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* Purpose.--To update the American Society of Clinical Oncology-College of American Pathologists (ASCO-CAP) recommendations for human epidermal growth factor receptor 2 (HER2) testing in breast cancer. An Update Panel is aware that a new generation of antibody-drug conjugates targeting the HER2 protein is active against breast cancers that lack protein overexpression or gene amplification. Methods.--The Update Panel conducted a systematic literature review to identify signals for updating recommendations. Results.--The search identified 173 abstracts. Of 5 potential publications reviewed, none constituted a signal for revising existing recommendations. Recommendations.--The 2018 ASCO-CAP recommendations for HER2 testing are affirmed. Discussion.--HER2 testing guidelines have focused on identifying HER2 protein overexpression or gene amplification in breast cancer to identify patients for therapies that disrupt HER2 signaling. This update acknowledges a new indication for trastuzumab deruxtecan when HER2 is not overexpressed or amplified but is immunohistochemistry (IHC) 1+ or 2+ without amplification by in situ hybridization. Clinical trial data on tumors that tested IHC 0 are limited (excluded from DESTINY-Breast04), and evidence is lacking that these cancers behave differently or do not respond similarly to newer HER2 antibody-drug conjugates. Although current data do not support a new IHC 0 versus 1+ prognostic or predictive threshold for response to trastuzumab deruxtecan, this threshold is now relevant because of the trial entry criteria that supported its new regulatory approval. Therefore, although it is premature to create new result categories of HER2 expression (eg, HER2-Low, HER2-Ultra-Low), best practices to distinguish IHC 0 from 1+ are now clinically relevant. This update affirms prior HER2 reporting recommendations and offers a new HER2 testing reporting comment to highlight the current relevance of IHC 0 versus 1+ results and best practice recommendations to distinguish these often subtle differences. Additional information is available at www.asco.org/breast-cancer-guidelines., The American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP) first published a practice guideline on human epidermal growth factor receptor 2 (HER2) testing in breast [...]

* Purpose.--To update key recommendations of the American Society of Clinical Oncology/College of American Pathologists estrogen receptor (ER) and progesterone receptor (PgR) testing in breast cancer guideline. Methods.--A multidisciplinary international Expert Panel was convened to update the clinical practice guideline recommendations informed by a systematic review of the medical literature. Recommendations.--The Expert Panel continues to recommend ER testing of invasive breast cancers by validated immunohistochemistry as the standard for predicting which patients may benefit from endocrine therapy, and no other assays are recommended for this purpose. Breast cancer samples with 1% to 100% of tumor nuclei positive should be interpreted as ER positive. However, the Expert Panel acknowledges that there are limited data on endocrine therapy benefit for cancers with 1% to 10% of cells staining ER positive. Samples with these results should be reported using a new reporting category, ER Low Positive, with a recommended comment. A sample is considered ER negative if < 1% or 0% of tumor cell nuclei are immunoreactive. Additional strategies recommended to promote optimal performance, interpretation, and reporting of cases with an initial low to no ER staining result include establishing a laboratory-specific standard operating procedure describing additional steps used by the laboratory to confirm/adjudicate results. The status of controls should be reported for cases with 0% to 10% staining. Similar principles apply to PgR testing, which is used primarily for prognostic purposes in the setting of an ER-positive cancer. Testing of ductal carcinoma in situ (DCIS) for ER is recommended to determine potential benefit of endocrine therapies to reduce risk of future breast cancer, while testing DCIS for PgR is considered optional. Additional information can be found at www.asco.org/breast-cancer-guidelines. (Arch Pathol Lab Med. 2020;144:545-563; doi: 10.5858/arpa.2019-0904-SA), INTRODUCTION First released in 2010, the American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) estrogen receptor (ER) and progesterone receptor (PgR) testing guideline is aimed at improving the [...]

Recently, the Journal of Clinical Oncology (JCO) received a letter to the editor from Rakha et al (1) about the American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) [...]

