primary tumors in this syndrome are widely recognized, the relative risk(s) of secondary malignancies, particularly breast cancer, in LS patients are still poorly characterized. To provide an improved assessment of these risks, MMR status was evaluated in secondary tumors from a series of patients with index tumors of known MMR status (both proficient and deficient). A total of 1252 tumors (index tumors) and all secondary malignancies were tested for MMR by immunohistochemistry (MSH2, MSH6, MLH1, PMS2) between 1992 and 2013. Tumors with MLH1/PMS2 deficiency were tested for hypermethylation or BRAF mutation, when appropriate. Of the 1252 index tumors, 162 were MMR deficient (dMMR), and, of that subset, 32 secondary tumors were identified (19.7%). In contrast, 80 secondary tumors were identified in the proficient (intact) group (7.3%). Although secondary malignancies were more common in the dMMR group (P=0.0001), there was no trend in tumor type. Specifically, breast cancer was not overly represented in the dMMR group. When secondary tumors had dMMR, they were more likely to have deficiency in MSH2/MSH6 than in MLH1/PMS2 (P=0.01). Of the patients with tumors exhibiting dMMR, women were more likely to have a dMMR secondary tumor in this series (P=0.0001); however, breast cancer was not overly represented, and our study provides no evidence that it is more frequent in LS. MSH2/MSH6 deficiency is more commonly associated with a secondary tumor compared with MLH1/PMS2 deficiency, when methylation/BRAF status is taken into account.

    View details for Web of Science ID 000343880200005

  • Risk of secondary malignancy (including breast) in patients with mismatch-repair protein deficiency. American journal of surgical pathology Clay, M. R., Allison, K. H., Folkins, A. K., Longacre, T. A. 2014; 38 (11): 1494-1500

    Abstract

    Lynch syndrome (LS) is an autosomal dominant inherited disease that is associated with an increased risk for colorectal and endometrial cancer due to germline mutations in mismatch-repair (MMR) genes. Whereas primary tumors in this syndrome are widely recognized, the relative risk(s) of secondary malignancies, particularly breast cancer, in LS patients are still poorly characterized. To provide an improved assessment of these risks, MMR status was evaluated in secondary tumors from a series of patients with index tumors of known MMR status (both proficient and deficient). A total of 1252 tumors (index tumors) and all secondary malignancies were tested for MMR by immunohistochemistry (MSH2, MSH6, MLH1, PMS2) between 1992 and 2013. Tumors with MLH1/PMS2 deficiency were tested for hypermethylation or BRAF mutation, when appropriate. Of the 1252 index tumors, 162 were MMR deficient (dMMR), and, of that subset, 32 secondary tumors were identified (19.7%). In contrast, 80 secondary tumors were identified in the proficient (intact) group (7.3%). Although secondary malignancies were more common in the dMMR group (P=0.0001), there was no trend in tumor type. Specifically, breast cancer was not overly represented in the dMMR group. When secondary tumors had dMMR, they were more likely to have deficiency in MSH2/MSH6 than in MLH1/PMS2 (P=0.01). Of the patients with tumors exhibiting dMMR, women were more likely to have a dMMR secondary tumor in this series (P=0.0001); however, breast cancer was not overly represented, and our study provides no evidence that it is more frequent in LS. MSH2/MSH6 deficiency is more commonly associated with a secondary tumor compared with MLH1/PMS2 deficiency, when methylation/BRAF status is taken into account.

    View details for DOI 10.1097/PAS.0000000000000259

    View details for PubMedID 24921635

  • Second opinion in breast pathology: policy, practice and perception. Journal of clinical pathology Geller, B. M., Nelson, H. D., Carney, P. A., Weaver, D. L., Onega, T., Allison, K. H., Frederick, P. D., Tosteson, A. N., Elmore, J. G. 2014; 67 (11): 955-960

    Abstract

    To assess the laboratory policies, pathologists' clinical practice and perceptions about the value of second opinions for breast pathology cases among pathologists practising in the USA.Cross-sectional data were collected from 252 pathologists who interpret breast specimens in eight states using a web-based survey. Descriptive statistics were used to characterise findings.Most participants had >10 years of experience interpreting breast specimens (64%), were not affiliated with academic centres (73%) and were not considered experts by their peers (79%). Laboratory policies mandating second opinions varied by diagnosis: invasive cancer 65%; ductal carcinoma in situ (DCIS) 56%; atypical ductal hyperplasia 36% and other benign cases 33%. 81% obtained second opinions in the absence of policies. Participants believed they improve diagnostic accuracy (96%) and protect from malpractice suits (83%), and were easy to obtain, did not take too much time and did not make them look less adequate. The most common (60%) approach to resolving differences between the first and second opinion is to ask for a third opinion, followed by reaching a consensus.Laboratory-based second opinion policies vary for breast pathology but are most common for invasive cancer and DCIS cases. Pathologists have favourable attitudes towards second opinions, adhere to policies and obtain them even when policies are absent. Those without a formal policy may benefit from supportive clinical practices and systems that help obtain second opinions.

    View details for DOI 10.1136/jclinpath-2014-202290

    View details for PubMedID 25053542

    View details for PubMedCentralID PMC4521120

  • Second opinion in breast pathology: policy, practice and perception JOURNAL OF CLINICAL PATHOLOGY Geller, B. M., Nelson, H. D., Carney, P. A., Weaver, D. L., Onega, T., Allison, K. H., Frederick, P. D., Tosteson, A. N., Elmore, J. G. 2014; 67 (11): 955-960

    View details for DOI 10.1136/jclinpath-2014-202290

    View details for Web of Science ID 000344067700005

  • Digitized Whole Slides for Breast Pathology Interpretation: Current Practices and Perceptions JOURNAL OF DIGITAL IMAGING Onega, T., Weaver, D., Geller, B., Oster, N., Tosteson, A. N., Carney, P. A., Nelson, H., Allison, K. H., O'Malley, F. P., Schnitt, S. J., Elmore, J. G. 2014; 27 (5): 642-648

    View details for DOI 10.1007/s10278-014-9683-2

    View details for Web of Science ID 000342432200011

  • Extracellular matrix stiffness and composition jointly regulate the induction of malignant phenotypes in mammary epithelium. Nature materials Chaudhuri, O., Koshy, S. T., Branco da Cunha, C., Shin, J., Verbeke, C. S., Allison, K. H., Mooney, D. J. 2014; 13 (10): 970-978

    Abstract

    In vitro models of normal mammary epithelium have correlated increased extracellular matrix (ECM) stiffness with malignant phenotypes. However, the role of increased stiffness in this transformation remains unclear because of difficulties in controlling ECM stiffness, composition and architecture independently. Here we demonstrate that interpenetrating networks of reconstituted basement membrane matrix and alginate can be used to modulate ECM stiffness independently of composition and architecture. We find that, in normal mammary epithelial cells, increasing ECM stiffness alone induces malignant phenotypes but that the effect is completely abrogated when accompanied by an increase in basement-membrane ligands. We also find that the combination of stiffness and composition is sensed through β4 integrin, Rac1, and the PI3K pathway, and suggest a mechanism in which an increase in ECM stiffness, without an increase in basement membrane ligands, prevents normal α6β4 integrin clustering into hemidesmosomes.

    View details for DOI 10.1038/nmat4009

    View details for PubMedID 24930031

  • Digitized whole slides for breast pathology interpretation: current practices and perceptions. Journal of digital imaging Onega, T., Weaver, D., Geller, B., Oster, N., Tosteson, A. N., Carney, P. A., Nelson, H., Allison, K. H., O'Malley, F. P., Schnitt, S. J., Elmore, J. G. 2014; 27 (5): 642-648

    Abstract

    Digital whole slide imaging (WSI) is an emerging technology for pathology interpretation; however, little is known about pathologists' practice patterns or perceptions regarding WSI. A national sample (N = 252) of pathologists from New Hampshire, Vermont, Washington, Oregon, Arizona, Alaska, Maine, and Minnesota were surveyed in this cross-sectional study (2011-2013). The survey included questions on pathologists' experience, WSI practice patterns, and perceptions using a six-point Likert scale. Agreement was summarized with descriptive statistics to characterize pathologists' use and perceptions of WSI. The majority of participating pathologists were males (63%) between 40 and 59 years of age (70%) and not affiliated with an academic medical center (72%). Experience with WSI was reported by 49%. Types of use reported included CME/board exams/teaching (28%), tumor board/clinical conference (22%), archival purposes (6%), consultative diagnosis (4%), research (4%), and other uses (12%). Most respondents (79%) agreed that accurate diagnoses can be made with this technology, and that WSI is useful for obtaining a second opinion (88%). However, 78% of pathologists agreed that digital slides are too slow for routine clinical interpretation. Fifty-nine percent agreed that the benefits of WSI outweigh concerns. The respondents were equally split as to whether they would like to adopt WSI (51%) or not (49%). About half of pathologists reported experience with the WSI technology, largely for CME, licensure/board exams, and teaching. Positive perceptions regarding WSI slightly outweigh negative perceptions. Understanding practice patterns with WSI as dissemination advances may facilitate concordance of perceptions with adoption of the technology.

    View details for DOI 10.1007/s10278-014-9683-2

    View details for PubMedID 24682769

  • Extracellular matrix stiffness and composition jointly regulate the induction of malignant phenotypes in mammary epithelium NATURE MATERIALS Chaudhuri, O., Koshy, S. T., da Cunha, C. B., Shin, J., Verbeke, C. S., Allison, K. H., Mooney, D. J. 2014; 13 (10): 970-978

    View details for DOI 10.1038/NMAT4009

    View details for Web of Science ID 000342743100018

  • Heterogeneity and Cancer ONCOLOGY-NEW YORK Allison, K. H., Sledge, G. W. 2014; 28 (9): 772-778

    Abstract

    Cancer heterogeneity, long recognized as an important clinical determinant of patient outcomes, was poorly understood at a molecular level. Genomic studies have significantly improved our understanding of heterogeneity, and have pointed to ways in which heterogeneity might be understood and defeated for therapeutic effect. Recent studies have evaluated intratumoral heterogeneity within the primary tumor, as well as heterogeneity observed between primary and metastasis. The existence of clonal heterogeneity in the primary and metastasis also affects response to therapy, since the Darwinian pressures of systemic therapy result in clonal selection for initially rare variants. Novel technologies (such as measurements of circulating tumor cells and circulating tumor DNA) may allow physicians to monitor the emergence of clonal subtypes and intervene at an early point to improve patient prognosis.

    View details for Web of Science ID 000342553000006

  • Heterogeneity and cancer. Oncology (Williston Park, N.Y.) Allison, K. H., Sledge, G. W. 2014; 28 (9): 772-778

    Abstract

    Cancer heterogeneity, long recognized as an important clinical determinant of patient outcomes, was poorly understood at a molecular level. Genomic studies have significantly improved our understanding of heterogeneity, and have pointed to ways in which heterogeneity might be understood and defeated for therapeutic effect. Recent studies have evaluated intratumoral heterogeneity within the primary tumor, as well as heterogeneity observed between primary and metastasis. The existence of clonal heterogeneity in the primary and metastasis also affects response to therapy, since the Darwinian pressures of systemic therapy result in clonal selection for initially rare variants. Novel technologies (such as measurements of circulating tumor cells and circulating tumor DNA) may allow physicians to monitor the emergence of clonal subtypes and intervene at an early point to improve patient prognosis.

    View details for PubMedID 25224475

  • Eye Movements as an Index of Pathologist Visual Expertise: A Pilot Study PLOS ONE Brunye, T. T., Carney, P. A., Allison, K. H., Shapiro, L. G., Weaver, D. L., Elmore, J. G. 2014; 9 (8)

    Abstract

    A pilot study examined the extent to which eye movements occurring during interpretation of digitized breast biopsy whole slide images (WSI) can distinguish novice interpreters from experts, informing assessments of competency progression during training and across the physician-learning continuum. A pathologist with fellowship training in breast pathology interpreted digital WSI of breast tissue and marked the region of highest diagnostic relevance (dROI). These same images were then evaluated using computer vision techniques to identify visually salient regions of interest (vROI) without diagnostic relevance. A non-invasive eye tracking system recorded pathologists' (N = 7) visual behavior during image interpretation, and we measured differential viewing of vROIs versus dROIs according to their level of expertise. Pathologists with relatively low expertise in interpreting breast pathology were more likely to fixate on, and subsequently return to, diagnostically irrelevant vROIs relative to experts. Repeatedly fixating on the distracting vROI showed limited value in predicting diagnostic failure. These preliminary results suggest that eye movements occurring during digital slide interpretation can characterize expertise development by demonstrating differential attraction to diagnostically relevant versus visually distracting image regions. These results carry both theoretical implications and potential for monitoring and evaluating student progress and providing automated feedback and scanning guidance in educational settings.

