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PURPOSETo update key recommendations of the American Society of Clinical Oncology/College of American Pathologists estrogen (ER) and progesterone receptor (PgR) testing in breast cancer guideline.METHODSA multidisciplinary international Expert Panel was convened to update the clinical practice guideline recommendations informed by a systematic review of the medical literature.RECOMMENDATIONSThe 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 .

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.

The alimentary tract serves as host to a large number of diseases. In the non-neoplastic group of disorders, conventional histochemistry continues to play an important diagnostic role. It is particularly important in recognizing specific infectious diseases, such as Helicobacter gastritis, Whipple disease, intestinal tuberculosis and other forms of mycobacteriosis, malakoplakia, intestinal spirochetosis, fungal enteritides, amebiasis, cryptosporidiosis, isosporiasis, and microsporidiosis. Those conditions and their histochemical properties are discussed in this review, along with the use of histochemistry in the characterization of structural gastrointestinal disorders. The latter include mucosal metaplasias, amyloidosis, glycogenic acanthosis of the esophagus, lymphocytic-collagenous colitis, gastric neuroendocrine hyperplasia, and pill gastritis.

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 .

All assays performed in anatomic and clinical pathology laboratories must be validated before they are placed into clinical service. This review summarizes strategies for validation of clinical immunohistochemistry assays, and is chiefly based on the recently released guideline released by The College of American Pathologists.

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.

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.

Context.—The American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) published guidelines in 2007 regarding testing accuracy, interpretation, and reporting of results for HER2 studies. A 2008 survey identified areas needing improved compliance.Objective.—To reassess laboratory response to those guidelines following a full accreditation cycle for an updated snapshot of laboratory practices regarding ASCO/CAP guidelines.Design.—In 2011, a survey was distributed with the HER2 immunohistochemistry (IHC) proficiency testing program identical to the 2008 survey.Results.—Of the 1150 surveys sent, 977 (85.0%) were returned, comparable to the original survey response in 2008 (757 of 907; 83.5%). New participants submitted 124 of 977 (12.7%) surveys. The median laboratory accession rate was 14 788 cases with 211 HER2 tests performed annually. Testing was validated with fluorescence in situ hybridization in 49.1% (443 of 902) of the laboratories; 26.3% (224 of 853) of the laboratories used another IHC assay. The median number of cases to validate fluorescence in situ hybridization (n = 40) and IHC (n = 27) was similar to those in 2008. Ninety-five percent concordance with fluorescence in situ hybridization was achieved by 76.5% (254 of 332) of laboratories for IHC− findings and 70.4% (233 of 331) for IHC+ cases. Ninety-five percent concordance with another IHC assay was achieved by 71.1% (118 of 168) of the laboratories for negative findings and 69.6% (112 of 161) of the laboratories for positive cases. The proportion of laboratories interpreting HER2 IHC using ASCO/CAP guidelines (86.6% [798 of 921] in 2011; 83.8% [605 of 722] in 2008) remains similar.Conclusions.—Although fixation time improvements have been made, assay validation deficiencies still exist. The results of this survey were shared within the CAP, including the Laboratory Accreditation Program and the ASCO/CAP panel revising the HER2 guidelines published in October 2013. The Laboratory Accreditation Program checklist was changed to strengthen HER2 validation practices.

Laboratories must validate all assays before they can be used to test patient specimens, but currently there are no evidence-based guidelines regarding validation of immunohistochemical assays.To develop recommendations for initial analytic validation and revalidation of immunohistochemical assays.The College of American Pathologists Pathology and Laboratory Quality Center convened a panel of pathologists and histotechnologists with expertise in immunohistochemistry to develop validation recommendations. A systematic evidence review was conducted to address key questions. Electronic searches identified 1463 publications, of which 126 met inclusion criteria and were extracted. Individual publications were graded for quality, and the key question findings for strength of evidence. Recommendations were derived from strength of evidence, open comment feedback, and expert panel consensus.Fourteen guideline statements were established to help pathology laboratories comply with validation and revalidation requirements for immunohistochemical assays.Laboratories must document successful analytic validation of all immunohistochemical tests before applying to patient specimens. The parameters for cases included in validation sets, including number, expression levels, fixative and processing methods, should take into account intended use and should be sufficient to ensure that the test accurately measures the analyte of interest in specimens tested in that laboratory. Recommendations are also provided for confirming assay performance when there are changes in test methods, reagents, or equipment.