Context.--Prostate cancer remains a significant public health problem. Recent publications of randomized trials and the US Preventive Services Task Force recommendations have drawn attention to overtreatment of localized, low-risk prostate cancer. Active surveillance, in which patients undergo regular visits with serum prostate-specific antigen tests and repeat prostate biopsies, rather than aggressive treatment with curative intent, may address overtreatment of low-risk prostate cancer. It is apparent that a greater awareness of the critical role of pathologists in determining eligibility for active surveillance is needed. Objectives.--To review the state of current knowledge about the role of active surveillance in the management of prostate cancer and to provide a multidisciplinary report focusing on pathologic parameters important to the successful identification of patients likely to succeed with active surveillance, to determine the role of molecular tests in increasing the safety of active surveillance, and to provide future directions. Design.--Systematic review of literature on active surveillance for low-risk prostate cancer, pathologic parameters important for appropriate stratification, and issues regarding interobserver reproducibility. Expert panels were created to delineate the fundamental questions confronting the clinical and pathologic aspects of management of men on active surveillance. Results.--Expert panelists identified pathologic parameters important for management and the related diagnostic and reporting issues. Consensus recommendations were generated where appropriate. Conclusions.--Active surveillance is an important management option for men with low-risk prostate cancer. Vital to this process is the critical role pathologic parameters have in identifying appropriate candidates for active surveillance. These findings need to be reproducible and consistently reported by surgical pathologists with accurate pathology reporting. (Arch Pathol Lab Med. 2014;138:1387-1405; doi: 10.5858/arpa.2014-0219-SA), In December 2011, the National Institutes of Health conducted a state-of-the-science conference with a summary statement on the role of active surveillance in the management of men with localized prostate [...]

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. (Arch Pathol Lab Med. 2014; 138:241-256; doi: 10.5858/arpa.2013-0953-SA), In 2007, a joint Expert Panel convened by the American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP) met to develop guidelines for when and how [...]

The College of American Pathologists (CAP) is dedicated to pathology and laboratory medicine quality. The CAP's Laboratory Accreditation Program, Proficiency Testing Program, Q-Probes and Q-Tracks, site-specific cancer checklists, webinars, annual meetings, and Advanced Practical Pathology series are all focused on providing superior patent quality. The CAP is synonymous with quality in pathology and laboratory medicine. As pathology practice becomes more sophisticated, the CAP's many programs will increasingly help pathologists provide appropriate, personalized patient care. (Arch Pathol Lab Med. 2011; 135:1441; doi: 10.5858/arpa.2011-0287-SAM), The College of American Pathologists (CAP) is synonymous with quality in pathology and laboratory medicine. The CAP historically has functioned in numerous ways to enhance quality in pathology. Probably the [...]

* Purpose.--To develop a guideline to improve the accuracy of immunohistochemical (IHC) estrogen receptor (ER) and progesterone receptor (PgR) testing in breast cancer and the utility of these receptors as predictive markers. Methods.--The American Society of Clinical Oncology and the College of American Pathologists convened an international Expert Panel that conducted a systematic review and evaluation of the literature in partnership with Cancer Care Ontario and developed recommendations for optimal IHC ER/PgR testing performance. Results.--Up to 20% of current IHC determinations of ER and PgR testing worldwide may be inaccurate (false negative or false positive). Most of the issues with testing have occurred because of variation in pre-analytic variables, thresholds for positivity, and interpretation criteria. Recommendations.--The Panel recommends that ER and PgR status be determined on all invasive breast cancers and breast cancer recurrences. A testing algorithm that relies on accurate, reproducible assay performance is proposed. Elements to reliably reduce assay variation are specified. It is recommended that ER and PgR assays be considered positive if there are at least 1% positive tumor nuclei in the sample on testing in the presence of expected reactivity of internal (normal epithelial elements) and external controls. The absence of benefit from endocrine therapy for women with ER-negative invasive breast cancers has been confirmed in large overviews of randomized clinical trials., ESTROGEN RECEPTOR PHYSIOLOGY AND MEASUREMENT The estrogen receptor (ER) is the paradigm tumor marker for management of patients with cancer. For more than three decades, ER has been the most [...]