    View details for DOI 10.1371/journal.pone.0103447

    View details for PubMedID 25084012

  • Understanding diagnostic variability in breast pathology: lessons learned from an expert consensus review panel HISTOPATHOLOGY Allison, K. H., Reisch, L. M., Carney, P. A., Weaver, D. L., Schnitt, S. J., O'Malley, F. P., Geller, B. M., Elmore, J. G. 2014; 65 (2): 240-251

    Abstract

    To gain a better understanding of the reasons for diagnostic variability, with the aim of reducing the phenomenon.In preparation for a study on the interpretation of breast specimens (B-PATH), a panel of three experienced breast pathologists reviewed 336 cases to develop consensus reference diagnoses. After independent assessment, cases coded as diagnostically discordant were discussed at consensus meetings. By the use of qualitative data analysis techniques, transcripts of 16 h of consensus meetings for a subset of 201 cases were analysed. Diagnostic variability could be attributed to three overall root causes: (i) pathologist-related; (ii) diagnostic coding/study methodology-related; and (iii) specimen-related. Most pathologist-related root causes were attributable to professional differences in pathologists' opinions about whether the diagnostic criteria for a specific diagnosis were met, most frequently in cases of atypia. Diagnostic coding/study methodology-related root causes were primarily miscategorizations of descriptive text diagnoses, which led to the development of a standardized electronic diagnostic form (BPATH-Dx). Specimen-related root causes included artefacts, limited diagnostic material, and poor slide quality. After re-review and discussion, a consensus diagnosis could be assigned in all cases.Diagnostic variability is related to multiple factors, but consensus conferences, standardized electronic reporting formats and comments on suboptimal specimen quality can be used to reduce diagnostic variability.

    View details for DOI 10.1111/his.12387

    View details for Web of Science ID 000340662300010

    View details for PubMedID 24511905

  • A framework for evaluating diagnostic discordance in pathology discovered during research studies. Archives of pathology & laboratory medicine Feng, S., Weaver, D. L., Carney, P. A., M Reisch, L., M Geller, B., Goodwin, A., Rendi, M. H., Onega, T., Allison, K. H., Tosteson, A. N., Nelson, H. D., Longton, G., Pepe, M., Elmore, J. G. 2014; 138 (7): 955-961

    Abstract

    Little is known about the frequency of discordant diagnoses identified during research.To describe diagnostic discordance identified during research and apply a newly designed research framework for investigating discordance.Breast biopsy cases (N = 407) from registries in Vermont and New Hampshire were independently reviewed by a breast pathology expert. The following research framework was developed to assess those cases: (1) compare the expert review and study database diagnoses, (2) determine the clinical significance of diagnostic discordance, (3) identify and correct data errors and verify the existence of true diagnostic discrepancies, (4) consider the impact of borderline cases, and (5) determine the notification approach for verified disagreements.Initial overall discordance between the original diagnosis recorded in our research database and a breast pathology expert was 32.2% (131 of 407). This was reduced to less than 10% after following the 5-step research framework. Detailed review identified 12 cases (2.9%) with data errors (2 in the underlying pathology registry, 3 with incomplete slides sent for expert review, and 7 with data abstraction errors). After excluding the cases with data errors, 38 cases (9.6%) among the remaining 395 had clinically meaningful discordant diagnoses (κ = 0.82; SE, 0.04; 95% confidence interval, 0.76-0.87). Among these 38 cases, 20 (53%) were considered borderline between 2 diagnoses by either the original pathologist or the expert. We elected to notify the pathology registries and facilities regarding discordant diagnoses.Understanding the types and sources of diagnostic discordance uncovered in research studies may lead to improved scientific data and better patient care.

    View details for DOI 10.5858/arpa.2013-0263-OA

    View details for PubMedID 24978923

  • Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: american society of clinical oncology/college of american pathologists clinical practice guideline update. Archives of pathology & laboratory medicine Wolff, A. C., Hammond, M. E., Hicks, D. G., Dowsett, M., McShane, L. M., Allison, K. H., Allred, D. C., Bartlett, J. M., Bilous, M., Fitzgibbons, P., Hanna, W., Jenkins, R. B., Mangu, P. B., Paik, S., Perez, E. A., Press, M. F., Spears, P. A., Vance, G. H., Viale, G., Hayes, D. F. 2014; 138 (2): 241-256

    Abstract

    Purpose.-To update the American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guideline recommendations for human epidermal growth factor receptor 2 (HER2) testing in breast cancer to improve the accuracy of HER2 testing and its utility as a predictive marker in invasive breast cancer. Methods.-ASCO/CAP convened an Update Committee that included coauthors of the 2007 guideline to conduct a systematic literature review and update recommendations for optimal HER2 testing. Results.-The Update Committee identified criteria and areas requiring clarification to improve the accuracy of HER2 testing by immunohistochemistry (IHC) or in situ hybridization (ISH). The guideline was reviewed and approved by both organizations. Recommendations.-The Update Committee recommends that HER2 status (HER2 negative or positive) be determined in all patients with invasive (early stage or recurrence) breast cancer on the basis of one or more HER2 test results (negative, equivocal, or positive). Testing criteria define HER2-positive status when (on observing within an area of tumor that amounts to >10% of contiguous and homogeneous tumor cells) there is evidence of protein overexpression (IHC) or gene amplification (HER2 copy number or HER2/CEP17 ratio by ISH based on counting at least 20 cells within the area). If results are equivocal (revised criteria), reflex testing should be performed using an alternative assay (IHC or ISH). Repeat testing should be considered if results seem discordant with other histopathologic findings. Laboratories should demonstrate high concordance with a validated HER2 test on a sufficiently large and representative set of specimens. Testing must be performed in a laboratory accredited by CAP or another accrediting entity. The Update Committee urges providers and health systems to cooperate to ensure the highest quality testing.

    View details for DOI 10.5858/arpa.2013-0953-SA

    View details for PubMedID 24099077

  • Preoperative MRI Improves Prediction of Extensive Occult Axillary Lymph Node Metastases in Breast Cancer Patients with a Positive Sentinel Lymph Node Biopsy ACADEMIC RADIOLOGY Loiselle, C., Eby, P. R., Kim, J. N., Calhoun, K. E., Allison, K. H., Gadi, V. K., Peacock, S., Storer, B. E., Mankoff, D. A., Partridge, S. C., Lehman, C. D. 2014; 21 (1): 92-98

    Abstract

    To test the ability of quantitative measures from preoperative dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to predict, independently and/or with the Katz pathologic nomogram, which breast cancer patients with a positive sentinel lymph node biopsy will have four or more positive axillary lymph nodes on completion axillary dissection.A retrospective review was conducted to identify clinically node-negative invasive breast cancer patients who underwent preoperative DCE-MRI, followed by sentinel node biopsy with positive findings and complete axillary dissection (June 2005-January 2010). Clinical/pathologic factors, primary lesion size, and quantitative DCE-MRI kinetics were collected from clinical records and prospective databases. DCE-MRI parameters with univariate significance (P < .05) to predict four or more positive axillary nodes were modeled with stepwise regression and compared to the Katz nomogram alone and to a combined MRI-Katz nomogram model.Ninety-eight patients with 99 positive sentinel biopsies met study criteria. Stepwise regression identified DCE-MRI total persistent enhancement and volume adjusted peak enhancement as significant predictors of four or more metastatic nodes. Receiver operating characteristic curves demonstrated an area under the curve of 0.78 for the Katz nomogram, 0.79 for the DCE-MRI multivariate model, and 0.87 for the combined MRI-Katz model. The combined model was significantly more predictive than the Katz nomogram alone (P = .003).Integration of DCE-MRI primary lesion kinetics significantly improved the Katz pathologic nomogram accuracy to predict the presence of metastases in four or more nodes. DCE-MRI may help identify sentinel node-positive patients requiring further local-regional therapy.

    View details for DOI 10.1016/j.acra.2013.10.001

    View details for Web of Science ID 000329018900013

    View details for PubMedID 24331270

  • Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. Journal of clinical oncology Wolff, A. C., Hammond, M. E., Hicks, D. G., Dowsett, M., McShane, L. M., Allison, K. H., Allred, D. C., Bartlett, J. M., Bilous, M., Fitzgibbons, P., Hanna, W., Jenkins, R. B., Mangu, P. B., Paik, S., Perez, E. A., Press, M. F., Spears, P. A., Vance, G. H., Viale, G., Hayes, D. F. 2013; 31 (31): 3997-4013

    Abstract

    To update the American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guideline recommendations for human epidermal growth factor receptor 2 (HER2) testing in breast cancer to improve the accuracy of HER2 testing and its utility as a predictive marker in invasive breast cancer.ASCO/CAP convened an Update Committee that included coauthors of the 2007 guideline to conduct a systematic literature review and update recommendations for optimal HER2 testing.The Update Committee identified criteria and areas requiring clarification to improve the accuracy of HER2 testing by immunohistochemistry (IHC) or in situ hybridization (ISH). The guideline was reviewed and approved by both organizations.The Update Committee recommends that HER2 status (HER2 negative or positive) be determined in all patients with invasive (early stage or recurrence) breast cancer on the basis of one or more HER2 test results (negative, equivocal, or positive). Testing criteria define HER2-positive status when (on observing within an area of tumor that amounts to > 10% of contiguous and homogeneous tumor cells) there is evidence of protein overexpression (IHC) or gene amplification (HER2 copy number or HER2/CEP17 ratio by ISH based on counting at least 20 cells within the area). If results are equivocal (revised criteria), reflex testing should be performed using an alternative assay (IHC or ISH). Repeat testing should be considered if results seem discordant with other histopathologic findings. Laboratories should demonstrate high concordance with a validated HER2 test on a sufficiently large and representative set of specimens. Testing must be performed in a laboratory accredited by CAP or another accrediting entity. The Update Committee urges providers and health systems to cooperate to ensure the highest quality testing. This guideline was developed through a collaboration between the American Society of Clinical Oncology and the College of American Pathologists and has been published jointly by invitation and consent in both Journal of Clinical Oncology and the Archives of Pathology & Laboratory Medicine. Copyright © 2013 American Society of Clinical Oncology and College of American Pathologists. All rights reserved. No part of this document may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without written permission by American Society of Clinical Oncology or College of American Pathologists.

    View details for DOI 10.1200/JCO.2013.50.9984

    View details for PubMedID 24101045

  • Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: american society of clinical oncology/college of american pathologists clinical practice guideline update. Journal of clinical oncology Wolff, A. C., Hammond, M. E., Hicks, D. G., Dowsett, M., McShane, L. M., Allison, K. H., Allred, D. C., Bartlett, J. M., Bilous, M., Fitzgibbons, P., Hanna, W., Jenkins, R. B., Mangu, P. B., Paik, S., Perez, E. A., Press, M. F., Spears, P. A., Vance, G. H., Viale, G., Hayes, D. F. 2013; 31 (31): 3997-4013

    View details for DOI 10.1200/JCO.2013.50.9984

    View details for PubMedID 24101045

  • Development of a diagnostic test set to assess agreement in breast pathology: practical application of the Guidelines for Reporting Reliability and Agreement Studies (GRRAS) BMC WOMENS HEALTH Oster, N. V., Carney, P. A., Allison, K. H., Weaver, D. L., Reisch, L. M., Longton, G., Onega, T., Pepe, M., Geller, B. M., Nelson, H. D., Ross, T. R., Tosteson, A. N., Elmore, J. G. 2013; 13

    Abstract

    Diagnostic test sets are a valuable research tool that contributes importantly to the validity and reliability of studies that assess agreement in breast pathology. In order to fully understand the strengths and weaknesses of any agreement and reliability study, however, the methods should be fully reported. In this paper we provide a step-by-step description of the methods used to create four complex test sets for a study of diagnostic agreement among pathologists interpreting breast biopsy specimens. We use the newly developed Guidelines for Reporting Reliability and Agreement Studies (GRRAS) as a basis to report these methods.Breast tissue biopsies were selected from the National Cancer Institute-funded Breast Cancer Surveillance Consortium sites. We used a random sampling stratified according to woman's age (40-49 vs. ≥50), parenchymal breast density (low vs. high) and interpretation of the original pathologist. A 3-member panel of expert breast pathologists first independently interpreted each case using five primary diagnostic categories (non-proliferative changes, proliferative changes without atypia, atypical ductal hyperplasia, ductal carcinoma in situ, and invasive carcinoma). When the experts did not unanimously agree on a case diagnosis a modified Delphi method was used to determine the reference standard consensus diagnosis. The final test cases were stratified and randomly assigned into one of four unique test sets.We found GRRAS recommendations to be very useful in reporting diagnostic test set development and recommend inclusion of two additional criteria: 1) characterizing the study population and 2) describing the methods for reference diagnosis, when applicable.

