Printer Friendly

Bone Marrow Synoptic Reporting for Hematologic Neoplasms: Guideline From the College of American Pathologists Pathology and Laboratory Quality Center.

Agreement on the diagnosis of hematologic neoplasms generally exists among pathologists, based on widely adopted classification schemes, such as the World Health Organization (WHO) Classification of Tumours of Haematopoietic and Lymphoid Tissues. (1) However, bone marrow pathology reports are highly variable, with diagnostic statements ranging from a one-line diagnosis of acute leukemia to lengthy narratives with the term acute leukemia buried in extensive textual paragraphs. The significant variability in reporting of bone marrow specimens may result in incomplete information or misleading information that is ill-defined and difficult to find in the report. This, in turn, may result in suboptimal care, including inappropriate treatment or incorrect prognostic information. There is ample evidence that synoptic reporting improves the accuracy and completeness of relevant data elements in solid tumors, such as colorectal cancer and breast cancer. (2-8) To address the challenges of bone marrow synoptic reporting, the College of American Pathologists (CAP) Pathology and Laboratory Quality Center (the Center) convened an expert panel to systematically review and evaluate scientific literature pertaining to the various elements informative for the diagnosis, prognosis, and treatment of neoplastic bone marrow disease. Disease categories addressed included acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), myelodysplastic syndromes (MDSs), myeloproliferative neoplasms (MPNs), plasma cell disorders, Hodgkin lymphoma, and non-Hodgkin lymphoma (NHL). Although aplastic anemia (AA) is not neoplastic, it was also addressed because of its overlap with MDSs.

The CAP Cancer Protocols have previously established a reporting foundation by adopting synoptic reporting principles as a key element. As currently defined by the CAP, synoptic reporting includes the following elements: reporting of scientifically validated data elements that influence clinical outcome and therapeutic decisions, display of each data element in a "variable:result" format on a single line, and display of data elements on separate lines. This report format ensures that critical information is transmitted consistently and succinctly in every report. It does not exclude incorporation of additional information, such as detailed differential counts, panels of immunohistochemical and special stains needed for pathologic workup, or explanatory narratives interpreting the clinical relevance of complex findings.

In recent years, the CAP has introduced evidence-based guidelines for specific high-impact topics, based on a comprehensive, systematic literature search with rigorous grading of evidence, supplemented by the considered judgment of a panel of experts. (9) The CAP Center guideline development process follows the Institute of Medicine's Clinical Practice Guidelines We Can Trust. (10) Rather than dictating a "one size fits all" approach to patient care, the CAP guidelines offer evaluation of the quality of the relevant scientific literature and an assessment of the likely benefits and harms of a particular practice.

In that spirit, the expert panel formulated key questions and organized the findings and recommendations presented in this guideline. This guideline is not intended to replace the Protocol for the Examination of Specimens From Patients With Hematopoietic Neoplasms Involving the Bone Marrow, that is included in the CAP Cancer Protocols (Cancer Protocol--Hematologic: Bone Marrow, version 3.0.1.1, posted June 15, 2012). (11) That particular checklist includes instructions on reporting specimen attributes and a comprehensive list of hematopoietic neoplasms based on the WHO classification. It also includes required reporting of immunophenotyping and cytogenetic analysis, whereas other additional testing, such as fluorescence in situ hybridization (FISH), molecular studies, and other pathologic findings, are optional. The explanatory notes of the checklist contain detailed information on recommended specimen preparation, fixation, and recording, as well as staging information for NHL and plasma cell myeloma. This proposed bone marrow reporting guideline does not include evidence-based analysis of specimen requirements because the topic was deemed out of the scope of the project. The practitioner is referred to existing recommendations, such as those outlined in the CAP Cancer Protocols. (12)

It became clear during the work on this guideline that one uniform set of data elements for all hematopoietic neoplasms was impractical. In addition, diagnostic bone marrow reporting poses unique challenges, particularly at initial diagnosis. Unlike solid tumors with identifiable, often single, mass lesions, bone marrow neoplasms may declare themselves indirectly via peripheral blood abnormalities that can be mimicked by a wide variety of secondary, often nonneoplastic, causes. A particular challenge to bone marrow diagnostics is that an accurate diagnosis may require consideration of ancillary data, which are often not available at the time of morphologic evaluation, and the need for incorporation of clinical information and data from other testing modalities (such as radiology). Gathering this information may be extremely challenging given diverse practice settings, limitations of access to patient medical records, difficulties in reaching clinicians, and the time constraints of a busy practice. Nevertheless, there is little doubt that incorporation of clinical and ancillary information represents good medical practice and further promotes the concept of a diagnostic management team as the optimal approach to patient care by helping to reach a clinicopathologic diagnosis relevant for treatment and outcome.

Consequently, the list of important data elements found in our query is somewhat lengthy, but only subsets are relevant for different diagnostic categories of neoplasms. A single reporting template for all bone marrow diseases is, therefore, unlikely to solve the complexity of bone marrow disease reporting without introducing an excessive amount of elements. A synoptic format does not preclude additional components in the bone marrow report. Narrative comments may follow the synoptic portion to clarify results, suggest further work, or discuss unusual features of a case, among others. However, for each major class of bone marrow neoplasms, there are data sets that are essential for clinical decisions, and these should be reliably reported every time in the structured format of a synoptic report.

The recommendations presented below provide a framework for evidence-based bone marrow synoptic reporting. The primary target audience for this guideline is pathologists reporting results from bone marrow examinations. Clinicians are the secondary target audience but should be involved in report design in the spirit of the diagnostic team effort. We have attempted to develop the recommendations presented herein to address diverse patient populations and diagnostic teams encountered in different practice environments.

METHODS

This evidence-based guideline was developed following the standards endorsed by the Institute of Medicine. A detailed description of the methods and a systematic review (including the quality assessment and complete analysis of the evidence) used to create this guideline can be found in the supplemental digital content available at www.archivesofpathology.org in the September 2016 table of contents.

Panel Composition

The CAP's Center convened an expert panel consisting of members with expertise in hematopathology. Panel members included 7 pathologists, 1 hematologist/oncologist, 1 methodologist consultant, and CAP staff. The CAP approved the appointment of the project chair and panel members. These panel members served as the expert panel for the systematic evidence review.

Conflict of Interest Policy

Before acceptance on the expert panel, potential members completed the CAP conflict of interest disclosure process, whose policy and form (in effect April 2010) requires disclosure of material financial interest in, or potential for benefit of significant value from, the guideline's development or its recommendations from 12 months before through the time of publication. Potential members completed the conflict of interest disclosure form, listing any relationship that could be interpreted as constituting an actual, potential, or apparent conflict. Everyone was required to disclose conflicts before beginning and continuously throughout the project at each virtual and face-to-face meeting. Disclosed conflicts of the expert panel members are listed in the Appendix. The CAP provided funding for the administration of the project; no industry funds were used in the development of the guideline. All panel members volunteered their time and were not compensated for their involvement, except for the contracted methodologist. Please see the SDC for full details on the conflict of interest policy.

Objective

The scope of the panel was to develop a series of evidence-based recommendations to standardize the basic components of a synoptic report template for bone marrow samples that would address the following domains: bone marrow morphologic descriptors, possible tests (by category) to be performed on the primary sample, relevant clinical and laboratory information, necessary components (regulatory, legal, financial, among others), and layout.

The key questions were as follows:

1. Considering the possible primary bone marrow morphologic descriptors, which ones are required on a synoptic report if completeness is the outcome of interest?

2. Considering the possible ancillary studies that could be ordered on a bone marrow specimen, which ones are required on a synoptic report if completeness is the outcome of interest?

3. What sequence of results reporting should be followed?

a. Considering the options available, is there an optimal report format that should be used if ease of use, error reduction, and fewer incompletes are the outcomes of interest?

b. Is there an optimal presentation for the elements of the minimum data set if the outcomes of interest are clarity and ease of use?

4. Which components required for correct coding and data repositories should be included in the report?

a. Coding

b. Registries

c. National guidelines (eg, National Comprehensive Cancer Network (13))

d. Physician payment incentive requirements (eg, Physician Quality Reporting System14)

5. What clinical or laboratory information should be included in the report?

There is an absence of recommendations pertaining to the quality of the primary bone marrow specimen. Although a high-quality specimen is desirable for optimal diagnostic workup, the minimum requirements depend on clinical circumstances and diagnostic needs. Because high-level evidence is not readily available for all scenarios, this was considered out of the scope for formal evidence-based recommendations at this time. The reader is referred to the CAP Cancer Protocols and existing guidelines pertaining to specimen quality. (15,16)

Literature Search and Selection

The systematic literature review for relevant evidence included a search using both OvidSP (http://ovidsp.ovid.com, accessed November 30, 2012; Ovid Technologies, New York City, New York) and PubMed (http://www.ncbi.nlm.nih.gov, accessed December 5, 2012; National Library of Medicine, Bethesda, Maryland) for articles published from January 2002 through November 2012. Medical subject headings and key words were selected to capture the concepts of bone marrow samples, ancillary testing, pathology reporting, and benign and malignant hematologic diagnostic entities. The searches were limited to human studies published in English, and a publication filter was applied to exclude less-rigorous study designs, as well as letters, commentaries, and editorials. A separate search for literature using PsycINFO (http:// www.apa.org/pubs/databases/psycinfo, accessed November 26, 2012; American Psychological Association, Washington, DC) was completed to identify articles that addressed the concepts of reading comprehension, communication, and clarity. Database searches were supplemented by a search for grey literature using Cochrane Library (http://www.cochranelibrary.com, accessed January 3, 2013; Cochrane Collaboration, London, England), TRIP database (http://www.tripdatabase.com, accessed January 3, 2013; Trip Database Ltd, Newport, Wales), Grey Literature Report (http:// www.greylit.org, accessed January 2, 2013; New York Academy of Medicine Library, New York), and Google Scholar (https://scholar. google.com, accessed January 2, 2013; Google, Mountain View, California), a review of relevant meeting abstracts (2011-2012), and a hand-search of selected relevant journals. A refresh of the Ovid and PsycINFO searches was completed (July 9, 2014) to capture studies published through June 2014. Detailed information regarding the literature search strategy can be found in the SCD.