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.

Biospecimens must have appropriate clinical annotation (data) to ensure optimal quality for both patient care and research. Clinical preanalytic variables are the focus of this study.To define the essential preanalytic variables (data fields) that should be attached to every collected biospecimen and to provide a complete list of such variables, along with their relative importance, which can vary, depending on downstream use, institutional needs, and information technology capabilities.The College of American Pathologists Diagnostic Intelligence and Health Information Technology Committee sponsored a Biorepository Working Group to develop a ranked list of the preanalytic variables for annotating biospecimens. Members of the working group were experts in anatomic, clinical, and molecular pathology; biobanking; medical informatics; and accreditation. Several members had experience with federal government programs, such as the National Cancer Institute's Biospecimens and Biorepository Branch and the National Cancer Institute's Community Cancer Center Program. Potential preanalytic variables were identified and ranked along with available supporting evidence, definitions, and potential negative effects if the variable was not attached to the biospecimen. Additional national and international stakeholders reviewed the draft manuscript.The ranked listing of 170 preanalytic variables produced can be used as a guide for site-specific implementation into patient care and/or research biorepository processes. Conclusions.-In our collective experience, it is often difficult to choose which of the many preanalytic variables to attach to any specific set of biospecimens used for patient care and/or research. The provided ranked list should aid in the selection of preanalytic variables for a given biospecimen collection.

The College of American Pathologists (CAP) has been developing guidelines on cancer data reporting for more than 25 years, with more than 80 regularly updated cancer case summaries now available for pathologists’ use. The protocols consist mostly of traditional data elements determined by gross and microscopic examination, but many of the case summaries within the protocols also include short sections on ‘‘ancillary testing.’’ As the frequency of biomarker testing and its importance in managing patients has grown, however, these results are no longer considered ancillary. The growing number of details related to this testing add to the length and complexity of the cancer resection report. Another problem with including biomarker testing in the cancer case summary is that the results are often not available at the time the primary cancer resection report is completed, either because they are still pending or because they are ordered later. In response to requests from pathologists to address these issues and streamline the CAP cancer protocol case summaries, a multidisciplinary group was assembled in 2012 to establish guidelines for reporting biomarker assays. The Cancer Biomarker Reporting Workgroup was composed of a steering committee and 3 initial site-specific expert panels charged with developing pilot biomarker reporting templates for breast, colorectal, and lung cancers. Panel members participated from a variety of organizations, including the CAP, the Association for Molecular Pathology, the American Society of Clinical Oncology, the Centers for Disease Control and Prevention, the American Joint Committee on Cancer, the North American Association of Central Cancer Registries, and other organizations. The workgroup goals were to establish reporting guidelines for commonly ordered biomarkers, create stand-alone reporting templates, and improve consistency and completeness of results reporting to assist tumor registrars and others involved in data collection, exchange, and surveillance. This issue of Archives of Pathology & Laboratory Medicine introduces new reporting templates for lung and colorectal cancer biomarkers (the template for breast cancer was harmonized with the recent update to the American Society of Clinical Oncology/CAP guideline for HER2 testing subsequent to the writing of this editorial and was completed in late 2013). These 3 templates incorporate standards based on existing guidelines as well as expert consensus where formal guidelines do not exist. These draft templates were reviewed by the CAP Cancer, Molecular Oncology, Immunohistochemistry, and Pathology Electronic Reporting Committees, followed by formal public comment and field-testing periods.

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.

Sentinel lymph node biopsy has been shown to be an accurate predictor of axillary nodal status in invasive breast cancer and is a useful alternative to axillary dissection for some patients. Because radioactive materials are often used to identify the sentinel lymph node, concerns have been raised regarding the safe handling of tissue specimens obtained by this technique. The Surgical Pathology Committee of the College of American Pathologists and the Association of Directors of Anatomic and Surgical Pathology have developed recommendations for the safe handling of radioactive specimens obtained by sentinel lymphadenectomy.