    View details for DOI 10.1186/1472-6874-13-3

    View details for Web of Science ID 000316730400001

    View details for PubMedID 23379630

  • Nonmalignant Breast Lesions: ADCs of Benign and High-Risk Subtypes Assessed as False-Positive at Dynamic Enhanced MR Imaging RADIOLOGY Parsian, S., Rahbar, H., Allison, K. H., DeMartini, W. B., Olson, M. L., Lehman, C. D., Partridge, S. C. 2012; 265 (3): 696-706

    Abstract

    To evaluate the diffusion-weighted (DW) imaging characteristics of nonmalignant lesion subtypes assessed as false-positive findings at conventional breast magnetic resonance (MR) imaging.This HIPAA-compliant retrospective study had institutional review board approval, and the need for informed patient consent was waived. Lesions assessed as Breast Imaging Reporting and Data System category 4 or 5 at clinical dynamic contrast material-enhanced MR imaging that subsequently proved nonmalignant at biopsy were retrospectively reviewed. One hundred seventy-five nonmalignant breast lesions in 165 women were evaluated. Apparent diffusion coefficients (ADCs) from DW imaging (b = 0, 600 sec/mm(2)) were calculated for each lesion and were compared between subtypes and with an ADC threshold of 1.81 × 10(-3) mm(2)/sec (determined in a prior study to achieve 100% sensitivity).Eighty-one (46%) lesions exhibited ADCs greater than the predetermined threshold. The most prevalent lesion subtypes with mean ADCs above the threshold were fibroadenoma ([1.94 ± 0.38 {standard deviation}] × 10(-3) mm(2)/sec; n = 30), focal fibrosis ([1.84 ± 0.48] × 10(-3) mm(2)/sec; n = 19), normal tissue ([1.81 ± 0.47] × 10(-3) mm(2)/sec; n = 13), apocrine metaplasia ([2.01 ± 0.38] × 10(-3) mm(2)/sec; n = 13), usual ductal hyperplasia ([1.83 ± 0.49] × 10(-3) mm(2)/sec; n = 12), and inflammation ([1.95 ± 0.46] × 10(-3) mm(2)/sec; n = 10). Atypical ductal hyperplasia ([1.48 ± 0.36] × 10(-3) mm(2)/sec; n = 23) was the most common lesion subtype with ADC below the threshold. Lymph nodes exhibited the lowest mean ADC of all nonmalignant lesions ([1.28 ± 0.23] × 10(-3) mm(2)/sec; n = 4). High-risk lesions (atypical ductal hyperplasia and lobular neoplasia) showed significantly lower ADCs than other benign lesions (P < .0001) and were the most common lesions with ADCs below the threshold.Assessing ADC along with dynamic contrast-enhanced MR imaging features may decrease the number of avoidable false-positive findings at breast MR imaging and reduce the number of preventable biopsies. The ability of DW imaging to help differentiate high-risk lesions requiring additional work-up from other nonmalignant subtypes may further improve patient care. Supplemental material: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.12112672/-/DC1.

    View details for DOI 10.1148/radiol.12112672

    View details for Web of Science ID 000311420300006

    View details for PubMedID 23033500

  • Molecular Pathology of Breast Cancer What a Pathologist Needs to Know AMERICAN JOURNAL OF CLINICAL PATHOLOGY Allison, K. H. 2012; 138 (6): 770-780

    Abstract

    Pathologists are now more than ever "diagnostic oncologists" and serve a critical role as clinical consultants on the biology of disease. In the last decade and a half, molecular information has transformed our thinking about the biologic diversity of breast cancers and redirected the way clinical treatment decisions are made. A basic understanding of the current molecular classification of breast cancers and the biologic pathways from precursors to invasive disease is key to both informing diagnostic practice and serving as clinical consultants. In addition, both single-marker and panel-based molecular tests are currently being utilized in breast cancer tissue to predict the benefit of specific therapies such as HER2-targeted biologic therapy and chemotherapy. Familiarity with the current issues involving these molecular tests as well as the pathologist's role in ensuring appropriate tissue handling, tissue selection, and results interpretation and correlation are paramount to providing optimal patient care.

    View details for DOI 10.1309/AJCPIV9IQ1MRQMOO

    View details for Web of Science ID 000311522400002

    View details for PubMedID 23161709

  • A protein complex of SCRIB, NOS1AP and VANGL1 regulates cell polarity and migration, and is associated with breast cancer progression ONCOGENE Anastas, J. N., Biechele, T. L., Robitaille, M., Muster, J., Allison, K. H., Angers, S., Moon, R. T. 2012; 31 (32): 3696-3708

    Abstract

    By analyzing public data sets of gene expression in human breast cancers we observed that increased levels of transcripts encoding the planar cell polarity (PCP) proteins SCRIB and VANGL1 correlate with increased risk of patient relapse. Experimentally, we found that reducing expression of SCRIB by short-hairpin RNAs (shRNAs) reduces the growth of human breast cancer cells in xenograft assays. To investigate SCRIB-associated proteins that might participate in the responses of breast cancer cells to altered levels of SCRIB, we used mass spectrometry and confocal microscopy. These studies reveal that SCRIB is present in at least two unique protein complexes: (1) a complex of SCRIB, ARHGEF, GIT and PAK (p21-activated kinase), and (2) a complex of SCRIB, NOS1AP and VANGL. Focusing on NOS1AP, we observed that NOS1AP colocalizes with both SCRIB and VANGL1 along cellular protrusions in metastatic breast cancer cells, but does not colocalize with either SCRIB or VANGL1 at cell junctions in normal breast cells. We investigated the effects of shRNA-mediated knockdown of NOS1AP and SCRIB in vitro, and found that reducing NOS1AP and SCRIB slows breast cancer cell migration and prevents the establishment of leading-trailing polarity. We also find that reduction of NOS1AP enhances anchorage-independent growth. Collectively these data point to the relevance of NOS1AP and SCRIB protein complexes in breast cancer.

    View details for DOI 10.1038/onc.2011.528

    View details for Web of Science ID 000307653800004

    View details for PubMedID 22179838

  • Biomarkers of progestin therapy resistance and endometrial hyperplasia progression 43rd Annual Meeting of the Society-for-Epidemiologic-Research Upson, K., Allison, K. H., Reed, S. D., Jordan, C. D., Newton, K. M., Swisher, E. M., Doherty, J. A., Garcia, R. L. MOSBY-ELSEVIER. 2012

    Abstract

    We sought to identify biomarkers associated with progestin therapy resistance and persistence/progression of endometrial hyperplasia.We performed a nested case-control study among women with complex (n = 73) and atypical (n = 41) hyperplasia treated with oral progestin, followed up 2-6 months for persistence/progression. We evaluated index endometrial protein expression for progesterone receptor isoform A, progesterone receptor isoform B (PRB), PTEN, Pax-2, and Bcl-2. Odds ratios and 95% confidence intervals (CIs) were estimated.Among women with atypical hyperplasia, high PRB expression was associated with 90% decreased risk of persistence/progression (95% CI, 0.01-0.8). High expression of progesterone receptor A and PRB suggested decreased risk of persistence/progression (odds ratio, 0.1; 95% CI, 0.02-1.0). These findings were not observed among women with complex hyperplasia. No associations were found with PTEN, Pax-2, and Bcl-2 protein expression.PRB expression shows promise as a biomarker of progestin response. Further research is warranted to understand how PRB expression may guide treatment decisions.

    View details for DOI 10.1016/j.ajog.2012.05.012

    View details for Web of Science ID 000305755000013

    View details for PubMedID 22727345

  • In Vivo Assessment of Ductal Carcinoma in Situ Grade: A Model Incorporating Dynamic Contrast-enhanced and Diffusion-weighted Breast MR Imaging Parameters RADIOLOGY Rahbar, H., Partridge, S. C., DeMartini, W. B., Gutierrez, R. L., Allison, K. H., Peacock, S., Lehman, C. D. 2012; 263 (2): 374-382

    Abstract

    To develop a model incorporating dynamic contrast material-enhanced (DCE) and diffusion-weighted (DW) magnetic resonance (MR) imaging features to differentiate high-nuclear-grade (HNG) from non-HNG ductal carcinoma in situ (DCIS) in vivo.This HIPAA-compliant study was approved by the institutional review board and requirement for informed consent was waived. A total of 55 pure DCIS lesions (19 HNG, 36 non-HNG) in 52 women who underwent breast MR imaging at 1.5 T with both DCE and DW imaging (b = 0 and 600 sec/mm(2)) were retrospectively reviewed. The following lesion characteristics were recorded or measured: DCE morphology, DCE maximum lesion size, peak initial enhancement at 90 seconds, worst-curve delayed enhancement kinetics, apparent diffusion coefficient (ADC), contrast-to-noise ratio (CNR) at DW imaging with b values of 0 and 600 sec/mm(2), and T2 signal effects (measured with CNR at b = 0 sec/mm(2)). Univariate and stepwise multivariate logistic regression modeling was performed to identify MR imaging features that optimally discriminated HNG from non-HNG DCIS. Discriminative abilities of models were compared by using the area under the receiver operating characteristic curve (AUC).HNG lesions exhibited larger mean maximum lesion size (P = .02) and lower mean CNR for images with b value of 600 sec/mm(2) (P = .004), allowing discrimination of HNG from non-HNG DCIS (AUC = 0.71 for maximum lesion size, AUC = 0.70 for CNR at b = 600 sec/mm(2)). Differences in CNR for images with b value of 0 sec/mm(2) (P = .025) without corresponding differences in ADC values were observed between HNG and non-HNG lesions. Peak initial enhancement was the only kinetic variable to approach significance (P = .05). No differences in lesion morphology (P = .11) or worst-curve delayed enhancement kinetics (P = .97) were observed. A multivariate model combining CNR for images with b value of 600 sec/mm(2) and maximum lesion size most significantly discriminated HNG from non-HNG (AUC = 0.81).The preliminary findings suggest that DCE and DW MR imaging features may aid in identifying patients with high-risk DCIS. Further study may yield a model combining MR characteristics with histopathologic data to facilitate lesion-specific targeted therapies. © RSNA, 2012.

    View details for DOI 10.1148/radiol.12111368

    View details for Web of Science ID 000303104300007

    View details for PubMedID 22517955

  • Lobular In-Situ Neoplasia on Breast Core Needle Biopsy: Imaging Indication and Pathologic Extent Can Identify Which Patients Require Excisional Biopsy ANNALS OF SURGICAL ONCOLOGY Rendi, M. H., Dintzis, S. M., Lehman, C. D., Calhoun, K. E., Allison, K. H. 2012; 19 (3): 914-921

    Abstract

    The surgical management of lobular in-situ neoplasia (LN) identified by core needle biopsy (CNB) is currently variable. Our institution has routinely excised LN on CNB since 2003, allowing for an unbiased assessment of upgrade rates.Cases of LN on CNB, including atypical lobular hyperplasia (ALH) and lobular carcinoma-in-situ (LCIS), were identified in our pathology database. CNBs with concurrent pleomorphic LCIS, ductal carcinoma-in-situ (DCIS), and invasive carcinoma were excluded. Imaging indication/modality, biopsy indication, and radiologic concordance were determined. Pathology review included scoring total foci of LN in each CNB. Upgrade rates to invasive carcinoma or DCIS at excision were calculated.A total of 106 cases of LN (73 ALH and 33 LCIS) on CNB were identified. Thirty patients had concurrent atypical ductal hyperplasia (ADH) and 76 had LN alone; 93 (88%) of the patients had available surgical follow-up (25 LN + ADH and 68 LN alone). The upgrade rate at excision was 16% (4 of 25) for LN + ADH and 4.4% (3 of 68) for LN alone. Patients with LN alone and discordant imaging, imaging for high-risk indications, or extensive LCIS (>4 foci) accounted for all the upgrades. Normal-risk patients who underwent biopsy to assess calcifications found by routine mammographic screening with LN alone did not result in upgrade.Women with a CNB diagnosis of LN for calcifications found on routine, normal-risk mammographic screening have a negligible risk of upgrade and may not require excisional biopsy. However, excisional biopsy should be offered to women undergoing imaging for other indications or with >4 foci of LN on CNB.