Inclusion Criteria

Published studies were selected for full text review if they met each of the following criteria:

1. Human studies,

2. Original research addressing bone marrow synoptic reporting and elements of the report that provided data or information relevant to 1 or more key questions,

3. English language articles of any study design,

4. Studies from the years of 2002 to 2012.

Exclusion Criteria

1. Noncomparative studies;

2. Studies that address conditions outside of this list:

a. Neoplastic: Multiple myeloma, amyloidosis, acute myeloid leukemia/acute lymphoblastic leukemia, chronic myelogenous leukemia, primary myelofibrosis, myeloproliferative neoplasms, myelodysplastic syndromes-clinical terms (eg, low risk, high risk, WHO-refractory anemias), myelodysplastic/myeloproliferative neoplasms, Hodgkin lymphoma, NHL, chronic lymphocytic leukemia (CLL);

b. Nonneoplastic: Anemia of chronic inflammation, parvovirus B19, iron deficiency anemia, vitamin B12 deficiency, folate deficiency, Paget disease of the bone, idiopathic immune thrombocytopenia, AA;

3. Studies that do not address reporting or factors that aid in reporting: text, font, order of elements, optimal presentation of data, document design, ease of use, clarity, error reduction (accuracy), minimizing incomplete reports, other important aspects of synoptic reporting;

4. Studies that do not address morphologic descriptors, flow cytometry, FISH cytogenetics, molecular studies, other important ancillary studies;

5. Editorials, letters, commentaries, invited opinions, or articles that did not address any key question were also excluded.

Quality Assessment

An assessment of the quality of the evidence (risk of bias assessment) was performed for all retained studies following application of the inclusion and exclusion criteria by a contracted methodologist. Using this method, studies deemed to be of low quality were not excluded from the systematic review but were retained and their methodological strengths and weaknesses were discussed where relevant. Studies were assessed by confirming the presence of items related to both internal and external validity, which are all associated with methodological rigor and a decrease in the risk of bias. (Refer to the SDC for items relating to internal and external validity.) The quality assessment of the studies was performed by determining the risk of bias by assessing key indicators, based on study design, against known criteria.

For strength of the evidence, the panel considered the level of evidence, its quantity, and the quality of included studies. The level of evidence was based on the study design as follows:

* Level I was evidence from systematic reviews or clinical practice guidelines of appropriate level II studies;

* Level II was evidence from good-quality, randomized, controlled trials;

* Level III was evidence from low-quality comparative studies;

* Level IV was evidence from studies without a comparator (Table 1). (71)

In general, evidence from levels I and II is considered most appropriate for answering clinical questions, but in the absence of such high-quality evidence, the panel considered data from lower-quality studies. The quantity of evidence refers to the number of studies and the number of cases included for each outcome in the recommendation. The quality of studies reflects how well the studies were designed to eliminate bias and threats to validity.

The appropriateness of the study design and data collected, the relevance and clarity of the findings, and the adequacy of the conclusions were evaluated. Each study was assessed individually (refer to the SDC for individual assessments and results) and then summarized by study type. Components such as generalizability and applicability were also considered when determining the strength of evidence. A summary of the overall quality of the evidence was given after considering the evidence in totality. Ultimately, the designation (ie, rating or grade) of the strength of evidence is a judgment by the expert panel of their level of confidence that the evidence from the studies informing the recommendations reflects true effect. Table 2 describes the grades for strength of evidence.

Assessing the Strength of Recommendations

Development of recommendations required that the panel review the identified evidence and make a series of key judgments. Grades for strength of recommendations were developed by the CAP Center and are described in Table 3.

Guideline Revision

This guideline will be reviewed every 4 years, or earlier in the event of publication of substantive and high-quality evidence that could potentially alter the original guideline recommendations. If necessary, the entire panel will reconvene to discuss potential changes. When appropriate, the panel will recommend revisions of the guideline to the CAP for review and approval.

Disclaimer

The CAP developed the Center as a forum to create and maintain evidence-based practice guidelines and consensus statements. Practice guidelines and consensus statements reflect the best-available evidence and expert consensus supported in practice. They are intended to assist physicians and patients in clinical decision-making and to identify questions and settings for further research. With the rapid flow of scientific information, new evidence may emerge between the time a practice guideline or consensus statement is developed and when it is published or read. Guidelines and statements are not continually updated and may not reflect the most-recent evidence. Guidelines and statements address only the topics specifically identified therein and are not applicable to other interventions, diseases, or stages of diseases. Furthermore, guidelines and statements cannot account for individual variation among patients and cannot be considered inclusive of all proper methods of care or exclusive of other treatments. It is the responsibility of the treating physician or other health care provider, relying on independent experience and knowledge, to determine the best course of treatment for the patient. Accordingly, adherence to any practice guideline or consensus statement is voluntary, with the ultimate determination regarding its application to be made by the physician in light of each patient's individual circumstances and preferences. The CAP makes no warranty, express or implied, regarding guidelines and statements and specifically excludes any warranties of merchantability and fitness for a particular use or purpose. The CAP assumes no responsibility for any injury or damage to persons or property arising out of, or related to, any use of this statement or for any errors or omissions.

RESULTS

Of the 1731 unique studies identified in the systematic review, 103 were selected for inclusion. These included 102 published peer-reviewed articles and 1 meeting abstract. Among the extracted documents, 8 articles did not meet minimum quality standards, presented incomplete data or data that were not in usable formats, or included only information based on expert opinion. These articles were not included in analyses or narrative summaries. The 95 remaining articles underwent data extraction and qualitative analysis.

The expert panel met 21 times through teleconference webinars from February 2, 2012, through March 31, 2015. Additional work was completed via electronic mail. The panel met in person November 2, 2013, to review evidence to date and to draft recommendations. An open comment period was held from April 21, 2014, through May 19, 2014, on the CAP website. Ten draft recommendations and 2 demographic questions were posted for peer review.

Agree and disagree responses were captured for every proposed recommendation. The website also received 178 written comments. All 10 draft recommendations achieved more than 80% agreement. Each expert panel member was assigned 3 pages of comments to review and summarize. After consideration of the comments, 2 draft recommendations were maintained with the original language; 6 were revised, and 2 draft recommendations were combined into one for 9 final recommendations. Resolution of all changes was obtained by unanimous consensus of the panel members using nominal group technique (rounds of teleconference webinars, email discussions, and multiple, edited recommendations). Final expert panel recommendations were approved by a formal vote. The panel considered laboratory efficiency and feasibility throughout the entire process although neither cost nor cost-effectiveness analyses were performed.

An independent review panel, masked to the expert panel and vetted through the conflict of interest process, provided a review of the guideline and recommended approval by the CAP Council on Scientific Affairs. The final recommendations are summarized in Table 4.

GUIDELINE STATEMENTS

1. Strong Recommendation.--Laboratories should adopt synoptic reporting as a component of bone marrow pathology reports for clearly defined neoplasia or widely applied classification schemes and receive appropriate institutional support.

The strength of evidence was convincing to support the superiority of synoptic reports over unstructured, narrative reports.

This recommendation is evidence-based and was supported by 11 studies, (2-8,17-20) all of which met the inclusion criteria for the systematic review. These studies comprised one randomized control trial (3) and 10 retrospective cohort studies (RCSs). (2,4-8,17-20) All 11 studies found statistically significant improvements for completeness associated with synoptic-reporting methods compared with nonsynopticreporting methods at P < .05, with reported values ranging from 4.1% to 100% for synoptic reports compared with values ranging from 0.2% to 97.3% for nonsynoptic reports. All studies were assessed for risk of bias, and none were found to have methodological flaws that would raise concerns about the studies' findings. Refer to Supplemental Table 12 in the SDC for the summary of studies' findings in support of the superiority of synoptic reporting over unstructured, narrative reports.

Levels I and II evidence demonstrated significant improvement of the completeness of reporting of required data elements for prostate cancer, (17) colorectal cancer, (2-6) pancreatic cancer, (18) breast cancer, (3,7,8) and melanoma. (20) In these studies, the required data fields were based on widely accepted clinical staging systems, including TNM staging, (6,17,18) nationally adopted guidelines based on specialty society clinical requirements, (2,3,5,7,8,20,21) and CAP Cancer Protocols. (4,6,18,19) In all reports that included a statistical analysis, the difference in completeness of required data elements was highly significant with P-values ranging from P < .05 to < .001. (Refer to Supplemental Table 12 in the SDC.) None of the available studies specifically addressed the completeness of bone marrow pathology reporting; however, the strength of evidence in favor of synoptic or checklist based reporting was preserved across multiple different organ systems.

Concerns that were raised in the open comment period revolved around 2 issues. There was the perception that synoptic reporting precludes the use of free text. This perception is incorrect because free text, such as explanatory narrative comments, may be critical to elucidating complex findings and to helping weigh the importance of particular data elements in the context of a specific clinical case. The other concern was that bone marrow synoptic reporting would place an unnecessary burden on community and nonexpert pathologists. Although this was not explicitly addressed in the studies, there are data to support that standardization through a synoptic format improves the nonexpert report and essentially equalizes the completeness of nonexpert to expert reports for common neoplastic conditions. (6) The expert panel recognized that building the synoptic report template required initial effort and information technology resources to implement successfully; therefore, appropriate institutional support is essential for implementation.

Based on these findings, the expert panel concluded that synoptic reporting should be adopted for clearly defined bone marrow neoplasia and AA classifiable by widely adopted classification schemes, such as the WHO classification.

2. Strong Recommendation.--When reporting on peripheral blood specimens for bone marrow synoptic reports, laboratories should report clinically and diagnostically pertinent elements, if available. These key elements may include one or more parameters from complete blood cell count, absolute cell counts, and relevant morphologic descriptors.

The strength of evidence was convincing to support this recommendation.

This recommendation is evidence-based and supported by 6 studies, (22-27) all of which met the inclusion criteria for the systematic review. These 6 studies comprise 2 prospective cohort studies (PCSs) (22,26) and 4 RCSs. (23-25,27) All studies were assessed for risk of bias, and none were found to have methodological flaws that would raise concerns about the studies' findings. One RCS (23) reported clinical significance for data on white blood cell counts in patients with Philadelphia-positive ([Ph.sup.+]) ALL and polycythemia vera.

Four studies, comprising 2 PCSs (22,26) and 2 RCS, (24,27) reported clinical significance for data on hemoglobin in patients with MDS and AA. Four studies, comprising 1 PCS (22) and 3 RCSs, (24,25,27) reported clinical significance for data on platelets in MDS, myeloproliferative disease, adult T-cell leukemia/lymphoma patients. Two RCSs (24,27) reported clinical significance for data on absolute neutrophil count in patients with AA, and 1 RCS (26) reported clinical significance for data on reticulocyte count and red cell distribution width in patients with AA and MDS. Refer to Table 5 for study data by outcome of significance for peripheral blood specimens.

Peripheral blood parameters are required for the correct classification of numerous bone marrow disorders and constitute an integral component of any hematologic evaluation. There was high-level evidence demonstrating significantly different clinical outcomes for white blood cell counts in Ph+ ALL and polycythemia vera (23,25); hemoglobin levels in myelodysplasia and AA26-28; platelet counts in myelodysplasia, myeloproliferative disease, adult T-cell leukemia/lymphoma (22,24,25,27); absolute neutrophil count in myelodysplasia (24,27); and red cell distribution width and reticulocyte counts in AA. (26) Other parameters, such as red blood cell morphologic descriptors, percentage of blasts, and white blood cell dysplasia, may be pertinent for diagnosis, clinical management, and documentation but showed insufficient statistical strength to inform clinical outcomes.