* Context.--Estrogen receptor and progesterone receptor status is assessed on all newly diagnosed, invasive breast carcinomas and in recurrences to determine patient eligibility for hormonal therapy, but 10% to 20% of estrogen receptor and progesterone receptor test results are discordant when tested in multiple laboratories. Objective.--To define the analytic (technical) validation requirements for estrogen receptor and progesterone receptor immunohistochemistry assays used to select patients for hormonal therapy. Data Sources.--Literature review and expert consensus. Conclusions.--A standardized process for initial test validation is described. We believe adoption of this process will improve the accuracy of hormone-receptor testing, reduce interlaboratory variation, and minimize false-positive and false-negative results. Required ongoing assay assessment procedures are also described. (Arch Pathol Lab Med. 2010;134:930-935), Validation of a clinical laboratory test means confirmation, through a defined process, that the test performs as intended or claimed. Proper validation provides reasonable, but not absolute, assurance that a [...]

* Context.--Intermountain Healthcare hospitals use a single, standardized laboratory and automated testing process for estrogen receptor/progesterone receptor (ER/ PR) tests to minimize testing errors. Objectives.--To test the (1) variability in ER/PR negativity among hospitals and (2) association between specimen handling conditions and ER/PR negativity. Design.--Retrospective study of women who had breast cancer surgery at 7 Intermountain hospitals and ER/PR tests ordered between 1997 and 2003. Data were extracted from cancer registry. Frequency of ER/PR negativity was calculated for each surgery day and compared among hospitals and between 2 groups: regular (specimens obtained Sunday through Thursday, more likely to be tested within 24 hours of surgery) and prolonged (specimens obtained on Friday and Saturday, more likely to be tested more than 24 hours after surgery) specimen handling conditions. Results.--Five thousand seventy-seven women were tested for ER/PR. The frequency of ER and PR negativity was 20.9% and 27.9%, respectively. It increased with each day of the week for both ER (P = .03) and PR (P = .059) and tended to be higher for prolonged specimens for ER (23.6% versus 20.4%; P = .03) and for PR (30.1% versus 27.4%; P = .11) compared with regular specimens. After controlling for age and tumor size, both ER (P = .02) and PR (P = .02) negativity was significantly different among the hospitals and was associated with prolonged specimens for ER (P = .04) but not for PR (P = .09). Conclusions.--Estrogen receptor and PR negativity remained highly variable among hospitals despite use of a single laboratory and tended to be significantly associated with prolonged specimen handling. More studies are needed to confirm these findings. (Arch Pathol Lab Med. 2010;134:606-612), The estrogen receptor/progesterone receptor (ER/PR) test is an important prognostic indicator in the management of patients with breast cancer. It is also an important predictive test used to select women [...]

* Context.--KRAS mutations can be detected in approximately 30% to 40% of all patients with colorectal cancer. Several recent studies have shown that patients with KRAS mutations in codons 12 or 13 in metastatic tumors do not benefit from anti-epidermal growth factor receptor therapy with cetuximab or panitumumab. Objective.--To review the literature on the role of KRAS mutation testing for management of patients with metastatic colorectal cancer and to discuss testing strategies. Data Sources.--This review is based on published, peer-reviewed literature; available information from medical organizations (eg, National Comprehensive Cancer Network, American Society of Clinical Oncology, College of American Pathologists); and information from clinical laboratories conducting KRAS mutation analysis. Conclusions.--Multiple methods for detecting KRAS mutations in colorectal tumors are available, and all methods in current clinical use appear to have adequate clinical sensitivity for predicting a lack of response to cetuximab and panitumumab. Pathologist expertise is essential to quality KRAS testing and to determining effective treatment for patients with metastatic colorectal cancer. (Arch Pathol Lab Med. 2009;133:1600-1606), In the United States, an estimated 108070 cases of colon cancer and 40 740 cases of rectal cancer were expected to occur in 2008. (1) Colorectal cancer (CRC) is the [...]