    View details for DOI 10.1245/s10434-011-2034-3

    View details for Web of Science ID 000300313800031

    View details for PubMedID 21861212

  • PAX2 Loss by Immunohistochemistry Occurs Early and Often in Endometrial Hyperplasia INTERNATIONAL JOURNAL OF GYNECOLOGICAL PATHOLOGY Allison, K. H., Upson, K., Reed, S. D., Jordan, C. D., Newton, K. M., Doherty, J., Swisher, E. M., Garcia, R. L. 2012; 31 (2): 159-167

    View details for DOI 10.1097/PGP.0b013e318226b376

    View details for Web of Science ID 000300457300010

  • PAX2 loss by immunohistochemistry occurs early and often in endometrial hyperplasia. International journal of gynecological pathology Allison, K. H., Upson, K., Reed, S. D., Jordan, C. D., Newton, K. M., Doherty, J., Swisher, E. M., Garcia, R. L. 2012; 31 (2): 151-159

    Abstract

    Immunohistochemical markers to assist in the diagnosis and classification of hyperplastic endometrial epithelial proliferations would be of diagnostic use. To examine the possible use of PAX2 as a marker of hyperplastic endometrium, cases of normal endometrium, simple and complex hyperplasia without atypia, atypical hyperplasia, and International Federation of Gynecology and Obstetrics (FIGO) grade 1 endometrioid carcinomas were stained for PAX2. Two hundred and six endometrial samples were available for interpretation of PAX2 staining. The percentage of cases with complete PAX2 loss (0% of cells staining) increased with increasing severity of hyperplasia: 0% of normal proliferative and secretory endometrium (n=28), 17.4% of simple hyperplasia (n=23), 59.0% of complex hyperplasia (n=83), 74.1% of atypical hyperplasia (n=54), and 73.3% of FIGO grade 1 endometrioid cancers (n=15). Partial loss of PAX2 expression did occur in normal endometrium (17.9%) but in smaller proportions of tissue and was less frequent than in simple hyperplasia (47.8% with partial loss), complex hyperplasia (32.5%), atypical hyperplasia (22.2%), and FIGO grade 1 carcinomas (20.0%). Uniform PAX2 expression was rare in complex (8.4%) and atypical hyperplasia (3.7%) and carcinoma (6.7%). When evaluating loss of PAX2 in histologically normal endometrium adjacent to lesional endometrium in a given case, statistically significant differences in staining were observed for simple hyperplasia (P=0.011), complex hyperplasia (P<0.001), atypical hyperplasia (P<0.001), and FIGO grade 1 endometrioid cancer (P=0.003). In summary, PAX2 loss seems to occur early in the development of endometrial precancers and may prove useful in some settings as a diagnostic marker in determining normal endometrium from complex and atypical hyperplasia and low-grade carcinomas. However, it is not useful in distinguishing between these diagnostic categories.

    View details for DOI 10.1097/PGP.0b013e318226b376

    View details for PubMedID 22317873

  • Routine pathologic parameters can predict Oncotype DXTM recurrence scores in subsets of ER positive patients: who does not always need testing? BREAST CANCER RESEARCH AND TREATMENT Allison, K. H., Kandalaft, P. L., Sitlani, C. M., Dintzis, S. M., GOWN, A. M. 2012; 131 (2): 413-424

    Abstract

    Oncotype DX(TM) is an RT-PCR-based assay used to predict chemotherapy benefit in patients with estrogen receptor (ER) positive breast cancers. We were interested if routinely available pathologic parameters could predict Oncotype DX Recurrence Scores (RS) in subsets of patients. We identified 173 breast cancers with available RSs and used 104 of these as a test set and 69 cases as a validation set. Pathologic characteristics including size, histologic type, Nottingham grade, and lymphatic invasion were recorded. Test set cases were stained for ER, progesterone receptor (PR), HER2, Ki67, CyclinD1, BCL2, D2-40, and P53. Statistical correlations with RS and regression tree analysis were performed. The validation set was subjected to analysis on the basis of grade, PR, and Ki67. In the test set, grade, PR levels and Ki67 had the strongest correlation with RS (P = 0.0002-0.0007). Regression tree analysis showed grade and PR as factors that could segregate cases into RS categories, with Ki67 adding value in certain subsets. A subset of cancers with a high likelihood of having a low RS (0-18) was identified with the following characteristics: grade 1, strong PR expression (Allred score ≥ 5) and Ki67 ≤ 10%. No cases with these characteristics had a high RS (≥ 31) and 73% had a low RS. Cancers highly likely to have a high RS were grade 3, low to absent PR expression (Allred score <5) and Ki67 > 10%. 80% of cases with these characteristics had a high RS and no cases had a low RS. Our validation set had similar findings in these two subsets. In conclusion, When cost and time are a consideration and the added value of Oncotype DX(TM) testing is in question, it may be reasonable to assume the results of this test in two specific subsets of breast cancers: (1) grade 1, high PR, low Ki67 cancers (low RS), and (2) grade 3, low PR, high Ki67 cancers (high RS).

    View details for DOI 10.1007/s10549-011-1416-3

    View details for Web of Science ID 000298752200005

    View details for PubMedID 21369717

  • Feasibility study of FDG PET as an indicator of early response to aromatase inhibitors and trastuzumab in a heterogeneous group of breast cancer patients EJNMMI RESEARCH Kurland, B. F., Gadi, V. K., Specht, J. M., Allison, K. H., Livingston, R. B., Rodler, E. T., Peterson, L. M., Schubert, E. K., Chai, X., Mankoff, D. A., Linden, H. M. 2012; 2

    View details for DOI 10.1186/2191-219X-2-34

    View details for Web of Science ID 000209435700034

  • Mouse cursor movement and eye tracking data as an indicator of pathologists' attention when viewing digital whole slide images. Journal of pathology informatics Raghunath, V., Braxton, M. O., Gagnon, S. A., Brunyé, T. T., Allison, K. H., Reisch, L. M., Weaver, D. L., Elmore, J. G., Shapiro, L. G. 2012; 3: 43-?

    Abstract

    Digital pathology has the potential to dramatically alter the way pathologists work, yet little is known about pathologists' viewing behavior while interpreting digital whole slide images. While tracking pathologist eye movements when viewing digital slides may be the most direct method of capturing pathologists' viewing strategies, this technique is cumbersome and technically challenging to use in remote settings. Tracking pathologist mouse cursor movements may serve as a practical method of studying digital slide interpretation, and mouse cursor data may illuminate pathologists' viewing strategies and time expenditures in their interpretive workflow.To evaluate the utility of mouse cursor movement data, in addition to eye-tracking data, in studying pathologists' attention and viewing behavior.Pathologists (N = 7) viewed 10 digital whole slide images of breast tissue that were selected using a random stratified sampling technique to include a range of breast pathology diagnoses (benign/atypia, carcinoma in situ, and invasive breast cancer). A panel of three expert breast pathologists established a consensus diagnosis for each case using a modified Delphi approach.Participants' foveal vision was tracked using SensoMotoric Instruments RED 60 Hz eye-tracking system. Mouse cursor movement was tracked using a custom MATLAB script.Data on eye-gaze and mouse cursor position were gathered at fixed intervals and analyzed using distance comparisons and regression analyses by slide diagnosis and pathologist expertise. Pathologists' accuracy (defined as percent agreement with the expert consensus diagnoses) and efficiency (accuracy and speed) were also analyzed.Mean viewing time per slide was 75.2 seconds (SD = 38.42). Accuracy (percent agreement with expert consensus) by diagnosis type was: 83% (benign/atypia); 48% (carcinoma in situ); and 93% (invasive). Spatial coupling was close between eye-gaze and mouse cursor positions (highest frequency ∆x was 4.00px (SD = 16.10), and ∆y was 37.50px (SD = 28.08)). Mouse cursor position moderately predicted eye gaze patterns (Rx = 0.33 and Ry = 0.21).Data detailing mouse cursor movements may be a useful addition to future studies of pathologists' accuracy and efficiency when using digital pathology.

    View details for DOI 10.4103/2153-3539.104905

    View details for PubMedID 23372984

  • Feasibility study of FDG PET as an indicator of early response to aromatase inhibitors and trastuzumab in a heterogeneous group of breast cancer patients. EJNMMI research Kurland, B. F., Gadi, V. K., Specht, J. M., Allison, K. H., Livingston, R. B., Rodler, E. T., Peterson, L. M., Schubert, E. K., Chai, X., Mankoff, D. A., Linden, H. M. 2012; 2 (1): 34-?

    Abstract

    In breast cancer endocrine therapy, post-therapy Ki-67 assay of biopsy material predicts recurrence-free survival but is invasive and prone to sampling error. [18F]Fluorodeoxyglucose (FDG) positron emission tomography (PET) has shown an early agonist or 'flare' response to tamoxifen and estradiol, but has not been tested in response to estrogen-lowering aromatase inhibitors (AIs). We hypothesized that decreased agonistic response to AIs would result in early FDG uptake decline. We also measured early response to trastuzumab (T), another targeted agent for breast cancer with differing mechanisms of action. Our study was designed to test for an early decline in FDG uptake in response to AI or T and to examine association with Ki-67 measures of early response.Patients with any stage of newly diagnosed or recurrent breast cancer were eligible and enrolled prior to initiation (or resumption) of AI or T therapy. FDG PET and tissue biopsy were planned before and after 2 weeks of AI or T therapy, with pretreatment archival tissue permitted. Cutoffs of ≥20% decline in standardized uptake value (SUV) as FDG PET early response and ≤5% post-treatment expression as Ki-67 early response were defined prior to analysis.Forty-two patients enrolled, and 40 (28 AI, 12 T) completed serial FDG-PET imaging. Twenty-two patients (17 AI, 5 T) had newly diagnosed disease, and 23 (14 AI, 9 T) had metastatic disease (5 newly diagnosed). Post-treatment biopsy was performed in 25 patients (63%) and was either refused or not feasible in 15. Post-treatment biopsy yielded tumor in only 17/25 cases (14 AI, 3 T). Eleven of 14 AI patients with post-therapy tissue showed FDG PET early response, and there was 100% concordance of PET and post-therapy Ki-67 early response. For the T group, 6/12 showed an FDG PET early response, including 2/3 patients with post-therapy biopsy, all with Ki-67 >5%.Substantial changes in FDG PET SUV occurred over 2 weeks of AI therapy and were associated with low post-therapy proliferation. SUV decline was seen in response to T, but few tissue samples were available to test association with Ki-67. Our results support further investigation of FDG PET as a biomarker for early response to AI therapy.

    View details for DOI 10.1186/2191-219X-2-34

    View details for PubMedID 22731662

  • Frequency of HER2 Heterogeneity by Fluorescence In Situ Hybridization According to CAP Expert Panel Recommendations Time for a New Look at How to Report Heterogeneity AMERICAN JOURNAL OF CLINICAL PATHOLOGY Allison, K. H., Dintzis, S. M., Schmidt, R. A. 2011; 136 (6): 864-871

    Abstract

    In 2009, a College of American Pathologists expert panel published supplemental HER2 testing recommendations suggesting that cases with between 5% and 50% individual cells amplified by fluorescence in situ hybridization be reported as "heterogeneous for HER2 gene amplification." We examined the implications of applying these recommendations to clinical practice in 1,329 consecutive breast cancer cases. By ratio criteria, 23.2% of cases met the proposed criteria for heterogeneity, of which 81.6% were not amplified and 15.5% were equivocal by standard criteria. In contrast, the proposed criteria based on HER2 signals per cell classified only 6.5% of cases as heterogeneous, of which only 8% (7/87) were not amplified and 79% (69/87) were equivocal by standard criteria. These results show that the 2 proposed criteria sets are not equivalent and that the ratio-based definition results in large numbers of nonamplified cases being classified as heterogeneous. Further definition of optimal criteria with clinical relevance is needed before HER2 heterogeneity reporting is adopted in routine practice.

    View details for DOI 10.1309/AJCPXTZSKBRIP07W

    View details for Web of Science ID 000297274500006

    View details for PubMedID 22095371

  • FOXP3+regulatory T-cells are abundant in vulvar Paget's disease and are associated with recurrence GYNECOLOGIC ONCOLOGY Press, J. Z., Allison, K. H., Garcia, R., Everett, E. N., Pizer, E., Swensen, R. E., Tamimi, H. K., Gray, H. J., Peters, W. A., Goff, B. A. 2011; 120 (2): 296-299

    Abstract

    To characterize clinical features of vulvar Paget's disease, and examine the quantity of immunosuppressive regulatory T-cells in vulvar Paget's tissue.Vulvar Paget's cases from 1992 to 2007 from two institutions were identified by pathology database search. Regulatory T-cells were identified with FOXP3 immunohistochemistry and quantified at the dermal-epidermal junction using image analysis software. Thirteen non-neoplastic inflammatory cases were stained for comparison.Cases included 33 women treated for primary vulvar Paget's, and 7 referred at recurrence. Of the 24 primary cases with greater than 5 months follow-up, recurrence was documented in 12/24(50%). Eight women (20%) recurred multiple times, but no recurrences were invasive. Significantly more patients with positive margins developed recurrent disease (82% vs 23%, p=0.01). Secondary neoplasms occurred in 10/40(25%). FOXP3+ cells at the dermal-epidermal junction were quantified in 29 primary and 13 recurrent tissue samples. FOXP3+ cells were absent in surrounding normal vulvar skin. FOXP3+ cells averaged 66/HPF in primary vulvar Paget's and 66/HPF in recurrent Paget's, compared to 22/HPF in non-neoplastic inflammatory cases (p=0.0003, p=0.001). Primary cases with positive surgical margins had more FOXP3+ cells than those with negative margins (85 vs 49, p=0.01). Recurrent cases with positive margins had more FOXP3+ cells than negative cases (84 vs 33, p=0.06). FOXP3 levels in primary specimens were higher in cases which recurred (78 vs 35, p=0.02).Increased regulatory T-cells may be associated with more extensive cases of vulvar Paget's disease that result in positive surgical margins and are associated with recurrence of disease, suggesting immunosuppression as a key factor.