In the open comment period, there was a broad consensus among 91% of respondents that peripheral blood parameters constituted an integral component of bone marrow evaluation. Concerns that were raised included duplication of data and cluttering of reports, in particular, when the bone marrow report is embedded in an electronic medical record in which complete blood cell count data are readily available. On the other hand, in particular outpatient settings or as part of documentation sent for consultative examination, these data may not be readily available and need to be supplied by the clinician requesting the bone marrow evaluation. This is especially critical at a first diagnosis, when it is not yet known whether bone marrow is neoplastic. This is further addressed in statement 9.

3. Strong Recommendation for Blast Percentage; Recommendation for All Other Parameters.--When reporting bone marrow aspirate results, laboratories should report clinically and diagnostically pertinent elements in the synoptic section. These key elements may include the evidence-based parameters, such as blast percentage, dysplasia, myeloid to erythroid ratio, morphology of myeloid/lymphoid elements, and enumeration of lymphoid elements and plasma cells; additional elements may be included in nonsynoptic sections of the report.

The evidence was convincing for blast percentage, but adequate for all other parameters (ie, strength of the evidence varied among the different key elements suggested in this recommendation).

This recommendation is evidence-based and supported by 13 studies, (23,24,26,29-38) all of which met the inclusion criteria for the systematic review. These 13 studies comprise 2 nonrandomized control trials (NRCTs), (32,33) 4 PCS, (26,29,31,35) and 7 RCS. (23,24,30,34,36-38) All studies were assessed for risk of bias, and none were found to have methodological flaws that would raise concerns about the studies' findings. Seven studies, * comprising 1 NRCT, (32) 3 PCSs, (26,29,35) and 3 RCSs, (23,24,34) reported clinical significance for data on blast percentage in ALL, AML, MDS, MPN, and AA. Five studies, (26,30,34,36,37) comprising 1 PCS (26) and 4 RCSs, (30,34,36,37) reported clinical significance for data on dysplasia in patients with MDS and MPN. Two studies, (33,38) comprising 1 NRCT (33) and 1 RCS, (38) reported clinical significance for data on lymphocyte percentage and/or lymphocyte morphology in patients with non-Hodgkin lymphoma and CLL. One PCS study (31) reported clinical significance for data on plasma cell percentage in patients with plasma cell myeloma. Refer to Table 6 for study data by outcome of significance for bone marrow aspirates.

The strongest support was for inclusion of the key element of blast percentage. ([dagger]) The evidence for reporting blast percentage was mainly with regard to diagnoses of ALL, (32) MDS, (24) MPN, (34) and AA. (26) Blast percentage also has relevance in determining response to therapy for acute leukemia, including at days 7 and 21 after induction therapy for ALL, (23,29) day 14 after induction therapy for AML, (35) and for prognosis in myelodysplastic neoplasms. (24)

Dysplasia of erythroid, myeloid, and megakaryocytic lineages also received considerable support, (26,30,34,36,37) primarily in the diagnosis of MDS and myelodysplastic/myeloproliferative neoplasms. A prospective study of patients with AML linked dysplasia with high-risk cytogenetics but did not demonstrate independent prognostic value in multivariate analysis. (39) Distribution and morphology of megakaryocytes is of particular relevance in MPN, (34) and morphology of megakaryocytes is relevant in determining response to therapy for chronic myelogenous leukemia. (34) Myeloid to erythroid ratio, as a specific element, received the least attention in the literature reviewed, with its relevance stated specifically only in chronic MPN, (34) although, by expert panel consensus, erythroid enumeration is also relevant to current diagnosis and classification of specific subtypes of AML, such as acute erythroblastic leukemia.

Of the lymphoid neoplasms, only 2 publications met criteria for high-level evidence with statistical differences in outcome. Bone marrow involvement with NHL was associated with a significantly different outcome in follicular lymphoma. (33) In low-grade NHL, the positive-predictive value of bone marrow aspirate was significantly higher than it was in aggressive NHL, when compared with bone marrow biopsy. (38) Because the literature search was restricted to years 2000-2012, earlier high-quality studies addressing bone marrow staging were not represented in this guideline.

Although the supporting publications did not meet the criteria for systematic review, by expert opinion consensus, additional parameters merit consideration because they can be useful for diagnosis and disease monitoring: morphology and enumeration of lymphoid cells in NHL and CLL, (40-43) with cell size (41) and distribution pattern (38,40,41) being frequently cited, relevant morphologic parameters. Enumeration of lymphoid cells was also reported as being relevant to disease monitoring, particularly in CLL. (43) Multiple studies emphasized complementarity of aspirate and core biopsies in lymphoma evaluations, (38,42) although aspirate evaluation is reported as having relatively limited utility in Hodgkin lymphoma. (42) There was high-level evidence to support plasma cell enumeration for diagnosis and monitoring of plasma cell myeloma. (31)

Given the variety of neoplastic and nonneoplastic disorders that are encountered in bone marrow aspirate evaluation, not all of the evidence-based elements are applicable to all reports. Although the literature search produced an evidence-based, minimum data set, incorporation of applicable elements into specific reporting templates depends on the patient populations at different institutions and may be weighted toward different types of cases; for example, transplant centers may see a predominance of follow-up bone marrow evaluations for leukemia and myeloma, whereas pathologists in outpatient settings may see more nonneoplastic disease and primary diagnostic evaluations. Most of the comments received during the open comment period dealt with what elements should or should not be included. In particular, many took issue with the proposed examples "morphology of lymphoid elements and enumeration of lymphoid cells and plasma cells." Following the open comment period, the expert panel concluded that each institution should have discretion in deciding how to incorporate the key elements of the aspirate evaluation into particular templates to best fit the needs of their patients and their clinicians. Reporting these key elements in synoptic format will provide clinicians with easy access to necessary diagnostic information in a familiar template and will facilitate comparison of data between sequential bone marrow evaluations of an individual patient; however, such templates may vary across institutions.

4. Strong Recommendation for Fibrosis; Recommendation for All Other Parameters.--When reporting bone marrow core biopsy results, laboratories should report clinically or diagnostically pertinent elements in the synoptic section. These key elements may include the evidence-based parameters, such as fibrosis, cellularity, distribution pattern of hematopoietic elements, morphology of lymphoid elements, and enumeration of lymphoid elements and plasma cells; additional elements may be included in the nonsynoptic sections of the report.

The strength of evidence was convincing for fibrosis, but adequate for all other parameters (that is, the strength of the evidence varied among the different key elements suggested in the recommendation).

This recommendation is evidence-based and supported by 12 studies, ([double dagger]) comprising 2 NRCTs, (33-47) 4 PCSs, (26,35,45,48) and 6 RCSs, (25,27,34,37,44,46) which reported on fibrosis, cellularity, involvement by lymphoma, or blast percentage. All studies were assessed for risk of bias, and none were found to have methodological flaws that would raise concerns about the studies' findings. Six studies, comprising 1 NRCT, (47) 1 PCS, (45) and 4 RCSs, (25,27,34,44) were obtained that all reported clinical significance for data on fibrosis outcomes for patients with MPN and MDS. One PCS26 and 2 RCSs (34,37) were obtained that reported clinical significance for data on cellularity outcomes for patients with MPN, AA, and myeloproliferative disease. Three studies, comprising 1 NRCT, (33) 1 PCS, (48) and 1 RCS, (46) were obtained that reported clinical significance for data on cellularity involvement in lymphoma for patients with Hodgkin lymphoma and NHL. One PCS35 was obtained that reported clinical significance for data on bone marrow blast percentage in patients with AML. Refer to Table 7 for study data by outcome of significance for bone marrow core biopsies.

The strongest support was regarding the key elements of fibrosis, (25,27,34,44,45,47) which was most applicable to patients with myeloid neoplasms, in particular MPN (25,34,44,45,47) and MDS. (27) The cellularity estimates and identification of involvement was relevant for lymphomas, (33,46,48) in the workup of AA versus hypocellular myelodysplastic processes, (26) and for evaluation of treatment effects or prognosis in MPN. (34,37) Of the lymphoid neoplasms, adverse outcomes were significantly associated with involvement by follicular lymphoma, peripheral T-cell lymphoma, and acute T-cell lymphoblastic leukemia/lymphoma. (33,46,48) Although, in the time period of publications searched for this guideline, no high-level evidence study was identified, determination of bone marrow involvement in Hodgkin lymphoma is standard practice in appropriately selected patients; it is well known that the bone marrow aspirate is insensitive compared with the trephine biopsy (no detection in bone marrow aspirates versus 5.2% positivity in biopsies). (49) Similar to reporting of bone marrow aspirate, enumeration and morphology of lymphoid neoplasms on the biopsy are valuable for diagnostic classification and treatment decisions, but the screened publications did not meet the systematic review criteria for high-level evidence regarding clinical outcomes.

There was substantial agreement during the comment period with this statement. Concerns that were raised, similar to those raised for reporting of the bone marrow aspirate, focused primarily on which key or essential elements should be included or were not required.

Suggestions as to inclusion of information regarding the presence of nonhematopoietic elements, such as bone trabeculae were most frequent. It is the consensus of the expert panel that this information would be important in a subset of cases but was not pertinent to many bone marrow tests, in particular bone marrow tests performed for diagnosis of hematologic processes. When appropriate, these elements should be included in the nonsynoptic portion of the report. Another issue raised during the open comment was the need for inclusion of a comment on the adequacy of the bone marrow biopsy as part of the synoptic report. The panel agreed on the importance of this element, in particular for staging of lymphoma; however, specimen requirements were determined to be out of the scope of this project and were not addressed at this point. Similarly, the presence of a metastatic, nonhematopoietic tumor on a bone marrow biopsy (or aspirate) is not specifically addressed in this guideline but is of obvious importance to the clinician.

5. Strong Recommendation.--If relevant ancillary testing studies are performed on the primary sample (blood or bone marrow), laboratories should report the results, general methodology, performance site, and interpretation site or have the data readily available. If the results are not available, pending status should be stated explicitly.

The strength of evidence was convincing to support this recommendation.

This recommendation is evidence-based and supported by 20 studies, (50-69) 19 of which met the inclusion criteria for the systematic review. (50-64,66-69) These studies comprise one quasirandomized control trial, (54) 3 NRCTs, (56,67,69) 13 PCSs, ([section]) and 2 RCSs. (63,66) All studies were assessed for risk of bias, and none were found to have methodological flaws that would raise concerns about the studies' findings. Eight studies, comprising 1 QRCT (54) and 7 PCSs (50,51,53,58-60,68) were obtained that all reported clinical significance for data on flow cytometry in patients with AML, ALL, MDS, lymphoma, and CLL. Three

PCSs (52,55,62) were obtained that all reported clinical significance for data on cytogenetics in patients with AML, MDS, and ALL. One of these PCSs (62) also reported clinical significance for FISH in a cohort of unspecified patients. One NRCT (69) reported clinical significance for immunohistochemistry in patients with CLL. Two studies, (64,65) comprising 1 PCS (64) included in the systematic review, reported clinical significance for bone marrow-isolated tumor-cell detection in a cohort of breast cancer patients. Six studies, comprising 2 NRCTs, (56,67) 2 PCSs, (57,61) and 2 RCSs, (63,66) reported clinical significance for data on molecular analysis in patients with AML, CLL, chronic myeloid leukemia, and lymphoma. Refer to Supplemental Table 16 in the SDC for the table summarizing the studies' findings.