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 American Society of Clinical Oncology and the College of American Pathologists convened an expert panel, which conducted a systematic review of the literature and developed recommendations for optimal HER2 testing performance. The guideline was reviewed by selected experts and approved by the board of directors for both organizations. Results Approximately 20% of current HER2 testing may be inaccurate. When carefully validated testing is performed, available data do not clearly demonstrate the superiority of either immunohistochemistry (IHC) or in situ hybridization (ISH) as a predictor of benefit from anti-HER2 therapy. Recommendations The panel recommends that HER2 status should be determined for all invasive breast cancer. A testing algorithm that relies on accurate, reproducible assay performance, including newly available types of brightfield ISH, is proposed. Elements to reliably reduce assay variation (for example, specimen handling, assay exclusion, and reporting criteria) are specified. An algorithm defining positive, equivocal, and negative values for both HER2 protein expression and gene amplification is recommended: a positive HER2 result is IHC staining of 3+ (uniform, intense membrane staining of > 30% of invasive tumor cells), a fluorescent in situ hybridization (FISH) result of more than six HER2 gene copies per nucleus or a FISH ratio (HER2 gene signals to chromosome 17 signals) of more than 2.2; a negative result is an IHC staining of 0 or 1+, a FISH result of less than 4.0 HER2 gene copies per nucleus, or FISH ratio of less than 1.8. Equivocal results require additional action for final determination. It is recommended that to perform HER2 testing, laboratories show 95% concordance with another validated test for positive and negative assay values. The panel strongly recommends validation of laboratory assay or modifications, use of standardized operating procedures, and compliance with new testing criteria to be monitored with the use of stringent laboratory accreditation standards, proficiency testing, and competency assessment. The panel recommends that HER2 testing be done in a CAP-accredited laboratory or in a laboratory that meets the accreditation and proficiency testing requirements set out by this document.

In this study, we estimated the prevalence of Helicobacter pylori infection and histologic gastritis in 58 asymptomatic Hispanic adult volunteers (mean age, 41 years; 59% male) by endoscopic biopsy of the upper gastrointestinal tract. Forty-six subjects (79%) were found to harbor H. pylori in gastric biopsies, and all had histologic gastritis. Four other subjects were found to have gastritis in the absence of H. pylori. Similar prevalences of H. pylori and gastritis were noted in all age groups and also in American-born and immigrant Hispanics. Biopsy data and serologic studies of H. pylori antibodies correlated well. We conclude that H. pylori infection is an almost universal finding in the gastric mucosa of asymptomatic adult Hispanics, regardless of age. The clinical significance of these findings is unknown, but we speculate that H. pylori and its associated gastritis could have a role in the high incidence of gastric carcinoma in Hispanic populations.

Purpose Reliable pathologic stage classification of axillary lymph nodes is an important determinant of prognosis and therapeutic decision making for patients with invasive breast cancer. Pathologists' distinction between micrometastasis (pN1mi) and isolated tumor cells [ITC; pN0(i+)] is variable using the American Joint Committee on Cancer (AJCC) Staging Manual (Sixth Edition). We sought to determine whether a set of clearly defined histologic criteria could lead to reproducible nodal classification by pathologists. Patients and Methods Digital images of sentinel lymph node biopsies from 56 patients with small-volume nodal metastases were examined by six experienced breast pathologists (MDs), first as a pre-test, and again as a post-test after studying a training program that outlined and illustrated the classification criteria. Results Post-test results, after study of the training program, were significantly improved. Compared with the reference MD, agreement improved from 76.2% (pre-test κ = 0.575; standard deviation [SD], 0.25) to 97.3% (post-test κ = 0.947; SD, 0.049). Multirater analysis of agreement among the six MDs improved from 71.5% (pre-test κ = 0.487; ASE, 0.039) to 95.7% (post-test κ = 0.915; ASE, 0.037). Agreement on lobular carcinoma metastasis classification improved from 55% (23 of 42; pre-test) to 100% (42 of 42; post-test) (P < .001), and agreement on ITC classification in nodal parenchyma improved from 67.6% (69 of 102; pre-test) to 98.0% (100 of 102; post-test; P < .001). Conclusion Application of current definitions for classification of small-volume nodal metastases are inconsistent, leading to variable classification of ITC and micrometastases. Reproducibility of pathologic nodal stage classification is achievable through study of a training set to clarify the AJCC criteria.