    View details for DOI 10.1016/j.ygyno.2010.10.019

    View details for Web of Science ID 000286856800025

    View details for PubMedID 21075432

  • Endogenous Versus Tumor-Specific Host Response to Breast Carcinoma: A Study of Stromal Response in Synchronous Breast Primaries and Biopsy Site Changes CLINICAL CANCER RESEARCH Wu, J. M., Beck, A. H., Pate, L. L., Witten, D., Zhu, S. X., Montgomery, K. D., Allison, K. H., van de Rijn, M., West, R. B. 2011; 17 (3): 437-446

    Abstract

    We recently described two types of stromal response in breast cancer derived from gene expression studies of tenosynovial giant cell tumors and fibromatosis. The purpose of this study is to elucidate the basis of this stromal response--whether they are elicited by individual tumors or whether they represent an endogenous host reaction produced by the patient.Stromal signatures from patients with synchronous dual primaries were analyzed by immunohistochemistry on a tissue microarray (n = 26 pairs) to evaluate the similarity of stromal responses in different tumors within the same patient. We also characterized the extent to which the stromal signatures were conserved between stromal response to injury compared to the stromal response to carcinoma using gene expression profiling and tissue microarray immunohistochemistry.The two stromal response signatures showed divergent associations in synchronous primaries: the DTF fibroblast response is more likely to be similar in a patient with multiple breast primaries (permutation analysis P = 0.0027), whereas CSF1 macrophage response shows no significant concordance in separate tumors within a given patient. The DTF fibroblast signature showed more concordance across normal, cancer, and biopsy site samples from within a patient, than across normal, cancer, and biopsy site samples from a random group of patients, whereas the CSF1 macrophage response did not.The results suggest that the DTF fibroblast response is host-specific, whereas the CSF1 response may be tumor-elicited. Our findings provide further insight into stromal response and may facilitate the development of therapeutic strategies to target particular stromal subtypes.

    View details for DOI 10.1158/1078-0432.CCR-10-1709

    View details for PubMedID 21098336

  • Atypical ductal hyperplasia on vacuum-assisted breast biopsy: suspicion for ductal carcinoma in situ can stratify patients at high risk for upgrade HUMAN PATHOLOGY Allison, K. H., Eby, P. R., Kohr, J., DeMartini, W. B., Lehman, C. D. 2011; 42 (1): 41-50

    Abstract

    We evaluated 97 cases of review-confirmed atypical ductal hyperplasia found on stereotactic vacuum-assisted breast biopsy of suspicious calcifications. The number and size of foci of atypical ductal hyperplasia and presence of a micropapillary component were noted. In addition, we recorded if a case was considered "atypical ductal hyperplasia suspicious for ductal carcinoma in situ" using specific qualitative criteria. The upgrade rate was 20.6% (20/97) for all cases and 48% (12/25) for cases suspicious for ductal carcinoma in situ. Suspicion for ductal carcinoma in situ was found to be a strong predictor of upgrade with an odds ratio of 7.4 (P = .0003). Suspicious cases with nuclear features bordering on intermediate nuclear grade had the highest upgrade rate of 75% (6/8). Cases with ≥ 3 foci had significantly higher upgrade rates (28%) than those with less than 3 foci (11%), but focal atypical ductal hyperplasia did upgrade (P = .04). In conclusion, qualitative features of atypical ductal hyperplasia on core biopsy such as suspicion for ductal carcinoma in situ may help stratify patients at the highest risk for upgrade.

    View details for DOI 10.1016/j.humpath.2010.06.011

    View details for Web of Science ID 000285527600006

    View details for PubMedID 20970167

  • The Molecular Pathogenesis of Hereditary Ovarian Carcinoma CANCER Norquist, B. M., Garcia, R. L., Allison, K. H., Jokinen, C. H., Kernochan, L. E., Pizzi, C. C., Barrow, B. J., Goff, B. A., Swisher, E. M. 2010; 116 (22): 5261-5271

    Abstract

    BRCA1 or BRCA2 (BRCA1/2)-mutated ovarian carcinomas may originate in the fallopian tube. The authors of this report investigated alterations in BRCA1/2 tubal epithelium to define the molecular pathogenesis of these carcinomas.Tubal epithelium was evaluated from 31 BRCA1/2 mutation carriers with gynecologic carcinomas (BRCA CA), 89 mutation carriers who underwent risk-reducing salpingo-oophorectomy (RRSO), and 87 controls. Ki-67 expression and p53 foci (≥10 of 12 consecutive staining cells) were scored by 2 investigators who were blinded to patient designations. Expression levels of p27 and p21 were evaluated within p53 foci. Loss of heterozygosity at the BRCA1/2 mutation site was evaluated in microdissected p53 foci and tubal neoplasms.Background tubal proliferation as measured by Ki-67 staining was increased in the BRCA1 RRSO group (P = .005) compared with the control group. Women who had BRCA1/2 mutations had more p53 foci identified per tubal segment than women in the control group (P = .02). Levels of p27 were decreased in 12 of 28 p53 foci from women with BRCA1 mutations and in 0 of 16 p53 foci from controls (P = .002). There was no loss of the wild type BRCA1/2 allele in 5 tested p53 foci. Tubal neoplasia lost the wild type allele in 6 of 6 foci (P = .002).The current results suggested a model of tubal carcinogenesis in women with BRCA1/2 mutations. Increased proliferation occurred globally in at-risk tubal epithelium. A mutation in the tumor protein p53 gene TP53 with clonal proliferation and loss of p27 occurred before neoplastic proliferation. Loss of the wild type BRCA1/2 allele occurred with neoplastic proliferation and before invasion.

    View details for DOI 10.1002/cncr.25439

    View details for Web of Science ID 000284047400018

    View details for PubMedID 20665887

  • Frequency, Upgrade Rates, and Characteristics of High-Risk Lesions Initially Identified With Breast MRI AMERICAN JOURNAL OF ROENTGENOLOGY Strigel, R. M., Eby, P. R., DeMartini, W. B., Gutierrez, R. L., Allison, K. H., Peacock, S., Lehman, C. D. 2010; 195 (3): 792-798

    Abstract

    The purpose of this article is to determine the frequency, outcomes, and imaging features of high-risk lesions initially detected by breast MRI, including atypical ductal hyperplasia, atypical lobular hyperplasia, lobular carcinoma in situ, and radial scar.A retrospective review of our MRI pathology database was performed to identify all lesions initially detected with MRI (January 2003 through May 2007) that underwent imaging-guided needle biopsy yielding high-risk histopathologic abnormalities. Patient age, clinical indication, MRI BI-RADS lesion features, biopsy method, and histopathologic diagnosis were recorded. The frequencies of high-risk findings at needle biopsy and rates of upgrade to malignancy at surgical excision were compared across lesion imaging features with Fisher's exact test.Four hundred eighty-two MRI-detected suspicious lesions underwent needle biopsy. High-risk histopathologic abnormalities were present in 61 (12.7%) of 482 lesions: 51 (10.6%) atypical ductal hyperplasias, six (1.2%) atypical lobular hyperplasias, three (0.6%) lobular carcinomas in situ, and one (0.2%) radial scar. Correlation between the lesion site and pathology at surgical excision was confirmed for 39 of 61 lesions. Twelve (30.8%) of those 39 lesions were upgraded to malignancy (11 atypical ductal hyperplasias and one atypical lobular hyperplasia); five (41.7%) of the 12 malignancies were invasive cancer, and seven (58.3%) were ductal carcinomas in situ. No significant lesion features predictive of subsequent upgrade to malignancy were discovered.There are no specific imaging features that predict upgrade for high-risk lesions when detected with MRI. Therefore, surgical excision is recommended because upgrade to invasive carcinoma or ductal carcinoma in situ can occur in up to 31% of cases, regardless of biopsy technique.

    View details for DOI 10.2214/AJR.09.4081

    View details for Web of Science ID 000281180500037

    View details for PubMedID 20729462

  • Complex Hyperplasia With and Without Atypia Clinical Outcomes and Implications of Progestin Therapy OBSTETRICS AND GYNECOLOGY Reed, S. D., Newton, K. M., Garcia, R. L., Allison, K. H., Voigt, L. F., Jordan, C. D., Epplein, M., Swisher, E., Upson, K., Ehrlich, K. J., Weiss, N. S. 2010; 116 (2): 365-373

    Abstract

    Limited data exist to inform clinicians and patients as to the likelihood of long-term endometrial hyperplasia response to progestin therapy, especially for atypical hyperplasia. We evaluated women with complex and atypical endometrial hyperplasia, comparing those prescribed progestin with those not prescribed progestin.This retrospective cohort study was conducted in 1985-2005 among women aged 18-88 years at an integrated health plan in Washington State. Women were ineligible if they achieved an outcome (endometrial carcinoma, hysterectomy, or both) within 8 weeks of hyperplasia diagnosis. Exposure was progestin use for at least 14 days by duration and recency. Outcomes included rate of 1) endometrial carcinoma, 2) hysterectomy, or 3) both. Analyses performed included Kaplan-Meier, incident rate ratios, and Cox proportional hazard ratios.One thousand four hundred forty-three eligible women were identified. One thousand two hundred one had complex (n=164 no progestin) and 242 had atypical (n=62 no progestin) hyperplasia. During follow-up, a median of 5.3 years (range 8 weeks to 20.8 years), 71 women were diagnosed with endometrial carcinoma (35 complex, 36 atypia) and 323 underwent hysterectomy (216 complex, 107 atypia). Among women with complex and atypical hyperplasia, rates of endometrial carcinoma among progestin users were 3.6 and 20.5 per 1,000 woman-years, respectively (compared with women who did not use progestin, 10.8 and 101.4). Among women with complex and atypical hyperplasia, rates of hysterectomy among progestin users were 23.3 and 61.4 per 1,000 woman-years, respectively (compared with women who did not use progestin, 55.1 and 297.3).Endometrial carcinoma risk is diminished approximately threefold to fivefold in women diagnosed with complex or atypical endometrial hyperplasia and dispensed progestin; hysterectomy risk is also decreased.II.

    View details for DOI 10.1097/AOG.0b013e3181e93330

    View details for Web of Science ID 000280186300017

    View details for PubMedID 20664397

  • Achieving 95% Cross-Methodological Concordance in HER2 Testing Causes and Implications of Discordant Cases AMERICAN JOURNAL OF CLINICAL PATHOLOGY Grimm, E. E., Schmidt, R. A., Swanson, P. E., Dintzis, S. M., Allison, K. H. 2010; 134 (2): 284-292

    Abstract

    We were interested in determining our concordance between fluorescence in situ hybridization (FISH) and a previously validated immunohistochemical HER2 assay to identify possible reasons for discordance and to determine if all reasons for discordance were addressed by the American Society of Clinical Oncology/College of American Pathologists guidelines. We reviewed 697 cases (2004-2007) in which HER2 immunohistochemical and FISH testing were concurrently done. Overall concordance between nonequivocal immunohistochemical and FISH results was 96%. Of the 19 discordant cases, 13 (68%) were interpreted as positive immunohistochemically but negative by FISH. The primary reason for this discordance was immunohistochemical interpretation. Weak stain intensity, granular staining, and interpretation in areas of crush artifact were identified as the most common issues. Of the 6 cases interpreted as immunohistochemically negative and FISH-positive, 2 were from patients known to be receiving trastuzumab at the time of biopsy, 1 was very close to the FISH equivocal category, and 4 cases had fewer than 1.5 CEP17 signals per cell (1 patient in this group was also receiving trastuzumab). Focusing on issues with HER2 immunohistochemical interpretation can improve concordance rates for immunohistochemically positive cases, but biologic reasons may explain some discordant immunohistochemically negative cases.

    View details for DOI 10.1309/AJCPUQB18XZOHHBJ

    View details for Web of Science ID 000280067600016

    View details for PubMedID 20660333

  • Risk of Upgrade of Atypical Ductal Hyperplasia after Stereotactic Breast Biopsy: Effects of Number of Foci and Complete Removal of Calcifications RADIOLOGY Kohr, J. R., Eby, P. R., Allison, K. H., DeMartini, W. B., Gutierrez, R. L., Peacock, S., Lehman, C. D. 2010; 255 (3): 723-730

    Abstract

    To determine if patients with fewer than three foci of atypical ductal hyperplasia (ADH) who have all of their calcifications removed after stereotactic 9- or 11-gauge vacuum-assisted breast biopsy (VABB) have a rate of upgrade to malignancy that is sufficiently low to obviate surgical excision.An institutional review board-approved, HIPAA-compliant retrospective review of 991 cases of consecutive 9- or 11-gauge stereotactic VABB performed during a 65-month period revealed 147 cases of atypia. One pathologist performed a blinded review of the results of procedures performed to assess for calcifications and confirmed ADH in 101 cases with subsequent surgical excision. Each large duct or terminal duct-lobular unit containing ADH was considered a focus and counted. Postbiopsy mammograms were reviewed to determine whether all calcifications were removed. Upgrade to malignancy was determined from excisional biopsy pathology reports. Upgrade rates as a function of both number of foci and presence or absence of residual calcifications were calculated and compared by using chi(2) tests.Upgrade to malignancy occurred in 20 (19.8%) of the 101 cases. The upgrade rate was significantly higher in cases of three or more foci of ADH (15 [28%] of 53 cases) than in cases of fewer than three foci (five [10%] of 48 cases) (P = .02). Upgrade rates were similar, regardless of whether all mammographic calcifications were removed (seven [17%] of 41 cases) or all were not removed (nine [20%] of 45 cases) (P = .77). Upgrade occurred in two (12%) of 17 cases in which there were fewer than three ADH foci and all calcifications were removed.The upgrade rate is significantly higher when ADH involves at least three foci. Surgical excision is recommended even when ADH involves fewer than three foci and all mammographic calcifications have been removed, because the upgrade rate is 12%.