Ancillary tests are, by definition, performed to supplement morphologic evaluation. Those performed on bone marrow samples typically include flow cytometry, immunohistochemistry, molecular studies, FISH, and conventional cytogenetics. Other ancillary tests used more sparingly include immunofluorescence, array comparative genomic hybridization, and mass spectrometry-based proteomic analysis, among others. Live cells are required for flow cytometry, conventional cytogenetics, and metaphase FISH, whereas air-dried or formalin-fixed, paraffin-embedded materials can be used for most other ancillary tests. In certain situations, some of these tests might be performed on a concurrent peripheral blood sample.

Inclusion of ancillary testing results is supported by strong evidence. This is not surprising because morphology currently comprises only one aspect of bone marrow evaluation, which increasingly relies on ancillary techniques for accurate diagnosis and is required in all current classification systems (such as WHO) for many hematolymphoid diseases. However, whereas incorporation of ancillary test results into the diagnostic bone marrow report is supported by high-level evidence, the inclusion of information regarding methodology and the laboratory or the site where testing and interpretation is performed is based on expert consensus. The panel contends that inclusion of the latter information in the bone marrow report provides context for the diagnosis, serves as a reference point for future follow-up, and creates transparency for testing location. Adequate evidence for including ancillary testing results exists for flow cytometry ([parallel]) cytogenetics, (52,55,62) FISH, (62) immunohistochemistry, (69) and molecular testing. (56,57,61,63,66,67) The association with clinical outcome was particularly strong for measurement of minimal residual disease by flow cytometry in lymphoma and AML, (50,51,53,58) for cytogenetic risk groups in AML, (52,55,62) and for BCR-ABL to ABL ratios by real-time polymerase chain reaction in chronic myeloid leukemia. (56,57,61,63,66) Supporting evidence for FISH studies demonstrated the high concordance of FISH and cytogenetic analysis in AML. (62) In some studies, detection of isolated metastatic tumor cells in the bone marrow of patients with breast cancer was significantly associated with adverse outcomes. (64,65) Although metastatic disease was not specifically addressed in the literature search and scope, these studies emerged based on the key questions and are retained as an example of ancillary studies that show statistical significance but have not found widespread adoption.

During the open comment period, the need to include relevant ancillary studies in the bone marrow synoptic was broadly supported. However, concerns were raised regarding the report timing of such studies because the results may not be available at the time of diagnosis. Other remarks indicated that some ancillary testing may not be essential for diagnosis and, thus, is not essential for report accuracy. Finally, a few commented on the difficulty of obtaining details about ancillary test methodology from external sources. This feedback informed the final wording of this statement, which provides additional flexibility for pathologists to address some of these challenges that may be specific to their practices or clinical situations.

6. Strong Recommendation for Inclusion of Data Groups for Diagnosis, Supporting Studies, and Ancillary Data; Recommendation for the Layout of the Data Groups.--Laboratories should include in the synoptic section of the report data groups for diagnosis, supporting studies, and ancillary data that are critical for diagnosis. Key morphologic descriptors should be included and may be in the diagnosis line if they are critical or a component of the disease classification. The diagnosis (or diagnosis group) should head the synoptic section when possible. A narrative, interpretative comment should immediately follow the synoptic section if required.

The strength of evidence was convincing to support this recommendation.

This recommendation is evidence-based and supported by 42 studies, (#) 40 of which met the inclusion criteria for the systematic review, ** comprising one systematic review, (70) 1 quasi-randomized control trial, (54) 6 NRCTs, (32,33,47,56,67,69) 19 PCSs, ([dagger][dagger]) and 13 RCSs. ([double dagger] [double dagger]) Six studies, (22-27) comprising 1 NRCT, (22) 1 PCS, (26) and 4 RCSs, (23-25,27) were obtained that reported clinical significance for data on peripheral blood parameters in patients with all hematopoietic neoplasms. Thirteen studies, (23,24,26,29-38) comprising 2 NRCTs, (32,33) 4 PCSs, (26,29,31,35) and 7 RCSs, (23,24,30,34,36-38) were obtained that reported clinical significance for data on bone marrow aspirate in patients with all hematopoietic neoplasms. Twelve studies, ([section][section]) comprising 2 NRCTs, (33,47) 4 PCSs, (26,35,45,48) and 6 RCSs, (25,27,34,37,44,46) were obtained that reported clinical significance for data on bone marrow biopsies in patients with all hematopoietic neoplasms. Twenty studies, (50-69) 19 of which met the inclusion criteria for the systematic review, (50-64,66-69) comprising 1 quasi-randomized control trial, (54) 3 NRCTs, (56,67,69) 13 PCSs, ([parallel][parallel]) and 2 RCSs, (63,66) were obtained that reported clinical significance for data on ancillary testing in patients with all hematopoietic neoplasms. All studies were assessed for risk of bias, and none were found to have methodological flaws that would raise concerns about the studies' findings.

Synoptic reporting ensures the pathologist that she or he is reporting all pertinent diagnostic information in a standardized and consistent manner. The variability in findings in hematopathologic diseases and the complexity of information assimilated and integrated into hematopathology results, impedes the creation of a single synoptic template applicable to all disease processes. Similarly, disease-specific checklists are impractical considering the many diagnostic entities, such as those in the WHO classification system. However, systematization of reports and a consistent grouping of data across disease entities in a synoptic format is an achievable goal. The results of our literature search and expert opinion support inclusion of the following data groups of studies supporting the diagnosis: peripheral blood findings, bone marrow aspirate findings, bone marrow biopsy findings, and ancillary testing on the primary specimen. These data groups are further detailed in statement 2, peripheral blood (22-27); statement 3, bone marrow aspirate (23,24,26,29-38); statement 4, bone marrow core biopsy (##); and statement 5, ancillary testing studies. (50-69) Specific components and ancillary supporting studies, such as special stains, within these data groups include the evidence-based elements, as outlined in the respective statements. Composition of the data groups may vary in different disease templates; however, consistency of overall layout and sequence of data groups would enhance reader comprehension.

The panel concluded that the diagnosis should head the synoptic section of the report. This is supported by adequate level evidence provided by a review by Valenstein, (70) with a recommendation for diagnostic headlines, and agreed upon by the expert panel. Additional useful principles outlined in this reference include maintenance of layout, optimization of information density, and reduction of extraneous information; these principles are derived from a thorough review of pertinent literature, which represents the best-available evidence.

The recommendation for inclusion of a narrative, interpretative comment immediately after the synoptic section is based on the expert opinion of the panel. In particular, if ancillary data, such as cytogenetics, molecular diagnostics, or critical radiographic and laboratory results, are not yet available at the time of sign-out of a morphology report, a narrative is often necessary to communicate differential diagnostic considerations and the effect of the pending tests on the diagnosis. Placement of the narrative comment after the synoptic portion should ensure that this important component does not get buried in other report elements. However, the choice of placement of the narrative comment should be consistent with other reports issued by individual institutions and other practices so clinicians can expect to find the comments in similar portions of all reports.

7. Strong Recommendation.--Laboratories should consider the integrity of electronic data transmission for formatting and data presentation of synoptic reports.

The strength of evidence was convincing to support this recommendation.

This recommendation is evidence-based and supported by a single, systematic review, (70) assessed to have a low risk of bias.

Because most pathology reports are distributed electronically, fidelity of content and formatting becomes very important. Correct data transmission is an issue important enough to comprise specific CAP accreditation requirements for both report review and report elements; pathologists must ensure that data are received and presented in acceptable formats for the end user. This requires interface validation and verification that the final data display recapitulates the content and intent of the pathologist's original report.

There was convincing evidence to support considerations of formatting and data presentation of synoptic reports. A comprehensive review article (70) addressed the limited capabilities of the most-common health level 7 interface, which significantly restricts formatting of pathology reports. In particular, tables, font variations, images, bold face, and bullets, among others, can enhance presentation but are problematic when data are transmitted across interfaces. This statement is further supported by the CAP Diagnostic Intelligence and Health Information Technology Committee's interoperability white paper (72) and the CAP Laboratory Accreditation (LAP) Checklists,73 which underwent data extraction, but were not included in the evidence-based references because they do not meet inclusion criteria. Although the synoptic reporting section should not include tables, bullets, and other formatting not conducive to electronic data integrity, these items can be used in a more comprehensive summary report that has validated data transmission, for example, portable document format (.pdf). In the open comment period, it became evident that specific recommendations regarding font and/or white space could not be rendered because of the wide diversity of information technology systems used in pathology, hospitals, and doctor's offices.

Based on the available evidence, the realities of electronic medical records, and expert consensus, the panel recommends that evaluation and validation of data transmission in the particular practice environment and electronic media is required.

8. No Recommendation.--No recommendation was made regarding the inclusion of coding terms in a synoptic report because coding terms are distinct from scientific terms and vary considerably among health authorities, payers, and different countries.

The strength of evidence was insufficient to support a recommendation; therefore, no recommendation is made.

In the United States and other countries, data extraction for payers and registries is based on coding schemes, such as the ICD9/10 (International Statistical Classification of Diseases and Related Health Problems), and SNOMED-CT (Systematized Nomenclature of Medicine--Clinical Terms). The committee considered whether harmonization with coding terminology was beneficial to diagnosis and data collection. There were no publications directly addressing coding terms in pathology reports. However, 3 of the retrieved references examined data extraction for cancer registries. Use of predefined forms led to a 28.4% (95% confidence interval [CI], 15.7-41.2) increase in complete reporting of a minimum data set required for cancer registration, and a 24.5% (95% CI, 11.0-38.0) increase in complete reporting of minimum data required for patient management. (3) Another study examining electronic transfer of required data elements uncovered incompleteness of the cancer protocols as a barrier to complete data transfer without statistical evaluation. (75) Similarly, improved reporting of key parameters to the national cancer registry was improved if the correct (national) template was used. (5) Therefore, the construction of synoptic templates should rely on scientifically proven data elements that then inform the data for coding and cancer registries. There was no significant disagreement in the open comment period.

9. Recommendation.--Laboratories should include clinical and laboratory data required for a definitive diagnosis in the synoptic section, along with its source(s), if applicable.

The strength of evidence was convincing to support this recommendation.