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.

A national task force consisting of members from the American College of Radiology, the American College of Surgeons, and the College of American Pathologists examined the issues surrounding stereotactic core-needle biopsy for occult breast lesions. Their report includes indications and contraindications, informed consent, specimen handling, and management of indeterminate, atypical, or discordant lesions.

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

Although some authors believe that Helicobacter pylori is the etiologic agent in chronic nonspecific gastritis, it has also been suggested that the bacterium colonizes inflamed mucosa as a secondary event. This study documents the prevalence of H. pylori in 28 patients with pernicious anemia and compares the findings with those of a group of 28 age-, race-, and sex-matched asymptomatic control subjects. All subjects underwent endoscopy with biopsy of the gastric antrum and corpus. A sample of serum was obtained before endoscopy for determination of antibodies (immunoglobulin A and immunoglobulin G) to H. pylori. The prevalence of H. pylori (by biopsy) in patients with pernicious anemia was significantly less than that in controls (11% vs. 71%, P less than 0.0001). All patients with pernicious anemia had abnormalities of corpus histology (inflammation and/or atrophy). In addition, 50% of patients with pernicious anemia had a lymphocytic infiltration of the antrum. All controls with H. pylori had gastritis, 50% having active chronic gastritis. Atrophic changes of the corpus were more commonly found in patients with pernicious anemia (75% vs. 7%, P less than 0.0001). Serology and biopsy results correlated poorly in the patients with pernicious anemia: all 5 patients with positive serology results had negative biopsy results, whereas all 3 patients with positive cultures on biopsy had negative serological studies. In conclusion, patients with pernicious anemia are protected from infection with H. pylori, and H. pylori does not passively colonize mucosa inflamed by an unrelated process.

We estimated the prevalences of Helicobacter pylori (formerly called Campylobacter pylori) infection and histologic gastritis in 113 asymptomatic persons, using endoscopic biopsy of the gastric antrum and corpus. Unsuspected lesions, mainly mucosal erosions, were revealed at endoscopy in 16 subjects (14 percent). Gastritis was found in 42 subjects (37 percent), of whom 36 (32 percent of the total) were found to be infected with H. pylori on the basis of hematoxylin-eosin staining. H. pylori was not found in any of the 71 subjects with normal histologic features. Gastritis and H. pylori were noted in both the antrum and corpus in 75 percent of those infected (n = 27). The prevalence of H. pylori infection increased from 10 percent (2 of 20 subjects) in those between the ages of 18 and 29, to 47 percent (7 of 15) in those between the ages of 60 and 69, but the effect of age did not reach statistical significance. The prevalence of gastritis increased significantly with advancing age. Stepwise logistic regression analysis revealed that the relative risk for H. pylori infection associated with recent (within six months) antibiotic use was 5.8 (95 percent confidence interval, 1.5 to 22.1), whereas the relative risk was 6.5 (95 percent confidence interval, 1.4 to 29.2) for those who had never used bismuth compounds. We conclude that histologic gastritis and H. pylori infection commonly occur in the stomach of apparently normal persons and increase in prevalence with advancing age. All the subjects with H. pylori infection had gastritis, suggesting a possible etiologic role for the bacterium in the histologic lesion.

A case of granular cell tumor involving the intrapancreatic portion of the common bile duct is reported. The tumor was misdiagnosed as a bile duct carcinoma clinically and at surgery. Intraoperative needle biopsy failed to provide a specific diagnosis and led to a pancreatico-duodenectomy. The importance of making a specific frozen section diagnosis and the difficulties associated with this in this setting are presented.

Adenosquamous carcinoma is a rare, but pathologically distinct, form of lung cancer. Seven cases involving unequivocal squamous and glandular differentiation were studied. These cases accounted for 0.6 per cent of the 1,125 primary lung cancers examined at a metropolitan hospital during a 15-year period. The tumors measured from 1.3 to 5.5 cm in diameter. Five were peripheral, and two were associated with scars. Three of five resected specimens had regional lymph node metastases. Five patients had died of the disease within two years of diagnosis, and two were short-term survivors.