    View details for DOI 10.1148/radiol.09091406

    View details for Web of Science ID 000278038500009

    View details for PubMedID 20173103

  • Tumor Metabolism and Blood Flow as Assessed by Positron Emission Tomography Varies by Tumor Subtype in Locally Advanced Breast Cancer CLINICAL CANCER RESEARCH Specht, J. M., Kurland, B. F., Montgomery, S. K., Dunnwald, L. K., Doot, R. K., Gralow, J. R., Ellis, G. K., Linden, H. M., Livingston, R. B., Allison, K. H., Schubert, E. K., Mankoff, D. A. 2010; 16 (10): 2803-2810

    Abstract

    Dynamic positron emission tomography (PET) imaging can identify patterns of breast cancer metabolism and perfusion in patients receiving neoadjuvant chemotherapy (NC) that are predictive of response. This analysis examines tumor metabolism and perfusion by tumor subtype.Tumor subtype was defined by immunohistochemistry in 71 patients with locally advanced breast cancer undergoing NC. Subtype was defined as luminal [estrogen receptor (ER)/progesterone receptor (PR) positive], triple negative [TN; ER/PR negative, human epidermal growth factor receptor 2 (HER2) negative], and HER2 (ER/PR negative, HER2 overexpressing). Metabolic rate (MRFDG) and blood flow (BF) were calculated from PET imaging before NC. Pathologic complete response (pCR) to NC was classified as pCR versus other.Twenty-five (35%) of 71 patients had TN tumors; 6 (8%) were HER2 and 40 (56%) were luminal. MRFDG for TN tumors was on average 67% greater than for luminal tumors (95% confidence interval, 9-156%) and average MRFDG/BF ratio was 53% greater in TN compared with luminal tumors (95% confidence interval, 9-114%; P<0.05 for both). Average BF levels did not differ by subtype (P=0.73). Most luminal tumors showed relatively low MRFDG and BF (and did not achieve pCR); high MRFDG was generally matched with high BF in luminal tumors and predicted pCR. This was not true in TN tumors.The relationship between breast tumor metabolism and perfusion differed by subtype. The high MRFDG/BF ratio that predicts poor response to NC was more common in TN tumors. Metabolism and perfusion measures may identify subsets of tumors susceptible and resistant to NC and may help direct targeted therapy.

    View details for DOI 10.1158/1078-0432.CCR-10-0026

    View details for Web of Science ID 000278597600012

    View details for PubMedID 20460489

  • Diffusion tensor magnetic resonance imaging of the normal breast MAGNETIC RESONANCE IMAGING Partridge, S. C., Murthy, R. S., Ziadloo, A., White, S. W., Allison, K. H., Lehman, C. D. 2010; 28 (3): 320-328

    Abstract

    The objective of this study was to evaluate diffusion anisotropy of the breast parenchyma and assess the range and repeatability of diffusion tensor imaging (DTI) parameters in normal breast tissue.The study was approved by our institutional review board and included 12 healthy females (median age, 36 years). Diffusion tensor imaging was performed at 1.5 T using a diffusion-weighted echo planar imaging sequence. Diffusion tensor imaging parameters including tensor eigenvalues (lambda(1), lambda(2), lambda(3)), fractional anisotropy (FA) and apparent diffusion coefficient (ADC) were measured for anterior, central and posterior breast regions.Mean normal breast DTI measures were lambda(1)=2.51 x 10(-3) mm(2)/s, lambda(2)=1.89 x 10(-3) mm(2)/s, lambda(3)=1.39 x 10(-3) mm(2)/s, ADC=1.95+/-0.24 x 10(-3) mm(2)/s and FA=0.29+/-0.05 for b=600 s/mm(2). Significant regional differences were observed for both FA and ADC (P<.05), with higher ADC in the central breast and higher FA in the posterior breast. Comparison of DTI values calculated using b=0, 600 s/mm(2) vs. b=0, 1000 s/mm(2), showed significant differences in ADC (P<.001), but not FA. Repeatability assessment produced within-subject coefficient of variations of 4.5% for ADC and 11.4% for FA measures.This study demonstrates anisotropy of water diffusion in normal breast tissue and establishes a normative range of breast FA values. Attention to the influence of breast region and b value on breast DTI measurements may be important for clinical interpretation and standardization of techniques.

    View details for DOI 10.1016/j.mri.2009.10.003

    View details for Web of Science ID 000276042400003

    View details for PubMedID 20061111

  • Fibroblast-Like Stromal Response Is Host-Dependent While Macrophage-Associated Stromal Response Is Tumor-Dependent: A Study of Stromal Response in Paired Breast Carcinomas from Patients with Dual Primaries 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology Wu, J. M., Beck, A. H., WITTEN, D., Allison, K., van de Rijn, M., West, R. B. NATURE PUBLISHING GROUP. 2010: 79A–79A

    View details for Web of Science ID 000274337300346

  • Primary breast lymphoma. Radiology case reports Voria, P., Eby, P. R., Allison, K. 2010; 5 (1): 351-?

    Abstract

    We report a case of primary breast lymphoma in a 75-year-old woman who noticed a lump in her right breast after trauma. Mammographic, ultrasonographic, and pathologic correlations are provided. The typical appearance of primary breast lymphoma on mammography is a solitary, uncalcified, circumscribed, or indistinctly marginated mass with adjacent lymphadenopathy. On ultrasound, primary breast lymphoma is usually hypoechoic with circumscribed or microlobulated margins demonstrating increased vascularity. The differential diagnosis for a mass with this appearance is discussed in detail and includes hematoma, abscess, primary breast lymphoma, invasive ductal carcinoma, phyllodes tumor, and metastatic disease.

    View details for DOI 10.2484/rcr.v5i1.351

    View details for PubMedID 27307845

  • Incidence of endometrial hyperplasia 75th Annual Meeting of the Pacific-Coast-Obstetrical-and-Gynecological-Society Reed, S. D., Newton, K. M., Clinton, W. L., Epplein, M., Garcia, R., Allison, K., Voigt, L. F., Weiss, N. S. MOSBY-ELSEVIER. 2009

    Abstract

    The objective of the study was to estimate the age-specific incidence of endometrial hyperplasia: simple, complex, and atypical, in order of increasing likelihood of progression to carcinoma.Women aged 18-90 years with endometrial pathology specimens (1985-2003) at a large integrated health plan were identified using automated data. Incidence rates were obtained by dividing the number of cases by the estimated number of female health plan enrollees who retained a uterus.Endometrial hyperplasia peak incidence was: simple, 142 per 100,000 woman-years, complex, 213 per 100,000 woman-years, both in the early 50s; and atypical, 56 per 100,000 woman-years in the early 60s. Age-adjusted incidence decreased over the study period, especially for atypical hyperplasia.Endometrial hyperplasia incidence without and with atypia peaks in the early postmenopausal years and in the early 60s, respectively. Given that some cases of endometrial hyperplasia likely go undiagnosed, the figures provided should be viewed as minimum estimates of the true incidence.

    View details for DOI 10.1016/j.ajog.2009.02.032

    View details for Web of Science ID 000266505300032

    View details for PubMedID 19393600

  • Frequency and Upgrade Rates of Atypical Ductal Hyperplasia Diagnosed at Stereotactic Vacuum-Assisted Breast Biopsy: 9-Versus 11-Gauge AMERICAN JOURNAL OF ROENTGENOLOGY Eby, P. R., Ochsner, J. E., DeMartini, W. B., Allison, K. H., Peacock, S., Lehman, C. D. 2009; 192 (1): 229-234

    Abstract

    Our goals were to determine the frequency and upgrade rate for atypical ductal hyperplasia (ADH) diagnosed with stereotactic 9-gauge vacuum-assisted breast biopsy and to compare the frequencies and upgrade rates of ADH between 9- and 11-gauge vacuum-assisted breast biopsy.We retrospectively reviewed the pathology results of 991 consecutive 9- or 11-gauge stereotactic vacuum-assisted breast biopsy procedures from February 2001 through June 2006 and identified lesions diagnosed as ADH. The final diagnosis after surgical excision was determined from medical records. The frequencies and upgrade rates to carcinoma were calculated for all ADH lesions and compared between 9- and 11-gauge procedures. The number of core samples was recorded and compared.One hundred forty-one of 991 (14.2%) lesions yielded a diagnosis of ADH at 9- or 11-gauge stereotactic vacuum-assisted breast biopsy. Upgrade to ductal carcinoma in situ or invasive carcinoma occurred in 26 of 123 (21.1%) patients. The frequency of ADH was 83 of 600 (13.8%) lesions for 9-gauge and 58 of 391 (14.8%) lesions for 11-gauge vacuum-assisted breast biopsy. The 9-gauge upgrade rate was 16 of 74 (21.6%) lesions compared with 10 of 49 (20.4%) lesions for 11-gauge vacuum-assisted breast biopsy. There was no significant difference between the number of core samples obtained with each device (p=0.40). Neither the frequency of ADH (p=0.66) nor the upgrade rates (p=0.87) were significantly different between 9- and 11-gauge vacuum-assisted breast biopsy.Compared with an 11-gauge vacuum-assisted breast biopsy device, the use of a larger 9-gauge vacuum-assisted breast biopsy needle does not decrease the upgrade rate of ADH. Our frequency of ADH at vacuum-assisted breast biopsy is higher than any previously reported and may reflect regional differences in the incidence of breast cancer or practice patterns of the pathologist.

    View details for DOI 10.2214/AJR.08.1342

    View details for Web of Science ID 000261851600034

    View details for PubMedID 19098204

  • Impact and Outcomes of Routine Microstaging of Sentinel Lymph Nodes in Breast Cancer: Significance of the pN0(i+) and pN1mi Categories ANNALS OF SURGICAL ONCOLOGY Pugliese, M. S., Beatty, J. D., Tickman, R. J., Allison, K. H., Atwood, M. K., Szymonifka, J., Arthurs, Z. M., Huynh, P. P., Dawson, J. H. 2009; 16 (1): 113-120

    Abstract

    In 2003, the American Joint Committee on Cancer (AJCC) initiated the 6th edition staging criteria, including pN0(i+) and pN1mi categories for breast cancer. However, the clinical significance of these categories is debated in the literature.A prospective registry was used to identify patients staged with sentinel lymph node (SLN) biopsy. SLN evaluation included routine serial sectioning and immunohistochemical stains. SLN biopsies performed before January 2003 were restaged according to the AJCC's 6th edition criteria.Of 954 SLN biopsies identified, on review, 491 N0i-, 86 N0i+, 73 N1mi, 146 N1a, 29 N2a, and 11 N3a patients were available for analysis with a median follow-up of 45.4 months. Significant prognostic and therapeutic differences existed between the groups. Differences in overall survival (OS) and recurrence-free survival (RFS) were only noted when the size of the metastases reached the N1a level. There were no statistically significant differences in OS or RFS between N0(i-) and N0(i+) or N1mi disease. Cases that were N0(i+) or N1mi were more likely to have other poor prognostic factors and to receive more aggressive therapy.SLN biopsy allows a more sensitive evaluation of lymph nodes for metastatic cells. This has led to the increased identification of very small axillary metastases. While the new microstaging categories are not yet clearly associated with a significantly decreased OS or DFS in this series, they are associated with other poor prognostic factors and more local/regional and systemic therapy. Further analysis of the microstaging categories is needed.

    View details for DOI 10.1245/s10434-008-0121-x

    View details for Web of Science ID 000262555000015

    View details for PubMedID 18949520

  • Immunosuppressive regulatory T cells are associated with aggressive breast cancer phenotypes: a potential therapeutic target MODERN PATHOLOGY Bohling, S. D., Allison, K. H. 2008; 21 (12): 1527-1532

    Abstract

    FoxP3 is a marker for immunosuppressive CD25+CD4+ regulatory T cells. These regulatory T cells are thought to play a role in inducing immune tolerance to antigens and may be selectively recruited by carcinomas. We investigated whether breast carcinomas had significant numbers of FoxP3-positive regulatory T cells by immunohistochemistry, and if their presence was associated with other prognostic factors, such as Nottingham grade, hormone receptor immunohistochemical profile, tumor size, or lymph node metastases. Ninety-seven needle core or excisional breast biopsies with invasive breast carcinoma diagnosed at the University of Washington were stained with antibodies to FoxP3, estrogen receptor, and Her2/neu. The numbers of FoxP3-positive cells present within the neoplastic epithelium, and immediately adjacent stroma were counted manually in three high-powered fields (HPFs; x 400) by two independent pathologists. The average scores were then correlated with the parameters of interest. A threshold of >or=15 FoxP3-positive cells/HPF was used to define a FoxP3-positive case in some analyses. Higher average numbers of FoxP3-positive cells present significantly correlated with higher Nottingham grade status (P=0.000229). In addition, the presence of significant numbers (>or=15/HPF) of FoxP3-positive cells in breast carcinoma was positively associated with higher Nottingham grade (P=0.00002585). Higher average numbers of FoxP3-positive cells were also significantly associated with larger tumor size (>2.0 cm; P=0.012824) and trended toward an association with estrogen receptor negativity. Interestingly, 'triple-negative' (estrogen and progesterone receptor negative and Her2/neu negative) Nottingham grade III cases were also significantly associated with high numbers of FoxP3 cells. These results argue that regulatory T cells may play a role in inducing immune tolerance to higher grade, more aggressive breast carcinomas, and are a potential therapeutic target for these cancers.