This recommendation is evidence-based and supported by 11 studies, (22-28,33,46,55,76) 10 of which met the inclusion criteria for the systematic review. (22-27,33,46,55,76) These studies comprise 2 NRCTs, (33,76) 3 PCSs, (22,26,55) and 5 RCSs. (23-25,27,46) All studies were assessed for risk of bias, and none were found to have methodological flaws that would raise concern about the studies' findings. Three RCSs (23,25,46) reported clinical significance for data on age in patients with ALL, myeloproliferative disorders essential thrombocythemia, polycythemia vera, idiopathic myelofibrosis, and peripheral T-cell lymphoma. Two studies, 1 RCS and 1 NRCT, (33,46) reported clinical significance for data on performance status in NHL and peripheral T-cell lymphoma. Four studies, (28,46,55,76) 3 of which were included in the systematic review, (46,55,76) comprising an NRCT, (76) a PCS, (55) and an RCS, (46) reported clinical significance for data on lactate dehydrogenase for patients with AML, peripheral T-cell lymphoma, primary bone marrow NHL, NHL, and hypoplastic MDS. Two studies, comprising an NRCT (33) and an RCS, (46) reported clinical significance for data on staging in patients with NHL and peripheral T-cell lymphoma. Two studies, comprising an NRCT (33) and an RCS, (46) reported clinical significance for data on prognostic scoring systems in patients with NHL and peripheral T-cell lymphoma. Six studies (22-27) comprising 2 PCSs, (22,26) and 4 RCSs, (23-25,27) reported clinical significance for data on peripheral blood parameters in patients with [Ph.sup.+] ALL, polycythemia vera, myelodysplasia, AA, myeloproliferative disease, and adult T-cell leukemia/lymphoma. Refer to Supplemental Table 17 in the SDC for table summarizing studies' findings.

When submitting a bone marrow specimen for interpretation, the referring institution should submit pertinent laboratory and clinical information for complete diagnostic evaluation. Initially, the clinician should provide as much detailed history and radiographic and physical findings as are available at the time of specimen submission. Specific data elements that are supported by high-level evidence include age, (23,25,46) performance status, (28,46) lactate dehydrogenase, (28,46,55,76) and staging and prognostic scoring systems. (33,46) In outpatient settings, in particular, the clinician or referring institution should submit peripheral blood parameters that may not be available to the pathologist receiving the bone marrow specimen, including hemoglobin level, (24,26,27) absolute neutrophil count, (24,27) and platelet count (22,24,25,27) (see also recommendation statement 2).

In the open comment period, there was general agreement with the necessity of including clinical and laboratory data but diverging opinions on whose responsibility it was to obtain and communicate those data and whether it was the duty of the pathologist to extract the data from the electronic medical record, if available. These responsibilities for the clinician and the pathologist are in a grey zone and are highly dependent on practice settings. In addition, this information is often not available for a first-time diagnosis and will only be generated after a diagnosis is rendered. Nevertheless, there is no doubt that communication and a collaborative effort between clinician and pathologist will improve the quality and specificity of the final diagnosis contained within the synoptic bone marrow report. In the opinion of the expert panel, pathologists and clinicians should define responsibilities as well as possible in their practice environment so that critical clinical and laboratory data are incorporated in the bone marrow report. It is equally important that clinicians recognize their responsibility in transmitting critical information to the pathologist to provide the appropriate context for bone marrow evaluation and diagnosis.

CONCLUSIONS

This evidence-based guideline has been developed during a 3-year period that has seen a dramatic increase in genomic information on hematologic neoplasms gained through whole genome sequencing and other molecular technologies. Many of the genomic studies were published after the search period for the guideline was closed or did not meet stringent review criteria and are, therefore, not represented in the final list of studies informing this guideline. On the other hand, some standard-of-care clinical practices, such as lymphoma staging or the link of cytogenetic studies to patient outcome in leukemias and myelodysplasias, were established before the search period began in 2002 and are, therefore, underrepresented. Nevertheless, inclusion of additional studies would not substantially change the list of data elements that are presented in this guideline. The genomic revolution advances our understanding and has already enabled new therapeutic interventions for hematopoietic diseases, many of which remain under active investigation in clinical trials or have just been approved by the US Food and Drug Administration within the past 1 to 2 years. The relevant ancillary, molecular testing can be incorporated in the data element of molecular tests as it applies to each institution and as it reaches maturity as standard clinical care. However, other more-traditional methods of diagnosis, prognostication, and prediction of response to therapy remain relevant for patient care and are not replaced by genomic analysis. In an environment of the increasing complexity of the diagnostic armamentarium, it becomes ever more important to work up and report bone marrow examinations in a methodical, consistent manner that clearly communicates critical information to the clinicians, to other members of the health care team, and increasingly, to patients.

This guideline advocates the use of synoptic reports for bone marrow examinations and has identified data elements that are directly relevant to patient outcomes and to reliable and complete reporting. As mentioned in statement 6, a single template for all bone marrow reporting would not fulfill the requirement for succinct data presentation that is free of clutter and irrelevant information. It is, therefore, up to individual institutions and practice environments to develop or adopt synoptic templates with the appropriate selection of evidence-based data elements outlined in statements 2 to 5 and 9. This guideline's relationship with the CAP Cancer Protocols will be discussed in the companion publications (eg, the "Frequently Asked Questions" document that the Center provides upon release of the guideline), possible journal correspondence, and in the next update of the guideline. A practical approach could be to initially determine the most commonly encountered disease categories and/or and diagnostic scenarios that cover 80% of the reports. Data elements that have not been identified in the evidence-based search but are important tools for the pathologist to arrive at a diagnosis can be reported in the nonsynoptic portion of the report; this can be standardized as well, such as bone marrow differential counts, immunohistochemistry antibodies used, and special stains performed. The most difficult recommendations to implement are statement 5, regarding ancillary testing on the primary specimen, and statement 9, regarding clinical data and test results other than the primary specimen. Because both clinical and ancillary data are often unavailable at all or within the period expected for a timely bone marrow report, it will require additional effort to implement systems to follow up on pending results, to communicate with clinicians, and to retrieve data from electronic medical records. Although this can be a daunting task, there is no doubt that it represents best practice and improves the accuracy of bone marrow diagnostics. Because it is increasingly difficult for clinicians to put together and understand correctly the complexities of all the data generated in the bone marrow diagnostic workup, it represents a great opportunity for pathologists to be valuable members of the diagnostic team and to strengthen collaboration with their clinician colleagues. It is our hope that, with experience and more widely practiced adoption of synoptic principles of bone marrow reports, additional guidance will emerge for future revisions of this practice guideline.

We thank advisory panel members Angela Dispenzieri, MD; Joan E. Etzell, MD; Kathryn Foucar, MD; John Tate, MD, PhD; Barbara Zehentner, PhD, HCLD (ABB); Center Advisor M. Elizabeth Hammond, MD; Sandi Larsen, MBA, MT(ASCP); John Olsen, MD; and CAP staff Megan Wick, MT(ASCP).

References

(1.) Swerdlow SH, Campo E, Harris NL, et al, eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. Lyon, France: IARC Press; 2008. World Health Organization Classification of Tumours. Vol. 2.

(2.) Beattie GC, McAdam TK, Elliott S, Sloan JM, Irwin ST. Improvement in quality of colorectal cancer pathology reporting with a standardized proforma--a comparative study. Colorectal Dis. 2003; 5(6):558-562.

(3.) Branston LK, Greening S, Newcombe RG, et al. The implementation of guidelines and computerised forms improves the completeness of cancer pathology reporting. The CROPS project: a randomised controlled trial in pathology. Eur J Cancer. 2002; 38(6):764-772.

(4.) Chan NG, Duggal A, Weir MM, Driman DK. Pathological reporting of colorectal cancer specimens: a retrospective survey in an academic Canadian pathology department. Can J Surg. 2008; 51(4):284-288.

(5.) Haugland HK, Casati B, Dorum LM, Bjugn R. Template reporting matters--a nationwide study on histopathology reporting on colorectal carcinoma resections. Hum Pathol. 2011; 42(1):36-40.

(6.) Messenger DE, McLeod RS, Kirsch R. What impact has the introduction of a synoptic report for rectal cancer had on reporting outcomes for specialist gastrointestinal and nongastrointestinal pathologists? Arch Pathol Lab Med. 2011; 135(11):1471-1475.

(7.) Austin R, Thompson B, Coory M, Walpole E, Francis G, Fritschi L. Histopathology reporting of breast cancer in Queensland: the impact on the quality of reporting as a result of the introduction of recommendations. Pathology. 2009; 41(4):361-365.

(8.) Harvey JM, Sterrett GF, McEvoy S, et al; Key Cancers Patterns of Care Study Group. Pathology reporting of breast cancer: trends in 1989-1999, following the introduction of mammographic screening in Western Australia. Pathology. 2005; 37(5):341-346.

(9.) Verkerk K, Van Veenendaal H, Severens JL, Hendriks EJ, Burgers JS. Considered judgement in evidence-based guideline development. Int J Qual Health Care. 2006; 18(5):365-369.

(10.) Graham R, Mancher M, Wolman DM, Greenfield S, Steinberg E, eds; Committee on Standards for Developing Trustworthy Clinical Practice Guidelines; Board of Health Care Services; Institute of Medicine. Clinical Practice Guidelines We Can Trust. Washington, DC: National Academies Press; 2011.

(11.) Hussong JW, Arber DA, Bradley KT, et al; for the Cancer Committee, College of American Pathologists. Protocol for the examination of specimens from patients with hematopoietic neoplasms involving the bone marrow. Version BoneMarrow 3.0.1.1. http://www.cap.org/ShowProperty?nodePath=/UCMCon/ Contribution%20Folders/WebContent/pdf/bone-13protocol-3111 .pdf. Published June 2012. Updated March 13, 2015. Accessed October 28, 2015.

(12.) College of American Pathologists. Cancer protocol templates. http://www. cap.org/web/oracle/webcenter/portalapp/pagehierarchy/cancer_ protocol_templates.jspx?_afrLoop=469363053348835#%40%3F_afrLoop% 3D4693 63053348835%2 6_adf.ctrl-state%3Dtrjqklj8z_104. Accessed October 28, 2015.

(13.) National Comprehensive Cancer Network. NCCN guidelines. http://www. nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed October 28, 2015.

(14.) Centers for Medicare & Medicaid Services. Physician quality reporting system. https://www.cms.gov/Medicare/Quality-Initiatives-Patient-AssessmentInstruments/PQRS/index.html?redirect=/pqri/. Updated June 12, 2015. Accessed October 28, 2015.

(15.) Lee SH, Erber WN, Porwit A, Tomonaga M, Peterson LC; International Council for Standardization in Hematology. ICSH guidelines for the standardization of bone marrow specimens and reports. Int J Lab Hematol. 2008; 30(5): 349-364.

(16.) Campbell JK, Matthews JP, Seymour JF, Wolf MM, Juneja SK; Australasian Leukaemia Lymphoma Group. Optimum trephine length in the assessment of bone marrow involvement in patients with diffuse large cell lymphoma. Ann Oncol. 2003; 14(2):273-276.

