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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.

he College of American Pathologists offers thesetemplates to assist pathologists in providing clinicallyuseful and relevant information when reporting results ofbiomarker testing. The College regards the reportingelements in the templates as important elements of thebiomarker test report, but the manner in which theseelements are reported is at the discretion of each specificpathologist, taking into account clinician preferences,institutional policies, and individual practice.The College developed these templates as educationaltools to assist pathologists in the useful reporting of relevantinformation. It did not issue them for use in litigation,reimbursement, or other contexts. Nevertheless, the Collegerecognizes that the templates might be used by hospitals,attorneys, payers, and others. The College cautions that useof the templates other than for their intended educationalpurpose may involve additional considerations that arebeyond the scope of this document.TEMPLATE FOR REPORTING RESULTS OF BIOMARKERTESTING OF SPECIMENS FROM PATIENTSWITH CARCINOMA OF THE BREASTCompletion of the template is the responsibility of thelaboratory performing the biomarker testingand/or providingthe interpretation. When both testing and interpretation areperformed elsewhere (eg, a reference laboratory), synopticreporting of the results by the laboratory submitting thetissue for testing is also encouraged to ensure that allinformation is included in the patient’s medical record andthus readily available to the treating clinical team.BIOMARKER REPORTING TEMPLATEBreastNote: Required elements in this template comply with the mostrecent versions of the American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines onHER2 and hormone receptor testing. Reporting elements arerequired only if applicable and only for tests performed. If somestudies were performed on different specimen(s), the specimennumber(s) should be provided.þ Data elements preceded by this symbol are not required.RESULTSEstrogen Receptor (ER)___ Positive (percentage of cells with nuclear positivity:___ %)þ Average intensity of staining:þ ___ Weakþ ___ Moderateþ ___ Strong___ Negative___ Internal controls present and ER positive (asexpected)___ Internal controls present but ER negative___ Internal controls absent___ Cannot be determined (explain): _________________Progesterone Receptor (PgR)___ Positive (percentage of cells with nuclear positivity:____ %)þ Average intensity of staining:þ ___ Weakþ ___ Moderateþ ___ Strong___ Negative___ Internal controls present and PgR positive (asexpected)___ Internal controls present but PgR negative

The College of American Pathologists offers these templates to assist pathologists in providing clinically useful and relevant information when reporting results of biomarker testing. The College regards the reporting elements in the templates as important elements of the biomarker test report, but the manner in which these elements are reported is at the discretion of each specific pathologist, taking into account clinician preferences, institutional policies, and individual practice.

The College of American Pathologists offers these templates to assist pathologists in providing clinically useful and relevant information when reporting results of biomarker testing. The College regards the reporting elements in the templates as important elements of the biomarker test report, but the manner in which these elements are reported is at the discretion of each specific pathologist, taking into account clinician preferences, institutional policies, and individual practice. The College developed these templates as educational tools to assist pathologists in the useful reporting of relevant information. It did not issue them for use in litigation, reimbursement, or other contexts. Nevertheless, the College recognizes that the templates might be used by hospitals, attorneys, payers, and others. The College cautions that use of the templates other than for their intended educational purpose may involve additional considerations that are beyond the scope of this document.

The immunohistochemistry (IHC) laboratory represents a dynamic area of surgical pathology with limited practice guidelines. Studies have shown significant interlaboratory variability in results.To establish baseline parameters for IHC validation procedures and practice, and to assess their feasibility of implementation.In September 2010, a questionnaire was distributed by the College of American Pathologists. It was composed of 32 questions relating to nonpredictive assays as well as non-US Food and Drug Administration (non-FDA)-approved, predictive IHC assays other than human epidermal growth factor 2 (HER2/neu).For non-FDA approved, nonpredictive IHC assays, 68% of laboratories had a written validation procedure. Eighty-six percent of laboratories validated the most recently introduced nonpredictive antibody. Seventy-five percent used 21 or fewer total cases for the validation and 40% used weakly or focally positive cases. Forty-six percent of respondents had a written procedure for validation procedures for non-FDA approved, predictive marker IHC assays other than HER2/neu. Seventy-five percent of laboratories validated the most recently introduced predictive antibody other than HER2/neu. Fewer than half used 25 or more cases for the validation, and 47% used weakly or focally positive cases.Some laboratories have written validation procedures that appear to build upon HER2/neu testing guidelines. Some laboratories also manage to validate new antibodies according to those standards; however, many do not. There appears to be a need for further validation guideline development for nonpredictive and non-FDA approved predictive antibody IHC assays.