Context.--Intratumoral heterogeneity of HER2 gene amplification has been well documented and represents subclonal diversity within the tumor. The reported incidence of intratumor HER2 amplification genetic heterogeneity ranges in the literature from approximately 5% to 30%. The presence of HER2 genetic heterogeneity may increase subjectivity in HER2 interpretation by the pathologist. Objectives.--To define HER2 genetic heterogeneity and to provide practice guidelines for examining and reporting breast tumors with genetic heterogeneity for improvement of HER2 testing in breast cancer. Design.--We convened an expert panel to discuss HER2 gene amplification testing by fluorescence in situ hybridization. Components addressed included a definition of HER2 amplification heterogeneity, practice guidelines for examination of the tissue, and reporting criteria for this analysis. Results.--Genetic heterogeneity for amplification of HER2 gene status in invasive breast cancer is defined and guidelines established for assessing and reporting HER2 results in these cases. These guidelines are additive to and expand those published in 2007 by the American Society of Clinical Oncology and the College of American Pathologists. Conclusion.--Standardized methods for analysis will improve the accuracy and consistency of interpretation of HER2 gene amplification status in breast cancer., In 2007, the American Society of Clinical Oncology and the College of American Pathologists (CAP) published guidelines for HER2 testing in breast cancer to improve accuracy and reproducibility of the [...]

The diagnosis of breast cancer is devastating news for women of any age and immediately raises a number of pressing questions for the patient: Will the tumor return in the [...]

* Purpose.--To develop a guideline to improve the accuracy of human epidermal growth factor receptor 2 (HER2) testing in invasive breast cancer and its utility as a predictive marker. Methods.--The [...]

A Basis for Checklists This protocol is intended to assist pathologists in providing clinically useful and relevant information as a result of the examination of surgical specimens. Use of this [...]

* Context.-- Inferences from tumor marker studies are complicated by a variety of statistical concerns, which can make proper interpretation of results difficult. This article focuses on important issues that should be addressed when designing, conducting, and analyzing tumor marker studies. Objective.--To highlight the importance of considering statistical significance, risk ratios, statistical power, reproducibility, multiple testing, confirmatory studies, and missing data in the design of marker studies used for prognosis. Results.--Suggestions are provided for more effectively conducting marker studies. These include more careful attention to adequacy of the number of subjects for a marker study and improved documentation and standardization of assay methods. The importance of complete reporting of study results and description of the statistical analysis methods used is also emphasized. Conclusion.--Cooperation among clinicians, laboratory scientists, and statisticians will be required to conduct statistically sound tumor marker studies and to facilitate prioritizing markers for new and confirmatory studies in an environment of limited patient and specimen resources. (Arch Pathol Lab Med. 2000;124:1011-1015), The authors deal routinely with statistical issues associated with tumor markers in cancer cooperative group and cancer center activities. In our presentation at the College of American Pathologists Conference XXXV, [...]