(17.) Aumann K, Amann D, Gumpp V, et al. Template-based synoptic reports improve the quality of pathology reports of prostatectomy specimens. Histopathology. 2012; 60(4):634-644.

(18.) Gill AJ, Johns AL, Eckstein R, et al; New South Wales Pancreatic Cancer Network (NSWPCN). Synoptic reporting improves histopathological assessment of pancreatic resection specimens. Pathology. 2009; 41(2):161-167.

(19.) Idowu MO, Bekeris LG, Raab S, Ruby SG, Nakhleh RE. Adequacy of surgical pathology reporting of cancer: a College of American Pathologists Q-Probes study of 86 institutions. Arch Pathol Lab Med. 2010; 134(7):969-974.

(20.) Karim RZ, van den Berg KS, Colman MH, McCarthy SW, Thompson JF, Scolyer RA. The advantage of using a synoptic pathology report format for cutaneous melanoma. Histopathology. 2008; 52(2):130-138.

(21.) Kahn C, Simonella L, Sywak M, Boyages S, Ung O, O'Connell D. Postsurgical pathology reporting of thyroid cancer in New South Wales, Australia. Thyroid. 2012; 22(6):604-610.

(22.) List A, Dewald G, Bennett J, et al; Myelodysplastic Syndrome-003 Study Investigators. Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. N Engl i Med. 2006; 355(14):1456-1465.

(23.) Gandemer V, Auclerc M-F, Perel Y, et al; FRALLE group. Impact of age, leukocyte count and day 21-bone marrow response to chemotherapy on the long-term outcome of children with Philadelphia chromosome-positive acute lymphoblastic leukemia in the pre-imatinib era: results of the FRALLE 93 study. BMC Cancer. 2009; 9:14.

(24.) Kao JM, McMillan A, Greenberg PL. International MDS risk analysis workshop (IMRAW)/IPSS reanalyzed: impact of cytopenias on clinical outcomes in myelodysplastic syndromes. Am J Hematol. 2008; 83(10):765-770.

(25.) Kvasnicka HM, Thiele J. The impact of clinicopathological studies on staging and survival in essential thrombocythemia, chronic idiopathic myelofibrosis, and polycythemia rubra vera. Semin Thromb Hemost. 2006; 32(4, pt 2): 362-371.

(26.) Wang W, Wang X, Xu X, Lin G. Diagnosis and treatment of acquired aplastic anaemia in adults: 142 cases from a multicentre, prospective cohort study in Shanghai, China. J Int Med Res. 2011; 39(5):1994-2005.

(27.) Greenberg PL, Tuechler H, Schanz J, et al. Revised international prognostic scoring system for myelodysplastic syndromes. Blood. 2012; 120(12):2454-2465.

(28.) Garcia-Manero G. Myelodysplastic syndromes: 2012 update on diagnosis, risk-stratification, and management. Am J Hematol. 2012; 87(7):692-701.

(29.) Basso G, Veltroni M, Valsecchi MG, et al. Risk of relapse of childhood acute lymphoblastic leukemia is predicted by flow cytometric measurement of residual disease on day 15 bone marrow. J Clin Oncol. 2009; 27(31):5168-5174.

(30.) Baumann I, Fuhrer M, Behrendt S, et al. Morphological differentiation of severe aplastic anaemia from hypocellular refractory cytopenia of childhood: reproducibility of histopathological diagnostic criteria. Histopathology. 2012; 61(1):10-17.

(31.) Fernandez de Larrea C, Tovar N, Rozman M, et al. Multiple myeloma in serologic complete remission after autologous stem cell transplantation: impact of bone marrow plasma cell assessment by conventional morphology on disease progression. Biol Blood Marrow Transplant. 2011; 17(7):1084-1087.

(32.) Jabbour E, Koscielny S, Sebban C, et al. High survival rate with the LMT-89 regimen in lymphoblastic lymphoma (LL), but not in T-cell acute lymphoblastic leukemia (T-ALL). Leukemia. 2006; 20(5):814-819.

(33.) Lombardo M, Morabito F, Merli F, et al. Bleomycin, epidoxorubicin, cyclophosphamide, vincristine and prednisone (BACOP) in patients with follicular non-Hodgkin's lymphoma: results of a prospective, multicenter study of the Gruppo Italiano Per Lo Studio Dei Linfomi (GISL). Leuk Lymphoma. 2002; 43(9):1795-1801.

(34.) Lugli A, Ebnoether M, Cogliatti SB, et al. Proposal of a morphologic bone marrow response score for imatinib mesylate treatment in chronic myelogenous leukemia. Hum Pathol. 2005; 36(1):91-100.

(35.) Rowe JM, Kim HT, Cassileth PA, et al. Adult patients with acute myeloid leukemia who achieve complete remission after 1 or 2 cycles of induction have a similar prognosis: a report on 1980 patients registered to 6 studies conducted by the Eastern Cooperative Oncology Group. Cancer. 2010; 116(21):5012-5021.

(36.) Liu D, Chen Z, Xue Y, et al. The significance of bone marrow cell morphology and its correlation with cytogenetic features in the diagnosis of MDSRA patients. Leuk Res. 2009; 33(8):1029-1038.

(37.) Thiele J, Kvasnicka HM, Mullauer L, Buxhofer-Ausch V, Gisslinger B, Gisslinger H. Essential thrombocythemia versus early primary myelofibrosis: a multicenter study to validate the WHO classification. Blood. 2011; 117(21):5710-5718.

(38.) Musolino A, Guazzi A, Nizzoli R, Panebianco M, Mancini C, Ardizzoni A. Accuracy and relative value of bone marrow aspiration in the detection of lymphoid infiltration in non-Hodgkin lymphoma. Tumori. 2010; 96(1):24-27.

(39.) Haferlach T, Schoch C, Loffler H, et al. Morphologic dysplasia in de novo acute myeloid leukemia (AML) is related to unfavorable cytogenetics but has no independent prognostic relevance under the conditions of intensive induction therapy: results of a multiparameter analysis from the German AML Cooperative Group studies. J Clin Oncol. 2003; 21(2):256-265.

(40.) Kent SA, Variakojis D, Peterson LC. Comparative study of marginal zone lymphoma involving bone marrow. Am J Clin Pathol. 2002; 117(5):698-708.

(41.) Martinez A, Ponzoni M, Agostinelli C, et al; International Extranodal Lymphoma Study Group. Primary bone marrow lymphoma: an uncommon extranodal presentation of aggressive non-Hodgkin lymphomas. Am J Surg Pathol. 2012; 36(2):296-304.

(42.) Moid F, DePalma L. Comparison of relative value of bone marrow aspirates and bone marrow trephine biopsies in the diagnosis of solid tumor metastasis and Hodgkin lymphoma: institutional experience and literature review. Arch Pathol Lab Med. 2005; 129(4):497-501.

(43.) Montillo M, Schinkoethe T, Elter T. Eradication of minimal residual disease with alemtuzumab in B-cell chronic lymphocytic leukemia (B-CLL) patients: the need for a standard method of detection and the potential impact of bone marrow clearance on disease outcome. Cancer Invest. 2005; 23(6):488-496.

(44.) Barbui T, Thiele J, Passamonti F, et al. Initial bone marrow reticulin fibrosis in polycythemia vera exerts an impact on clinical outcome. Blood. 2012; 119(10): 2239-2241.

(45.) Campbell PJ, Bareford D, Erber WN, et al. Reticulin accumulation in essential thrombocythemia: prognostic significance and relationship to therapy. J Clin Oncol. 2009; 27(18):2991-2999.

(46.) Gallamini A, Stelitano C, Calvi R, et al; Intergruppo Italiano Linfomi. Peripheral T-cell lymphoma unspecified (PTCL-U): a new prognostic model from a retrospective multicentric clinical study. Blood. 2004; 103(7):2474-2479.

(47.) Hultdin M, Sundstrom G, Wahlin A, et al. Progression of bone marrow fibrosis in patients with essential thrombocythemia and polycythemia vera during anagrelide treatment. Med Oncol. 2007; 24(1):63-70.

(48.) Takasaki Y, Iwanaga M, Tsukasaki K, et al. Impact of visceral involvements and blood cell count abnormalities on survival in adult T-cell leukemia/ lymphoma (ATLL). Leuk Res. 2007; 31(6):751-757.

(49.) Howell SJ, Grey M, Chang J, et al. The value of bone marrow examination in the staging of Hodgkin's lymphoma: a review of 955 cases seen in a regional cancer centre. Br j Haematol. 2002; 119(2):408-411.

(50.) Bjorklund E, Matinlauri I, Tierens A, et al. Quality control of flow cytometry data analysis for evaluation of minimal residual disease in bone marrow from acute leukemia patients during treatment. J Pediatr Hematol Oncol. 2009; 31(6): 406-415.

(51.) Bottcher S, Ritgen M, Buske S, et al; EU MCL MRD Group. Minimal residual disease detection in mantle cell lymphoma: methods and significance of four-color flow cytometry compared to consensus IGH-polymerase chain reaction at initial staging and for follow-up examinations. Haematologica. 2008; 93(4):551-559.

(52.) Chen Y, Cortes J, Estrov Z, et al. Persistence of cytogenetic abnormalities at complete remission after induction in patients with acute myeloid leukemia: prognostic significance and the potential role of allogeneic stem-cell transplantation. J Clin Oncol. 2011; 29(18):2507-2513.

(53.) Langebrake C, Creutzig U, Dworzak M, et al; MRD-AML-BFM Study Group. Residual disease monitoring in childhood acute myeloid leukemia by multiparameter flow cytometry: the MRD-AML-BFM Study Group. J Clin Oncol. 2006; 24(22):3686-3692.

(54.) Irving J, Jesson J, Virgo P, et al; UKALL Flow MRD Group; UK MRD Steering Group. Establishment and validation of a standard protocol for the detection of minimal residual disease in B lineage childhood acute lymphoblastic leukemia by flow cytometry in a multi-center setting. Haematologica. 2009; 94(6): 870-874.

(55.) Kern W, Haferlach T, Schoch C, et al. Early blast clearance by remission induction therapy is a major independent prognostic factor for both achievement of complete remission and long-term outcome in acute myeloid leukemia: data from the German AML Cooperative Group (AMLCG) 1992 trial. Blood. 2003; 101(1):64-70.

(56.) Martinelli G, Iacobucci I, Rosti G, et al. Prediction of response to imatinib by prospective quantitation of BCR-ABL transcript in late chronic phase chronic myeloid leukemia patients. Ann Oncol. 2006; 17(3):495-502.

(57.) Merx K, Muller MC, Kreil S, et al. Early reduction of BCR-ABL mRNA transcript levels predicts cytogenetic response in chronic phase CML patients treated with imatinib after failure of interferon a. Leukemia. 2002; 16(9):1579-1583.