Context.—Recognizing the difficulty in applying the concept of critical values to anatomic pathology diagnoses, the College of American Pathologists and the Association of Directors of Anatomic and Surgical Pathology have chosen to reevaluate the concept of critical diagnoses.Objective.—To promote effective communication of urgent and significant, unexpected diagnoses in surgical pathology and cytology.Design.—A comprehensive literature search was conducted and reviewed by an expert panel.Results.—A policy of effective communication of important results in surgical pathology and cytology is desirable to enhance patient safety and to address multiple regulatory requirements.Conclusions.—Each institution should create its own policy regarding urgent diagnoses and significant, unexpected diagnoses in anatomic pathology. This policy should be separate from critical results or panic-value policies in clinical pathology, with the expectation of a different time frame for communication. Urgent diagnosis is defined as a medical condition that, in most cases, should be addressed as soon as possible. Significant, unexpected diagnosis is defined as a medical condition that is clinically unusual or unforeseen and should be addressed at some point in the patient's course. Further details of this statement are provided.

Context.—The number of paraffin blocks submitted for patients enrolled in clinical research trials appears to be declining. Objective.—To obtain information on laboratory policies and procedures in complying with requests to submit paraffin blocks for research. Design.—A questionnaire was sent to members of a voluntary market research panel composed of pathologists representing a broad spectrum of experience and practice settings. The questions addressed departmental policies and the likely responses to requests to submit pathology materials for patients enrolled in clinical trials. Results.—The survey was completed by 609 of 762 pathologists (80%) who responded to the invitation. More than 90% of respondents stated that they comply with these requests. Although 14% have a policy precluding the release of blocks for research, 84% of those will send limited tissue samples in lieu of blocks. When tumor is confined to a single block, most laboratories will not release the block but will send unstained slides. Very few laboratories require reimbursement before releasing tissues. Conclusions.—Pathologists attempt to comply with requests for materials but usually refuse to release the only diagnostic paraffin block so that materials are retained for possible future needs. Other problems identified in this survey include difficulties in getting blocks returned when needed and poor communication between researchers and laboratories. Lack of reimbursement and inadequate consent are not significant barriers to release of materials.

Context.—To ensure quality human epidermal growth receptor 2 (HER2) testing in breast cancer, the American Society of Clinical Oncology/College of American Pathologists guidelines were introduced with expected compliance by 2008. Objective.—To assess the effect these guidelines have had on pathology laboratories and their ability to address key components. Design.—In late 2008, a survey was distributed with the HER2 immunohistochemistry (IHC) proficiency testing program. It included questions regarding pathology practice characteristics and assay validation using fluorescence in situ hybridization or another IHC laboratory assay and assessed pathologist HER2 scoring competency. Results.—Of the 907 surveys sent, 757 (83.5%) were returned. The median laboratory accessioned 15 000 cases and performed 190 HER2 tests annually. Quantitative computer image analysis was used by 33% of laboratories. In-house fluorescence in situ hybridization was performed in 23% of laboratories, and 60% of laboratories addressed the 6- to 48-hour tissue fixation requirement by embedding tissue on the weekend. HER2 testing was performed on the initial biopsy in 40%, on the resection specimen in 6%, and on either in 56% of laboratories. Testing was validated with only fluorescence in situ hybridization in 47% of laboratories, whereas 10% of laboratories used another IHC assay only; 13% used both assays, and 12% and 15% of laboratories had not validated their assays or chose “not applicable” on the survey question, respectively. The 90% concordance rate with fluorescence in situ hybridization results was achieved by 88% of laboratories for IHC-negative findings and by 81% of laboratories for IHC-positive cases. The 90% concordance rate for laboratories using another IHC assay was achieved by 80% for negative findings and 75% for positive cases. About 91% of laboratories had a pathologist competency assessment program. Conclusions.—This survey demonstrates the extent and characteristics of HER2 testing. Although some American Society of Clinical Oncology/College of American Pathologists guidelines have been implemented, gaps remain in validation of HER2 IHC testing.

The College of American Pathologists offers these protocols to assist pathologists in providing clinically useful and relevant information when reporting results of surgical specimen examinations. The College regards the reporting elements in the ‘‘Surgical Pathology Cancer Case Summary (Checklist)’’ portion of the protocols as essential elements of the pathology report. However, the manner in which these elements are reported is at the discretion of each specific pathologist, taking into account clinician preferences, institutional policies, and individual practice. The College developed these protocols as an educational tool to assist pathologists in the useful reporting of relevant information. It did not issue the protocols for use in litigation, reimbursement, or other contexts. Nevertheless, the College recognizes that the protocols might be used by hospitals, attorneys, payers, and others. Indeed, effective January 1, 2004, the Commission on Cancer of the American College of Surgeons mandated the use of the checklist elements of the protocols as part of its Cancer Program Standards for Approved Cancer Programs. Therefore, it becomes even more important for pathologists to familiarize themselves with these documents. At the same time, the College cautions that use of the protocols other than for their intended educational purpose may involve additional considerations that are beyond the scope of these documents.