    View details for DOI 10.1038/modpathol.2008.160

    View details for Web of Science ID 000261109000014

    View details for PubMedID 18820666

  • Estrogen Receptor Expression in Breast Cancer We Cannot Ignore the Shades of Gray AMERICAN JOURNAL OF CLINICAL PATHOLOGY Allison, K. H. 2008; 130 (6): 853-854

    View details for DOI 10.1309/AJCP3P3XHTCYGZIA

    View details for Web of Science ID 000260999900002

    View details for PubMedID 19019759

  • Is Surgical Excision Necessary for Focal Atypical Ductal Hyperplasia Found at Stereotactic Vacuum-Assisted Breast Biopsy? ANNALS OF SURGICAL ONCOLOGY Eby, P. R., Ochsner, J. E., DeMartini, W. B., Allison, K. H., Peacock, S., Lehman, C. D. 2008; 15 (11): 3232-3238

    Abstract

    Our goal was to determine the upgrade rate for lesions described as focal atypical ductal hyperplasia (ADH) after 9- or 11-gauge stereotactic vacuum-assisted breast biopsy (VABB) to determine whether surgical excision is indicated in this setting.We retrospectively reviewed the results of 991 consecutive 9- or 11-gauge stereotactic core VABB procedures from February 2001 through June 2006 and identified lesions diagnosed as ADH. On the basis of the descriptions in pathology reports each lesion was placed in one of three categories: (1) focal ADH, (2) ADH suspicious for ductal carcinoma-in-situ, or (3) ADH not otherwise specified. The final diagnosis after surgical excisional biopsy was determined from medical records. The frequencies and upgrade rates to carcinoma were calculated and compared for all lesions and for each ADH category.A total of 141 (14.2%) of 991 lesions yielded ADH at stereotactic core VABB, and 123 (87.2%) of 141 underwent surgical excisional biopsy of the stereotactic core VABB site. A total of 56 (45.5%) of 123 were categorized as focal ADH, and 7 (12.5%) of 56 were upgraded to carcinoma. A total of 49 (39.8%) of 123 were categorized as ADH not otherwise specified, and 11 (22.4%) of 49 were upgraded. Eighteen (14.6%) of 123 were categorized as suspicious for ductal carcinoma-in-situ, and 8 (44.4%) of 18 were upgraded. Neither the frequency of ADH (P = .66) nor the upgrade rates (P = .87) were significantly different between 9- and 11-gauge VABB.Surgical excisional biopsy is indicated to exclude carcinoma in cases of focal ADH discovered at 9- or 11-gauge VABB.

    View details for DOI 10.1245/s10434-008-0100-2

    View details for Web of Science ID 000260509400034

    View details for PubMedID 18696163

  • Immunohistochemical markers in endometrial hyperplasia: Is there a panel with promise? A review APPLIED IMMUNOHISTOCHEMISTRY & MOLECULAR MORPHOLOGY Allison, K. H., Tenpenny, E., Reed, S. D., Swisher, E. M., Garica, R. L. 2008; 16 (4): 329-343

    Abstract

    Despite advances in defining the biology of endometrial carcinomas, there has been little progress in determining markers that distinguish preinvasive endometrial proliferations. The goal of this literature review was to identify studies on endometrial hyperplasia (EH) that describe markers with potential to predict response to progestin therapy or potential for progression to invasive disease.Articles published between January 2000 and October 2006 were identified using the key words endometrial hyperplasia and progesterone receptor or estrogen receptor or biologic marker or immunohistochemistry/immunohistochemical. Articles that reported immunohistochemical studies on specimens of human EH +/-endometrioid endometrial carcinoma with a normal comparison group were included. Only those who reported hyperplasia with atypia separately from nonatypical hyperplasia and with a sample size greater than 10 specimens for the sum of complex and atypical samples were included.A total of 289 abstracts were reviewed and 150 articles potentially met inclusion criteria. Of these, 123 described immunohistochemical studies on human EH specimens. Only 46 met all criteria for analysis of 61 different markers.PTEN seems to have the greatest potential for diagnostic utility in EH, perhaps in combination with Bcl-2 and Bax. However, more uniform and rigorous studies are required to confirm these and additional markers' utility diagnostically in a diagnostic panel. As a major clinical priority is to determine which lesions can be treated medically and which require surgical intervention, focusing future studies on markers that distinguish response to hormone therapy or are involved in hormone regulation, will be important future considerations.

    View details for Web of Science ID 000257270100006

    View details for PubMedID 18528284

  • Intratumoral T cells, tumor-associated macrophages, and regulatory T cells: Association with p53 mutations, circulating tumor DNA and survival in women with ovarian cancer GYNECOLOGIC ONCOLOGY Shah, C. A., Allison, K. H., Garcia, R. L., Gray, H. J., Goff, B. A., Swisher, E. M. 2008; 109 (2): 215-219

    Abstract

    Forty percent of women with ovarian cancer have circulating free tumor DNA. We sought to determine if the tumor immune infiltrate varied based on tumor p53 mutation status or presence of circulating tumor DNA.We performed immunohistochemistry on 119 ovarian cancer specimens with CD3 and CD8 (Intratumoral T cells (TILs)), CD68 (tumor-associated macrophages (TAMs)), and FoxP3 (T regulatory cells (Tregs)). Tumors had been previously sequenced for mutations in exons 4-10 of p53, and plasma from women characterized for free tumor DNA.TIL and TAM levels were positively correlated (P<0.0001). High levels of TILs were identified in 54 of 119 tumors (45.4%). No survival difference was identified according to the presence of TILs or TAMs. Patients with greater TILs were more likely to be optimally cytoreduced (P=0.005). p53 mutations were associated with more TILs (P=0.008). The presence of circulating tumor DNA did not correlate with TILs, TAMs, or Tregs. In the subgroup with a low host antitumor immune response, the intermediate response Tregs group did have a survival advantage (P=0.049).p53 mutations are associated with higher levels of TILs. The ratio of Tregs to TILS may be more important than absolute levels. A brisk T cell response within the tumor predicts adequacy of cytoreduction, suggesting successful cytoreduction may be partially due to underlying tumor biology and host response.

    View details for DOI 10.1016/j.ygyno.2008.01.010

    View details for Web of Science ID 000256205600012

    View details for PubMedID 18314181

  • Diagnosing endometrial hyperplasia - Why is it so difficult to agree? AMERICAN JOURNAL OF SURGICAL PATHOLOGY Allison, K. H., Reed, S. D., Voigt, L. F., Jordan, C. D., Newton, K. M., Garcia, R. L. 2008; 32 (5): 691-698

    Abstract

    Current World Health Organization classification of endometrial hyperplasia is problematic because of poor diagnostic reproducibility. We sought to determine factors that cause diagnostic disagreement in a review of 2601 endometrial specimens. Blinded random specimens of normal endometrium, hyperplasias, and carcinoma were reviewed by 2 pathologists, with review by a third pathologist in cases with disagreement. All cases of endometrial hyperplasia or carcinoma were scored for degree of glandular crowding, architectural complexity, and cytologic atypia. Sample adequacy, hyperplasia volume, presence of metaplasia, or endometrial polyp were also scored. The overall kappa for agreement was 0.71, with a lower kappa of 0.36 when cases called "no hyperplasia" were excluded. The percent specific agreement was 90.3% for no hyperplasia, 31.1% for simple hyperplasia, 51.1% for complex hyperplasia, 49.8% for atypical hyperplasia, and 57.5% for adenocarcinoma. Cases categorized as "low volume hyperplasia" had more diagnostic disagreement than "high volume," (62% vs. 39%, P=0.003). Similarly, cases called "scant" had more diagnostic disagreement than "not scant" (65% vs. 57%, P=0.013). The histologic feature associated with the most diagnostic disagreement was cytologic atypia (P<0.0001). Architectural crowding, architectural complexity, or the presence of a polyp were all associated with diagnostic disagreement (P<0.0001). High diagnostic disagreement in endometrial hyperplasia is related to both sample adequacy and interpretation of histologic features present. Although obtaining additional tissue may increase diagnostic reproducibility, differences in interpretation of key histologic features like cytologic atypia remain major factors contributing to diagnostic disagreement.

    View details for Web of Science ID 000255559800005

    View details for PubMedID 18347507

  • Defining an appropriate threshold for the diagnosis of serous borderline tumor of the ovary: When is a full staging procedure unnecessary? INTERNATIONAL JOURNAL OF GYNECOLOGICAL PATHOLOGY Allison, K. H., Swisher, E. M., Kerkering, K. M., Garcia, R. L. 2008; 27 (1): 10-17

    Abstract

    How much borderline change in an otherwise typical ovarian serous cystadenoma should warrant classification as a serous ovarian "borderline tumor?" We correlated estimated volume and percent borderline change with stage in 56 cases of serous ovarian neoplasms (excluding carcinomas) diagnosed as at least focal borderline change to see if we could define an appropriate threshold for the diagnosis of borderline tumor that would justify full surgical staging. Forty-three cases were completely staged, 6 had "fertility-sparing" but otherwise complete staging, and 7 cases had "limited" staging. Thirty-eight cases were stage 1a-1c, and 18 were greater than stage 1. Cases with stage 1 disease had a significantly lower mean volume of borderline change sampled of 2.0 compared with 5.6 cm in cases with greater than stage 1 disease (P = 0.0002). All high-stage cases had at least 1.0 cm or more of borderline change sampled (range, 1.0-12). Cases with stage 1 disease had a significantly lower mean estimated total percent borderline change of 34.8% compared with 77.2% in cases with greater than stage 1 disease (P < 0.0001). All high-stage cases had 20% or more total borderline change (range, 20%-100%). In addition, a grossly exophytic growth pattern component was highly predictive of high stage (P < or = 0.0001). Two cases recurred-both were advanced-stage and high-percent borderline change. There were no deaths due to disease (mean follow-up, 85 months). Our study supports a conservative 10% cutoff for classification as a "borderline tumor," and that complete surgical staging is not necessary when a serous neoplasm with an intracystic growth pattern has less than 10% or 0.5-cm borderline change.

    View details for DOI 10.1097/pgp.0b013e318133a9b7

    View details for Web of Science ID 000252124400002

    View details for PubMedID 18156968

  • Alternate molecular genetic pathways in ovarian carcinomas of common histological types HUMAN PATHOLOGY Willner, J., Wurz, K., Allison, K. H., Galic, V., Garcia, R. L., Goff, B. A., Swisher, E. M. 2007; 38 (4): 607-613

    Abstract

    We evaluated alterations in p53, PIK3CA, PTEN, CTNNB1 (beta-catenin), MLH1, and BRAF among common histological subsets of epithelial ovarian tumors to characterize patterns of alterations of different molecular pathways. There were 12 clear cell, 26 endometrioid, and 51 serous carcinomas evaluated by direct DNA sequencing for mutations in p53, PIK3CA, PTEN, BRAF, and CTNNB1. Methylation-specific polymerase chain reaction (PCR) assessed MLH1 promoter methylation status. Quantitative PCR identified PIK3CA amplification in 22 EC/CC and 94 SC. p53 mutations were identified in 25 (49%) of 51 SC, 11 (42%) of 26 EC, and 1 (8.3%) of 12 CC neoplasms and were more common in grade 3 EC (P = .045) and advanced-stage EC/CC (P = .007). PIK3CA mutations were identified in 3 (25%) of 12 CC, 3 (12%) of 26 EC, and 0 of 51 SC. PTEN mutations were significantly more common in EC (8/26, 31%) compared with CC (0/12; P = .04) and SC (2/51, 4%; P = .002). CTNNB1 mutations were identified, 6 (23%) EC and no CC or SC (P = .008). Both PTEN and CTNNB1 mutations were more common in low-grade EC/CC, whereas PIK3CA mutations occurred only in grade 3 cancers. PTEN and PIK3CA mutations were more common in p53 wild-type tumors (P = .003). PIK3CA amplification occurred in fewer EC/CC (0/22) versus SC (19/94, 20%; P = 0.02) and were slightly more common in p53 wild-type compared with p53 mutant SC (P = .08). Of 26 EC, 22 (85%) had a mutation in one of the genes studied compared with 4 33% of 12 CC (P = .003). Women with EC/CC had significantly better overall survival (P = .0008), and this remained significant after accounting for stage (P=.04). Mutations in p53 or in PTEN/PIK3CA are alternative pathways in ovarian carcinogenesis. Activation of PIK3CA occurs by gene amplification in SC but via somatic mutation of PIK3CA or PTEN in EC and CC. PIK3CA mutations are associated with high-grade tumors, whereas PTEN and CTNNB1 mutations are associated with low-grade tumors. Mutations in p53, PIK3CA, PTEN, and CTNNB1 account for most EC tumors; most CC remain unexplained. EC/CC histology is a favorable prognostic factor.