(58.) Moreton P, Kennedy B, Lucas G, et al. Eradication of minimal residual disease in B-cell chronic lymphocytic leukemia after alemtuzumab therapy is associated with prolonged survival. J Clin Oncol. 2005; 23(13):2971-2979.

(59.) Morgado JMT, Sanchez-Munoz L, Teodosio CG, et al. Immunophenotyping in systemic mastocytosis diagnosis: 'CD25 positive' alone is more informative than the 'CD25 and/or CD20 WHO criterion. Mod Pathol. 2012; 25(4):516-521.

(60.) Perea G, Domingo A, Villamor N, et al; for CETLAM Group Spain. Adverse prognostic impact of CD36 and CD2 expression in adult de novo acute myeloid leukemia patients. Leuk Res. 2005; 29(10):1109-1116.

(61.) Quintas-Cardama A, Kantarjian H, Jones D, et al. Delayed achievement of cytogenetic and molecular response is associated with increased risk of progression among patients with chronic myeloid leukemia in early chronic phase receiving high-dose or standard-dose imatinib therapy. Blood. 2009; 113(25):6315-6321.

(62.) Vance GH, Kim H, Hicks GA, et al. Utility of interphase FISH to stratify patients into cytogenetic risk categories at diagnosis of AML in an Eastern Cooperative Oncology Group (ECOG) clinical trial (E1900). Leuk Res. 2007; 31(5):605-609.

(63.) Lane S, Saal R, Mollee P, et al. A [greater than or equal to] 1 log rise in RQ-PCR transcript levels defines molecular relapse in core binding factor acute myeloid leukemia and predicts subsequent morphologic relapse. Leuk Lymphoma. 2008; 49(3):517-523.

(64.) Wiedswang G, Borgen E, Presen R, et al. Detection of isolated tumor cells in bone marrow is an independent prognostic factor in breast cancer. J Clin Oncol. 2003; 21(18):3469-3478.

(65.) Janni W, Rack B, Kasprowicz N, Scholz C, Hepp P. DTCs in breast cancer: clinical research and practice. Recent Results Cancer Res. 2012; 195:173-178.

(66.) Lundan T, Juvonen V, Mueller MC, et al. Comparison of bone marrow high mitotic index metaphase FISH to peripheral blood and bone marrow real time quantitative polymerase chain reaction on the International Scale for detecting residual disease in chronic myeloid leukemia. Haematologica. 2008; 93(2):178-185.

(67.) Liu H, Johnson JL, Koval G, et al. Detection of minimal residual disease following induction immunochemotherapy predicts progression free survival in mantle cell lymphoma: final results of CALGB 59909. Haematologica. 2012; 97(4):579-585.

(68.) Chopra A, Pati H, Mahapatra M, et al. Flow cytometry in myelodysplastic syndrome: analysis of diagnostic utility using maturation pattern-based and quantitative approaches. Ann Hematol. 2012; 91(9):1351-1362.

(69.) Schlette EJ, Admirand J, Wierda W, et al. p53 expression by immunohistochemistry is an important determinant of survival in patients with chronic lymphocytic leukemia receiving frontline chemo-immunotherapy. Leuk Lymphoma. 2009; 50(10):1597-1605.

(70.) Valenstein PN. Formatting pathology reports: applying four design principles to improve communication and patient safety. Arch Pathol Lab Med. 2008; 132(1):84-94.

(71.) Howick J, Chalmers I, Glasziou P, et al. Explanation of the 2011 Oxford Centre for Evidence-Based Medicine (OCEBM) levels of evidence (background document). Oxford Centre for Evidence-Based Medicine website. http://www. cebm.net/index.aspx?o=5653. Accessed January 28, 2016.

(72.) Beckwith BA, Aller RD, Brassel JH, Brodsky VB, de Baca ME; College of American Pathologists. White paper: laboratory interoperability best practices--ten mistakes to avoid. http://www.cap.org/apps/docs/committees/informatics/ cap_dihit_lab_interop_final_march_2013.pdf. Published March 2013. Accessed October 28, 2015.

(73.) College of American Pathologists. Accreditation checklists. http://www. cap.org/web/oracle/webcenter/portalapp/pagehierarchy/accreditation_checklists. jspx?_afrLoop=5269688438738#%40%3F_afrLoop%3D5269688438738%26_ adf.ctrl-state%3D1a12lc679g_34. Accessed March 28, 2015.

(74.) Guyatt GH, Oxman AD, Vist GE, et al; GRADE Working Group. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BjM. 2008; 336(7650):924-926.

(75.) Hassell L, Aldinger W, Moody C, et al. Electronic capture and communication of synoptic cancer data elements from pathology reports: results of the Reporting Pathology Protocols 2 (RPP2) project. J Registry Manag. 2009; 36(4):117-124; quiz 163-165.

(76.) Czuczman MS, Grillo-Lopez AJ, Alkuzweny B, Weaver R, Larocca A, McLaughlin P. Prognostic factors for non-Hodgkin's lymphoma patients treated with chemotherapy may not predict outcome in patients treated with rituximab. Leuk Lymphoma. 2006; 47(9):1830-1840.

APPENDIX
Conflicts of Interest Table; Disclosed Interests and Activities
August 2011-June 2015 (a)

Name                      Interest/Activity Type

Charles L. Abbott, MD     Board or advisory board

                          Leadership in other associations
Monica E. de Baca, MD     Consultancies
                          Board or advisory board

Sherrie L. Perkins, MD,   Royalties
  PhD                     Leadership in other associations

                          Lecture fees paid by entity (honoraria)
                          Grants

                          Elected or appointed positions in other
                            national/international medical
                            organizations
                          Institutional financial interests
Kaaren Kemp Reichard,     Lecture fees paid by entity (honoraria)
  MD                      Royalties

Cordelia Sever, MD        Elected or appointed positions in other
                            national/international medical
                            organizations
                          Leadership in other associations
                          Grants
Ann Taylor, MD            Ownership or beneficial ownership of stock
Howard R. Terebelo, DO    Board or advisory board
                          Lecture fees paid by entity (honoraria)

                          Ownership or beneficial ownership of stock
R. Bryan Rumble, MSc      Consultancy

                          Vendor to College of American Pathologists
Nicole E. Thomas, MPH,    Grants
CT(ASCP)cm

Name                      Entity

Charles L. Abbott, MD     NeoGenomics Medical Scientific Advisory
                            Board
                          Massachusetts Society of Pathologists
Monica E. de Baca, MD     Millipore/Amnis
                          Clinical Laboratory Improvement Advisory
                            Committee
                          DoveMed
Sherrie L. Perkins, MD,   American Society for Clinical Pathology
  PhD                     Society for Hematopathology
                          American Society for Clinical Pathology
                          Children's Oncology Group
                          College of American Pathologists
                          St. Baldrick's Foundation
                          Children's Oncology Group
                          Children's Oncology Group

                          ARUP Laboratories
Kaaren Kemp Reichard,     College of American Pathologists
  MD                      American Society for Clinical Pathology
                          Amirsys Publishing Company
Cordelia Sever, MD        Greater Albuquerque Medical Association

                          TriCore Reference Laboratories
                          HORIBA Medical
Ann Taylor, MD            Utah Pathology Services, Inc
Howard R. Terebelo, DO    Celgene
                          Celgene
                          Amgen
                          Millennium
                          Pharmacyclics
                          Pharmacyclics
R. Bryan Rumble, MSc      American Society for Clinical Pathology
                          Association for Molecular Pathology
                          American Society of Clinical Oncology
                          American Society of Hematology
                          College of American Pathologists
Nicole E. Thomas, MPH,    Centers for Disease Control and Prevention
CT(ASCP)cm

(a) Joseph D. Khoury, MD, and Carol Colasacco, MLIS, SCT(ASCP), have
no reported conflicts of interest to disclose.


Cordelia Sever, MD; Charles L. Abbott, MD; Monica E. de Baca, MD; Joseph D. Khoury, MD; Sherrie L. Perkins, MD, PhD; Kaaren Kemp Reichard, MD; Ann Taylor, MD; Howard R. Terebelo, DO; Carol Colasacco, MLIS, SCT(ASCP); R. Bryan Rumble, MSc; Nicole E. Thomas, MPH, CT(ASCP)cm

Accepted for publication November 24, 2015.

Published as an Early Online Release February 23, 2016.

Supplemental digital content is available for this article at www. archivesofpathology.org in the September 2016 table of contents.

From the Department of Hematopathology, Pathology Associates of Albuquerque, Albuquerque, New Mexico (Dr Sever); the Department of Pathology, Berkshire Medical Center, Pittsfield, Massachusetts (Dr Abbott); Medical Laboratory Associates, Seattle, Washington (Dr de Baca); the Department of Pathology, University of Texas MD Anderson Cancer Center, Houston (Dr Khoury); the Department of Pathology, University of Utah, Salt Lake City (Dr Perkins); the Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota (Dr Reichard); Utah Pathology Services, Inc, Salt Lake City (Dr Taylor); the Department of Hematology/Medical Oncology, Newland Medical Associates, Novi, Michigan (Dr Terebelo); the Departments of Governance (Ms Colasacco) and Surveys (Ms Thomas), College of American Pathologists, Northfield, Illinois; and the Quality and Guidelines Department, American Society of Clinical Oncology, Alexandria, Virginia (Mr Rumble).

Authors' disclosures of potential conflicts of interest and author contributions are found in the Appendix at the end of this article.

Reprints: Cordelia Sever, MD, Department of Hematopathology, Pathology Associates of Albuquerque, PO Box 26666, PHS, Lab S1, Albuquerque, NM 87125-6666 (email: Cordelia.Sever@tricore.org).

* References 23, 24, 26, 29, 32, 34, 35.

([dagger]) References 23, 24, 26, 29, 32, 34, 35.

([double dagger]) References 25-27, 33-35, 37, 44-48.

([section]) References 50-53, 55, 57-62, 64, 68.

([parallel]) References 50, 51, 53, 54, 58-60, 68.

(#) References 22-27, 29-38, 44-48, 50-70.

** References 23-27, 29-38, 44-48, 50-64, 66-70.

([dagger][dagger]) References 26, 29, 31, 35, 45, 48, 50-53, 55, 57-62, 64, 68.

([double dagger][double dagger]) References 23-25, 27, 30, 34, 36-38, 44, 46, 63, 66.

([section][section]) References 25-27, 33-35, 37, 44-48.

([parallel][parallel]) References 50-53, 55, 57-62, 64, 68.

(##) References 25-27, 33-35, 37, 44-48.
Table 1. Levels of Evidence

Designation   Description

Level I       Evidence derived from systematic reviews
                of appropriate level-II studies and/or
                clinical practice guidelines
Level II      Evidence derived from randomized control
                trials
Level III     Evidence derived from comparative studies
                (eg, prospective cohort studies,
                retrospective cohort studies)
Level IV      Evidence without a comparator (eg, case
                reports, case series, narrative reviews)

Data derived from National Health and Medical Research Council.A
guide to the development, implementation and evaluation of clinical
practice guidelines.https://www.nhmrc.gov.au/_files_nhmrc/
publications/attachments/cp30.pdf.1999.Accessed February 9, 2016.