* Background.--Under the auspices of the College of American Pathologists, the current state of knowledge regarding pathologic prognostic factors (factors linked to outcome) and predictive factors (factors predicting response to therapy) in colorectal carcinoma was evaluated. A multidisciplinary group of clinical (including the disciplines of medical oncology, surgical oncology, and radiation oncology), pathologic, and statistical experts in colorectal cancer reviewed all relevant medical literature and stratified the reported prognostic factors into categories that reflected the strength of the published evidence demonstrating their prognostic value. Accordingly, the following categories of prognostic factors were defined. Category I includes factors definitively proven to be of prognostic import based on evidence from multiple statistically robust published trials and generally used in patient management. Category IIA includes factors extensively studied biologically and/or clinically and repeatedly shown to have prognostic value for outcome and/or predictive value for therapy that is of sufficient import to be included in the pathology report but that remains to be validated in statistically robust studies. Category IIB includes factors shown to be promising in multiple studies but lacking sufficient data for inclusion in category I or IIA. Category III includes factors not yet sufficiently studied to determine their prognostic value. Category IV includes factors well studied and shown to have no prognostic significance. Materials and Methods.--The medical literature was critically reviewed, and the analysis revealed specific points of variability in approach that prevented direct comparisons among published studies and compromised the quality of the collective data. Categories of variability recognized included the following: (1) methods of analysis, (2) interpretation of findings, (3) reporting of data, and (4) statistical evaluation. Additional points of variability within these categories were defined from the collective experience of the group. Reasons for the assignment of an individual prognostic factor to category I, II, III, or IV (categories defined by the level of scientific validation) were outlined with reference to the specific types of variability associated with the supportive data. For each factor and category of variability related to that factor, detailed recommendations for improvement were made. The recommendations were based on the following aims: (1) to increase the uniformity and completeness of pathologic evaluation of tumor specimens, (2) to enhance the quality of the data needed for definitive evaluation of the prognostic value of individual prognostic factors, and (3) ultimately, to improve patient care. Results and Conclusions.--Factors that were determined to merit inclusion in category I were as follows: the local extent of tumor assessed pathologically (the pT category of the TNM staging system of the American Joint Committee on Cancer and the Union Internationale Contre le Cancer [AJCC/UICC]); regional lymph node metastasis (the pN category of the TNM staging system); blood or lymphatic vessel invasion; residual tumor following surgery with curative intent (the R classification of the AJCC/UICC staging system), especially as it relates to positive surgical margins; and preoperative elevation of carcinoembryonic antigen elevation (a factor established by laboratory medicine methods rather than anatomic pathology). Factors in category IIA included the following: tumor grade, radial margin status (for resection specimens with nonperitonealized surfaces), and residual tumor in the resection specimen following neoadjuvant therapy (the ypTNM category of the TNM staging system of the AJCC/UICC). Factors in category lib included the following: histologic type, histologic features associated with microsatellite instability (MSI) (ie, host lymphoid response to tumor and medullary or mucinous histologic type), high degree of MSI (MSI-H), loss of heterozygosity at 18q (DCC gene allelic loss), and tumor border configuration (infiltrating vs pushing border). Factors grouped in category III included the following: DNA content, all other molecular markers except loss of heterozygosity 18q/DCC and MSI-H, perineural invasion, microvessel density, tumor cell-associated proteins or carbohydrates, peritumoral fibrosis, peritumoral inflammatory response, focal neuroendocrine differentiation, nuclear organizing regions, and proliferation indices. Category IV factors included tumor size and gross tumor configuration. This report records findings and recommendations of the consensus conference group, organized according to structural guidelines defined herein. (Arch Pathol Lab Med. 2000;124:979-994), College of American Pathologists Consensus Statement 1999 CATEGORY I FACTORS Local Extent of Tumor Assessed Pathologically (pT Category) Overview.--Despite universal recognition of the prognostic importance of the local extent of [...]

* Medicine has been identified as a profession for almost 3000 years based on a core premise that physicians have the right to evaluate their own quality. Because medicine is a profession and because of the special privileges granted to physicians by society, quality-based principles that evolved in the manufacturing business have been difficult to adapt to medical practice. Physicians learn from other physicians and medical literature. This leads to wide variation in what is considered best practice. Variation has complex association, including the variation in expert opinion, the complexity of medical knowledge, the variation in physician decision-making potential, and human error. Guidelines or algorithms are a strategy that are finding favor as a solution. The control of variation through guideline development, iterative refinement of guidelines, and feedback to physicians will improve medical practice. By removing variation, physicians can honor the fiduciary trust that they have made to patients, make reasoned decisions, improve outcomes, and focus attention on making medical improvements. (Arch Pathol Lab Med. 2000;124:1001-1003), Medicine has been identified as a profession for almost 3000 years. This long history stems from a core premise: physicians reserve to themselves the right to evaluate their own quality. [...]