    View details for DOI 10.1016/j.humpath.2006.10.007

    View details for Web of Science ID 000245319800011

    View details for PubMedID 17258789

  • Epithelioid trophoblastic - Tumor review of a rare neoplasm of the chorionic-type intermediate trophoblast ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE Allison, K. H., Love, J. E., Garcia, R. L. 2006; 130 (12): 1875-1877

    Abstract

    We present a brief review of epithelioid trophoblastic tumor, a rare trophoblastic neoplasm derived from chorionic-type intermediate trophoblastic cells that typically presents in reproductive-age women between 1 and 18 years following a previous gestation. Histologic features include a nodular growth pattern of monomorphic, epithelioid cells within a hyaline matrix. Areas of necrosis and mitotic activity (0-9 mitoses per 10 high-power fields) are additional features of this neoplasm. Positive immunostaining for p63 and cytokeratin, frequent location in the lower uterine segment and endocervix, as well as the epithelioid appearance can lead to confusion with squamous cell carcinoma. Inhibin-alpha is typically expressed, as well as focal, more variable expression of other trophoblastic markers including beta-human chorionic gonadotropin, human placental lactogen, placental alkaline phosphate, and Mel-CAM (CD148). The clinical behavior of this rare form of gestational trophoblastic disease is difficult to predict. Although most cases follow a benign course following resection, there is a potential for metastatic disease.

    View details for Web of Science ID 000242645000030

    View details for PubMedID 17149967

  • Accuracy of intraoperative imprint cytology of sentinel lymph nodes in breast cancer 7th Annual Meeting of the American-Society-of-Breast-Surgeons Pugliese, M. S., Kohr, J. R., Allison, K. H., Wang, N. P., Tickman, R. J., Beatty, J. D. EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC. 2006: 516–19

    Abstract

    In breast cancer treatment, immediate completion of axillary lymph node dissection (ALND) can be performed if the intraoperative sentinel lymph node (SLN) examination is positive. This study evaluates the accuracy of intraoperative imprint cytology (IC) for detecting SLN metastases.Pathology reports from 385 SLN biopsy examinations were reviewed retrospectively. The SLNs were serially sectioned perpendicular to the long axis and IC was performed intraoperatively. The SLNs then were formalin-fixed for permanent sections. Final pathology was compared with the intraoperative IC results.The sensitivities for IC detection of N0(i+) (n = 36), N1mi (n = 24), and N1a-3a (n = 65) metastases were 0%, 4%, and 74%, respectively. The specificity was 100%.Final pathology identified 89 (23%) patients with N1 or greater disease. IC allowed 49 (55%) of these patients to undergo synchronous completion of ALND. No unnecessary completion ALNDs were performed. The sensitivity of IC decreased with decreasing size of the metastasis.

    View details for DOI 10.1016/j.amjsurg.2006.05.014

    View details for Web of Science ID 000240750800026

    View details for PubMedID 16978964

  • Can an immunoassay become a standard technique in detecting oxycodone and its metabolites? JOURNAL OF ANALYTICAL TOXICOLOGY Abadie, J. M., Allison, K. H., Black, D. A., Garbin, J., Saxon, A. J., Bankson, D. D. 2005; 29 (8): 825-829

    Abstract

    Opiate toxicology testing is routinely performed in the hospital setting to identify abusers and/or to determine those patients who are not taking prescribed opiate analgesics such as oxycodone. Commercially available assays for opiate detection in urine have decreased sensitivity for oxycodone, which contributes to a high false-negative rate. Functioning as a beta site, our Veterans Affairs hospital evaluated a new enzyme immunoassay, DRI Oxycodone Assay, for its use in the qualitative and semiquantitative detection of oxycodone in urine. We hypothesize that an immunoassay for oxycodone with superior sensitivity and specificity, when compared to the traditional opiate assays, would reduce the need for more expensive and time-consuming confirmatory testing. We used the new liquid homogenous enzyme immunoassay to determine oxycodone results in a total of 148 urine samples from 4 different sample groups. Gas chromatography-mass spectroscopy was subsequently used to confirm the presence or absence of oxycodone (or its primary metabolite, noroxycodone). We also evaluated within-run, between-run, and linearity studies and conducted a crossover study to establish a cutoff value for oxycodone. In our patient population, we used the new DRI immunoassay to evaluate 17,069 urine samples to estimate oxycodone misuse profiles (patients not taking prescribed oxycodone or taking oxycodone without a prescription) during a 4-month period. The sensitivity and specificity of the new oxycodone immunoassay were 97.7% and 100%, respectively, at the cutoff concentration of 300 ng/mL. The assay linearity was 1,250 ng/mL, and the sensitivity was 10 ng/mL. Within-run precision and between-run coefficient of variation were 2.3% and 1.8%, respectively. None of the 15 compounds that we evaluated for interference had crossover significant enough to produce a positive oxycodone result when using 300 ng/mL as the cutoff value. None of the 17,069 oxycodone immunoassays was followed with a request for confirmation. Among patients with positive results (n = 224), 93 (41.5%) were not prescribed oxycodone. The new DRI Oxycodone Assay is a sensitive and specific screening test for the determination of oxycodone. The improved opiate screening results may lead to better patient and prescription management, to decreased laboratory spending, and to the identification of oxycodone abusers, which could result in decreased oxycodone-related mortality.

    View details for Web of Science ID 000233448800011

    View details for PubMedID 16374942

  • Superficial malignant peripheral nerve sheath tumor - A rare and challenging diagnosis AMERICAN JOURNAL OF CLINICAL PATHOLOGY Allison, K. H., Patel, R. M., Goldblum, J. R., Rubin, B. P. 2005; 124 (5): 685-692

    Abstract

    We reviewed the clinicopathologic features of 5 cases of malignant peripheral nerve sheath tumor (MPNST) manifesting in superficial locations associated with cutaneous neurofibromas (4 cases) or superficial peripheral nerve (1 case). Four cases had spindle cell morphologic features and were at least focally positive for S-100 protein, whereas the associated benign neural elements had more extensive S-100 immunoreactivity. The single epithelioid case was diffusely and strongly positive for S-100 protein. Melanoma markers, epithelial membrane antigen, glial fibrillary acidic protein, neurofilament, pancytokeratin (AE1/AE3), CD34, smooth muscle actin, and desmin were negative in all cases. There were no local recurrences, but 3 patients died of metastatic disease within 2 to 30 months (median, 21 months). MPNSTs can occur in a superficial location and may have an aggressive clinical course. Immunohistochemical markers are helpful in excluding other lesions in the differential diagnosis. However, identification of a benign precursor or origin from a nerve may be the most definitive way to properly classify these rare lesions.

    View details for DOI 10.1309/VBXMK5R78O96V090

    View details for Web of Science ID 000232836500003

    View details for PubMedID 16203275

  • Radiographically occult, diffuse intrasinusoidal hepatic metastases from primary breast carcinomas - A clinicopathologic study of 3 autopsy cases Annual Meeting of the United-States-and-Canadian-Association-of-Pathologists Allison, K. H., Fligner, C. L., Parks, T. COLL AMER PATHOLOGISTS. 2004: 1418–23

    Abstract

    Liver metastases usually present as radiographically detectable mass lesions that do not significantly compromise liver function. Rarely, metastatic carcinoma can diffusely infiltrate hepatic sinusoids, a pattern of metastasis that may be missed on imaging studies, and can result in liver failure.To describe the clinicopathologic features of 3 cases of diffuse intrasinusoidal hepatic metastases from primary breast carcinomas identified at autopsy.Clinical histories and radiographic, macroscopic, and microscopic appearances of the livers were compared. Sampled liver tissue was stained with antibodies to E-cadherin, smooth muscle actin, and CD44.Two of 3 cases had a history of infiltrating ductal carcinoma of the breast and presented with new-onset liver failure, but no hepatic metastases were identified on radiologic imaging. An additional case had no history of carcinoma, presented with a severe thrombocytopenic thrombotic purpura-like syndrome, and metastatic carcinoma of the breast was diagnosed only at autopsy. The livers in all 3 cases at autopsy were homogeneous, firm, and tan-yellow, and contained no large metastatic lesions. Microscopically, poorly differentiated carcinoma diffusely infiltrated hepatic sinusoids. Antibodies to smooth muscle actin stained activated hepatic stellate cells lining involved sinusoids. Cell surface adhesion molecules, E-cadherin or CD44, were not detected in any hepatic metastases.Diffuse intrasinusoidal hepatic metastases of breast carcinoma can occupy a large percentage of the hepatic volume, yet remain occult both radiographically and macroscopically. This type of metastatic spread can present as cryptogenic liver failure. The 3 cases we studied were associated with an absence of E-cadherin and CD44 expression.

    View details for Web of Science ID 000225720100023

    View details for PubMedID 15578887

  • Angiosarcoma involving the gastrointestinal tract - A series of primary and metastatic cases AMERICAN JOURNAL OF SURGICAL PATHOLOGY Allison, K. H., Yoder, B. J., Bronner, M. P., Goldblum, J. R., Rubin, B. P. 2004; 28 (3): 298-307

    Abstract

    Angiosarcoma occurs very rarely in the intestinal tract as either a primary or metastatic malignancy and can present great diagnostic difficulty, especially when it displays epithelioid cytomorphology. Since only isolated case reports have been published, the purpose of this study is to more fully delineate the histopathological and clinical features from a series of 8 angiosarcomas involving the gastrointestinal tract. There were 5 male and 3 female patients whose ages ranged from 25-85 years (median 57). Presenting symptoms included intestinal bleeding, anemia and pain. Five cases involved the small bowel and 3 involved the colon/rectum. Four cases were primary to the intestinal tract, 2 patients initially presented with secondary involvement of the large bowel from occult retroperitoneal primaries, 1 patient presented with disseminated disease including small bowel involvement, and 1 case was metastatic from a breast primary. Seven cases were composed predominantly of sheets of malignant appearing epithelioid cells with subtle areas forming cleft-like spaces suggestive of vascular differentiation. Immunohistochemical studies revealed the lesional cells to be immunoreactive for CD31 (8/8), CD34 (8/8), Factor VIII (8/8), cytokeratins AE1/AE3 (7/8), cytokeratin 7 (2/8), Cam5.2/cytokeratin 8 (5/8), and cytokeratin 19 (5/8). Cytokeratin 20 was negative in all eight cases, which contrasts sharply with the characteristic positivity for cytokeratin 20 in virtually all intestinal carcinomas. One case was weakly and focally positive for EMA and all cases were negative for S-100 protein. Cytokeratin staining was variable and ranged from focal to extensive. Follow-up was available in eight cases and ranged from 1-33 months (median 12.5). Five patients died of disease, between 1 and 33 months (median 6) after diagnosis. One recently diagnosed patient is alive with disease 18 months after diagnosis, and one patient is free of disease 27 months after original diagnosis. Angiosarcomas of the gastrointestinal tract commonly display epithelioid cytomorphology, may be diffusely and strongly positive for cytokeratins and only show subtle signs of vascular differentiation, creating potential diagnostic confusion with primary or metastatic carcinoma. Given the clinically aggressive behavior of angiosarcoma, proper classification and treatment is important. Immunohistochemistry with vascular markers, CK20, and S-100 protein may be helpful in differentiating angiosarcoma from carcinoma and melanoma.

    View details for Web of Science ID 000189316500002

    View details for PubMedID 15104292

  • An unusual case of multiple giant myelolipomas: Clinical and pathogenetic implications ENDOCRINE PATHOLOGY Allison, K. H., Mann, G. N., Norwood, T. H., Rubin, B. P. 2003; 14 (1): 93-100

    Abstract

    Myelolipomas are benign tumors composed of both mature adipose and myeloid tissues. They typically present as an incidental mass in one of the adrenal glands proper. However, they can occur in ectopic adrenal tissue or, rarely, without associated adrenal tissue in various locations and can grow to weights of several kilograms. These tumors have been linked to endocrinopathies, such as Cushing disease and congenital adrenal hyperplasia, which involve overproduction of adrenocorticotropic hormone. We report a case of three giant adrenal myelolipomas arising in a persistently virilized female with congenital adrenal hyperplasia, supporting a role for hormonal stimuli in myelolipoma formation.

    View details for Web of Science ID 000183026300010

    View details for PubMedID 12746567

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