Context.—We have developed tissue microarray-based surveys to allow laboratories to compare their performance in staining predictive immunohistochemical markers, including proto-oncogene CD117 (c-kit), which is characteristically expressed in gastrointestinal stromal tumors (GISTs). GISTs exhibit activating mutations in the c-kit proto-oncogene, which render them amenable to treatment with imatinib mesylate. Consequently, correct identification of c-Kit expression is important for the diagnosis and treatment of GISTs. Objective.—To analyze CD117 immunohistochemical staining performance by a large number of clinical laboratories. Design.—A mechanical device was used to construct tissue microarrays consisting of 3 × 1-mm cores of 10 tumor samples, which can be used to generate hundreds of tissue sections from the arrayed cases, suitable for large-scale interlaboratory comparison of immunohistochemical staining. Results.—An initial survey of 63 laboratories and a second survey of 90 laboratories, performed in 2004 and 2005, exhibited >81% concordance for 7 of 10 cores, including all 4 GIST cases, which were immunoreactive for CD117 with >95% staining concordance. Three of the cores achieved less than 81% concordance of results, possibly due to the presence of foci of necrosis in one core and CD117-positive mast cells in 2 cores of CD117-negative neoplasms. Conclusions.—There was good performance among a large number of laboratories performing CD117 immunohistochemical staining, with consistently higher concordance of results for CD117-positive GIST cases than for nonimmunoreactive cases. Tissue microarrays for CD117 and other predictive markers should be useful for interlaboratory comparisons, quality assurance, and education of participants regarding staining nuances such as the expression of CKIT by nonneoplastic mast cells.

T 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 protocol is intended to be entirely voluntary. If equally valid protocols or similar documents are applicable, the pathologist is, of course, free to follow those authorities. Indeed, ultimate judgment regarding the propriety of any specific procedure must be made by the physician in light of the individual circumstances presented by a specific patient or specimen. It should be understood that adherence to this protocol will not guarantee a successful result. Nevertheless, pathologists are urged to familiarize themselves with the document. Should a physician choose an alternative approach owing to the circumstances of a particular patient or specimen, the physician is advised to make a contemporaneous written notation of the reason for the procedure followed. The College recognizes that this document may be used by hospitals, attorneys, managed care organizations, insurance carriers, and other payers. However, the document was developed solely as a tool to assist pathologists in the diagnostic process by providing information that reflects the state of relevant medical knowledge at the time the protocol was first published. It was not developed for credentialing, litigation, or reimbursement purposes. The College cautions that any uses of the protocol for these purposes involve considerations that are beyond the scope of this document.

Background.—Under the auspices of the College of American Pathologists, a multidisciplinary group of clinicians, pathologists, and statisticians considered prognostic and predictive factors in breast cancer and stratified them into categories reflecting the strength of published evidence. Materials and Methods.—Factors were ranked according to previously established College of American Pathologists categorical rankings: category I, factors proven to be of prognostic import and useful in clinical patient management; category II, factors that had been extensively studied biologically and clinically, but whose import 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 about existing prognostic factors, and (3) improving patient care. Results and Conclusions.—Factors ranked in category I included TNM staging information, histologic grade, histologic type, mitotic figure counts, and hormone receptor status. Category II factors included c-erbB-2 (Her2-neu), proliferation markers, lymphatic and vascular channel invasion, and p53. Factors in category III included DNA ploidy analysis, microvessel density, epidermal growth factor receptor, transforming growth factor-α, bcl-2, pS2, and cathepsin D. This report constitutes a detailed outline of the findings and recommendations of the consensus conference group, organized according to structural guidelines as defined.

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.

Review of histologic sections and cytologic smears is often a key component of civil litigation in cases of alleged negligence or medical malpractice. While the outcome of such cases may hinge on the testimony of expert witnesses, determining who is qualified to serve as an expert in such cases is generally left to the court. The Board of Governors of the College of American Pathologists has adopted separate statements for review of histologic slides and Papanicolaou (Pap) tests that outline some of the issues that should be considered in this context. These guidelines were developed in an effort to ensure accuracy and fairness in expert testimony when histologic or cytologic slides are reviewed as part of litigation.

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.

C in surgical pathology are a routine exercise in most laboratories. In 1993, the Association of Directors of Anatomic and Surgical Pathology published recommendations to help optimize the consultation process.1 This document emphasized the role of the pathologists involved in the consultation process, specifically addressing personal consultations, which were defined as consultations sent to a specific pathologist for a second opinion. In that article, the responsibilities of the pathologist seeking a consultation were emphasized more than those of the consultant pathologist. Although personal consultations comprise an important component of many consultation practices, institutional consultations often represent a major part of pathology service activity in tertiary referral centers. Institutional consultations occur when a patient goes to a different hospital or clinic for additional evaluation or treatment, and the pathologists at the ‘‘new’’ institution are asked to review the pathology report and slides. The Association of Directors of Anatomic and Surgical Pathology1 discussed this form of consultation, albeit rather briefly, and recommended that such review be standard practice. Supporting this recommendation, Silverberg2 argued that pathologists should educate clinicians to obtain relevant

to be misdiagnosed, but this illustrates the effect of selection bias on studies of diagnostic error. Although the actual frequency of interpretive variation in routine surgical pathology practice may be lower than that suggested by some authors, these studies have resulted in calls for routine or ‘‘mandatory’’ review by a second pathologist. 2,3 For example, a recent conference on this subject concluded with recommendations for second opinion in a wide