* Background.--Under the auspices of the College of American Pathologists, a multidisciplinary group of clinicians, pathologists, and statisticians considered prognostic and predictive factors in prostate cancer and stratified them into categories reflecting the strength of published evidence and taking into account the expert opinions of the Prostate Working Group members. Materials and Methods.--Factors were ranked according to the previous College of American Pathologists categorical rankings: category I, factors proven to be of prognostic importance and useful in clinical patient management; category II, factors that have been extensively studied biologically and clinically but whose importance remains to be validated in statistically robust studies; and category III, all other factors not sufficiently studied to demonstrate their prognostic value. Factors in categories I and II were considered with respect to variations in methods of analysis, interpretation of findings, reporting of data, and statistical evaluation. For each factor, detailed recommendations for improvement were made. Recommendations were based on the following aims: (1) increasing uniformity and completeness of pathologic evaluation of tumor specimens, (2) enhancing the quality of data collected pertaining to existing prognostic factors, and (3) improving patient care. Results and Conclusions.--Factors ranked in category I included preoperative serum prostate-specific antigen level, TNM stage grouping, histologic grade as Gleason score, and surgical margin status. Category II factors included tumor volume, histologic type, and DNA ploidy. Factors in category III included perineural invasion, neuroendocrine differentiation, microvessel density, nuclear roundness, chromatin texture, other karyometric factors, proliferation markers, prostate-specific antigen derivatives, and other factors (oncogenes, tumor suppressor genes, apoptosis genes, etc). (Arch Pathol Lab Med. 2000;124:995-1000), College of American Pathologists Consensus Statement 1999 CATEGORY I Prostate-Specific Antigen[1-6] Method Variation Issues * Multiple methods are available ([is greater than] 30 different assays). Hybritech and Abbott AXSYM are [...]

* The College of American Pathologists convened a prognostic factor conference in June 1999 to consider prognostic and predictive factors in breast, colon, and prostate cancer, and to stratify these factors into categories reflecting the strength of published evidence. Because so little progress in prognostic factor clinical utility has been made in the last 5 years, the conference participants focused their attention on decreasing variation in methods, interpretation, and reporting of these factors so that greater clarity of value could be achieved. The conference was organized to promote discussion, broad input, and future planning. An initial plenary session provided an overview of the status of tumor marker research, the impact of variation in medicine and pathology, and statistical issues related to prognostic factor research. In working group sessions for each cancer type, participants interactively evaluated and refined the documents created by the expert panels. A second plenary session dealt with issues common to all 3 groups, including the problem of micrometastases in lymph nodes in these sites; statistical issues that arose during the breakout discussions; and issues of variation in methods, interpretation, and reporting of immunohistochemical assays. A faculty session brainstormed strategies that could be used to implement the changes recommended. This session included invited representatives of the Food and Drug Administration, Health Care Financing Administration, Centers for Disease Control and Prevention, National Cancer Institute, American Joint Committee on Cancer, and International Union Against Cancer. Cancer site and general recommendations were presented and discussed during a final session to achieve consensus of the conference participants and to address feasibility of implementation of these recommendations. A final discussion focused on future initiatives that might lead to implementation of the changes proposed in the conference by the various organizations represented. This report summarizes the general conference recommendations, cancer working group recommendations, and plans for implementation of the recommendations. (Arch Pathol Lab Med. 2000;124:958-965), Summary Document and Recommendations for Implementation In 1994, the College of American Pathologists (CAP) and its Cancer Committee sponsored a conference to address which prognostic factors were clinically useful in [...]