We report the histologic and ultrastructural findings on two sisters with familial visceral myopathy who presented with acquired megacolon that necessitated subtotal colectomy. Both patients were mentally retarded and had repeated episodes of constipation and fecal impaction. Each presented near the age of 30 with massive dilatation of the colon and without clinical evidence of small intestinal involvement. Histologic abnormalities primarily involved smooth muscle and included marked nuclear enlargement and irregularity, interstitial fibrosis, and cytoplasmic vacuolation. These changes were most severe in the muscularis propria, but similar abnormalities were found in the muscularis mucosae and blood vessels. In the most advanced stages, collagen had completely replaced the muscularis propria, with extreme thinning of the intestinal wall. Abnormalities were noted in all segments of the colon and the appendix, but there was little correlation between severity of involvement and the segment examined. This study not only confirms the variable nature of morphologic changes in familial visceral myopathy, but also provides evidence of more extensive involvement of intestinal smooth muscle than has been previously reported.

Flow cytometric quantitation of the proliferation-associated nuclear antigen p105 and DNA content was performed on nuclear suspensions from 12 paraffin-embedded pituitary macroadenomas and one pituitary carcinoma and correlated with clinical outcome. Median follow-up was 41 months (range, 33 to 48 months). Three of the 13 tumors (23%) had an identifiable aneuploid peak. Of the four tumors that recurred or metastasized, only one was aneuploid. Nuclear antigen analysis of all diploid tumors showed enhanced p105 expression in G2M phase cells compared to G0G1 cells. The G2M/G0G1 fluorescence ratio for p105 was consistently higher (P less than 0.05) for the three diploid tumors that recurred (median, 1.32 arbitrary fluorescence units; range, 1.27 to 1.80) than for the seven nonrecurrent diploid tumors (median, 1.20 arbitrary fluorescent units; range 1.14 to 1.22). These findings indicate a low incidence of DNA aneuploidy among pituitary tumors and suggest that for diploid adenomas, measurement of p105 may provide information useful in predicting prognosis and directing postoperative adjuvant therapy.

Mucosal biopsies were obtained from 116 asymptomatic volunteers (50% were male; mean age, 46 years; age range, 19-91 years) to study the prevalence of duodenal gastric metaplasia (GM) and its association with inflammation and Campylobacter pylori in a normal population. GM was identified in 25 subjects (22%). Eighty-three subjects (72%) had histologic duodenitis, but in only 10 did the infiltrate include neutrophils (grade 2 duodenitis). C. pylori was found in the stomach in 36 subjects (31%), all of whom had gastritis, but was not identified histologically in the duodenum. There were no significant differences between the overall frequency of duodenitis and either GM or antral C. pylori. Although the frequency of severe (grade 2) duodenitis was not significantly different between those with and those without GM, grade 2 duodenitis was found in 9 of 36 subjects with antral C. pylori but in only 1 of 80 without antral C. pylori (P less than 0.001). These findings suggest that gastric metaplasia is a common finding in the normal population and that grade 1 duodenitis is most likely clinically unimportant, whereas grade 2 duodenitis is usually associated with antral C. pylori.

The clinical and pathologic features of 10 patients with malignant melanoma metastatic to the ovary were studied. Seven were from surgical patients who presented with possible primary ovarian neoplasms and three were autopsy cases. Six had unilateral involvement, and all but one of the metastases were grossly cystic. Two predominant histologic patterns were identified: the more common (six cases) consisted of small oval to spindle-shaped cells with inconspicuous or absent melanin pigment and a focal storiform architecture. Three of these six were initially misinterpreted as ovarian stromal neoplasms. The other four tumors had large epithelioid cells with abundant cytoplasm and melanin pigment, and were readily classified as metastatic melanoma. Six of the seven surgical cases were reactive with antibodies to S-100 protein and vimentin but nonreactive with antibodies to keratin.

The cases of two patients who presented with breast masses suggesting carcinoma and no other clinical features of sarcoidosis are reported. Biopsies in both patients revealed noncaseating, epithelioid granulomas. Mycobacteria, fungi, and foreign material were not identified. In une of the patients, other sites of involvement were discovered five years later. These cases illustrate that sarcoidosis should be considered in patients with granulomatous breast disease, even without evidence of disease elsewhere.