Table 2. Grades for Strength of Evidence

Designation    Description               Quality of Evidence

Convincing     High confidence that      High/intermediate
                 available evidence        quality evidence
                 reflects true effect.
                 Further research is
                 very unlikely to
                 change the confidence
                 in the estimate of
                 effect.
Adequate       Moderate confidence       Intermediate/low
                 that available            quality of evidence
                 evidence reflects
                 true effect. Further
                 research is likely to
                 have an important
                 effect on the
                 confidence in the
                 estimate of effect
                 and may change the
                 estimate.
Inadequate     Little confidence         Low/insufficient
                 that available            evidence; expert panel
                 evidence reflects         uses formal consensus
                 true effect. Further      process to reach
                 research is very          recommendation
                 likely to have an
                 important effect on
                 the confidence in the
                 estimate of effect
                 and is likely to
                 change the estimate.
Insufficient   Evidence is               Insufficient
                 insufficient to           evidence; expert
                 discern net effect.       panel uses formal
                 Any estimate of           consensus process to
                 effect is very            reach recommendation
                 uncertain.

Adapted by permission from BMJ Publishing Group Limited. GRADE: an
emerging consensus on rating quality of evidence and strength of
recommendations. Guyatt GH, et al; GRADE Working Group.
2008; 336(7650):924-926.74

Table 3. Grades for Strength of Recommendations

Designation         Recommendation

Strong              Recommend for or against a particular bone
  recommendation      marrow synoptic reporting practice (Can
                      include must or should)
Recommendation      Recommend for or against a particular bone
                      marrow synoptic reporting practice (Can
                      include should or may)

Expert consensus    Recommend for or against a particular bone
  opinion             marrow synoptic reporting practice (Can
                      include should or may)

No recommendation   No recommendation for or against a
                      particular bone marrow synoptic reporting
                      practice

Designation         Rationale

Strong              Supported by convincing (high) or adequate
  recommendation      (intermediate) quality of evidence and clear
                      benefit that outweighs any harms
Recommendation      Some limitations in quality of evidence
                      (adequate [intermediate] or inadequate [low]),
                      balance of benefits and harms, values, or
                      costs, but panel concludes that there is
                      sufficient evidence and/or benefit to inform a
                      recommendation
Expert consensus    Serious limitations in quality of evidence
  opinion             (inadequate [low] or insufficient), balance of
                      benefits and harms, values or costs, but panel
                      consensus is that a statement is necessary
No recommendation   Insufficient evidence or agreement of the
                      balance of benefits and harms, values, or costs
                      to provide a recommendation

Data derived from (74).

Table 4. Guideline Statements and Strength of
Recommendations

Guideline Statement                           Strength of
                                              Recommendation

1. Laboratories should adopt synoptic         Strong
   reporting as a component of bone marrow      recommendation
   pathology reports for clearly defined
   neoplasia or widely applied
   classification schemes and receive
   appropriate institutional support.
2. When reporting on peripheral blood         Strong
   specimens for bone marrow synoptic           recommendation
   reports, laboratories should report
   clinically and diagnostically pertinent
   elements, if available. These key
   elements may include one or more
   parameters from complete blood cell
   count, absolute cell counts, and
   relevant morphologic descriptors.
3. When reporting bone marrow aspirate        Strong
   results, laboratories should report          recommendation for
   clinically and diagnostically pertinent      blast percentage;
   elements in the synoptic section. These      recommendation for
   key elements may include the                 all other parameters
   evidence-based parameters, such as blast
   percentage, dysplasia, myeloid to
   erythroid ratio, morphology of
   myeloid/lymphoid elements, and
   enumeration of lymphoid elements and
   plasma cells; additional elements may be
   included in nonsynoptic sections of the
   report.
4. When reporting bone marrow core biopsy     Strong
   results, laboratories should report          recommendation for
   clinically or diagnostically pertinent       fibrosis;
   elements in the synoptic section. These      recommendation for
   key elements may include the                 all other parameters
   evidence-based parameters, such as
   fibrosis, cellularity, distribution
   pattern of hematopoietic elements,
   morphology of lymphoid elements, and
   enumeration of lymphoid elements and
   plasma cells; additional elements may be
   included in nonsynoptic sections of the
   report.
5. If relevant ancillary testing studies      Strong
   are performed on the primary sample          recommendation
   (blood or bone marrow), laboratories
   should report the results, general
   methodology, performance site, and
   interpretation site or have the data
   readily available. If the results are
   not available, pending status should be
   explicitly stated.
6. Laboratories should include in the         Strong
   synoptic section of the report data          recommendation for
   groups for diagnosis, supporting             inclusion of data
   studies, and ancillary data that are         groups for
   critical for diagnosis. Key morphologic      diagnosis,
   descriptors should be included and may       supporting studies,
   be in the diagnosis line if critical or      and ancillary data;
   if a component of the disease                recommendation for
   classification. The diagnosis (or            the layout of the
   diagnosis group) should head the             data groups
   synoptic section when possible. A
   narrative, interpretative comment should
   immediately follow the synoptic section,
   if required.
7. Laboratories should consider the           Strong recommendation
   integrity of electronic data
   transmission for formatting and data
   presentation of synoptic reports.
8. No recommendation is made regarding the    No recommendation
   inclusion of coding terms in a synoptic
   report because coding terms are distinct
   from scientific terms and vary
   considerably among health authorities,
   payers, and different countries.
9. Laboratories should include clinical and   Recommendation
   laboratory data required for a
   definitive diagnosis in the synoptic
   section, along with its source(s), if
   applicable.

Table 5. Key Elements of Synoptic Reports for Peripheral Blood
Specimens

Element With Significant      Relevant Disease       Studies Reporting
Outcome Difference              or Diagnosis            Significant
                                                     Differences, No.

WBC count                  [Ph.sup.+] ALL                    1
Hgb                        Myelodysplasia, AA                2

Plt                        Myelodysplasia,                   5
                             myeloproliferative
                             disease, adult T-cell
                             leukemia/lymphoma

Absolute neutrophil        Myelodysplasia                    2
  count
Reticulocyte count         AA                                1
RDW                        AA, MDS                           1

Element With Significant              Source, y
Outcome Difference

WBC count                  Gandemer et al, (23) 2009
Hgb                        Kao et al, (24) 2008
                           Greenberg et al, (27) 2012
Plt                        List et al, (22) 2006

                           Kao et al, (24) 2008
                           Kvasnicka and Thiele, (25) 2006
                           Wang et al, (26) 2011
                           Greenberg et al, (27) 2012
Absolute neutrophil        Kao et al, (24) 2008
  count                    Greenberg et al, (28) 2012
Reticulocyte count         Wang et al, (26) 2011
RDW                        Wang et al, (26) 2011

Abbreviations: AA, aplastic anemia; ALL, acute lymphoblastic
leukemia; AML, acute myeloid leukemia; EFS, event free survival;
Hgb, hemoglobin;  Int-1/Int-2, intermediate-1/intermediate-2; IPSS,
International Prognostic Scoring System; MCV, mean corpuscular
volume; MDS, myelodysplastic syndrome; OS, overall
survival; [Ph.sup.+], Philadelphia-positive;
Plt, platelet; RDW, red cell distribution width; WBC, white blood
cell count.

Table 5. Extended

Results Summary                     Comparison Favors/Shows Benefit/
                                    Difference for (Outcome)

Peripheral blood WBC < 100 000      EFS: 55% low risk, 18% high
  and bone marrow blast < 5% on d     risk; OS: 79% low risk, 27%
  21 (low risk) was associated        high risk
  with significantly better EFS
  and OS in [Ph.sup.+] pediatric
  ALL
Hgb level has additive              Hgb > 10 g/dL is associated
  prognostic value in MDSs for        with better OS in Int-1 and
  Int-1 and Int-2 categories          Int-2 MDS
In MDS, significantly different     In MDS, significantly different
  survival and evolution to AML       survival and evolution to AML
  was associated with Hgb < 10 g      was associated with Hgb < 10 g,
                                      Plt < 100 000, absolute
                                      neutrophil count < 0.08
Plt count < 100 000 at baseline     Thrombocytopenia < 100 000 at
  significantly associated with       baseline was associated with
  reduced probability of              39% transfusion independence
  transfusion independence and        versus 73% without
  cytogenetic response in             thrombocytopenia; odds ratio
  lenalidomide treatment in MDS       for decreased cytogenetic
  with 5q31 deletion                  response with, versus without,
                                      thrombocytopenia was 4.78
Plt count < 100 000 was             Plt > 100 000 was associated
  significantly associated with       with 63% overall y- median
  IPSS categories, OS, and AML        survival versus 5% <20 000
  evolution in MDS

Plt counts have prognostic          Plt counts have prognostic
  effect in idiopathic                effect in idiopathic
  myelofibrosis                       myelofibrosis
Peripheral blood parameters         Plt count, MCV, reticulocyte
  Plt, MCV, reticulocyte count,       counts, and percentage of
  and percentage of lymphocytes       lymphocytes were significantly
  are significantly different in      different between severe AA and
  severe AA versus hypoplastic        hypoplastic MDS
  MDS in adults
In MDS, significantly different     In MDS, significantly different
  survival and evolution to AML       survival and evolution to AML
  was associated with Plt < 100       was associated Plt < 100 000,
  000
Absolute neutrophil count >         Absolute neutrophil count >
  1500 was significantly              1500 had 62% median OS versus
  associated with IPSS                6% y-median OS
  categories, OS, and AML
  evolution in MDS
In MDS, significantly different     In MDS, significantly different
  survival and evolution to AML       survival and evolution to AML
  was associated with absolute        was associated with absolute
  neutrophil count < 0.8              neutrophil count < 0.8
Reticulocyte count is               Mean reticulocyte count severe
  significantly different in          AA, 13.5; versus nonsevere AA,
  severe AA as compared with          35.7; MDS 55.5 X107L
  nonsevere AA and MDS
RDW is significantly different      Mean RDW, 16.8% severe AA;
  in severe and nonsevere AA          17.4% nonsevere AA;  versus
  versus hypoplastic MDS              20.4% MDS

Results Summary                     P Value

Peripheral blood WBC < 100 000      .002 (EFS)
  and bone marrow blast < 5% on d   .003 (OS)
  21 (low risk) was associated
  with significantly better EFS
  and OS in [Ph.sup.+] pediatric
  ALL
Hgb level has additive              <.001
  prognostic value in MDSs for
  Int-1 and Int-2 categories
In MDS, significantly different     <.001
  survival and evolution to AML
  was associated with Hgb < 10 g

Plt count < 100 000 at baseline     .001 transfusion
  significantly associated with       independence
  reduced probability of            .02 cytogenetic
  transfusion independence and        response
  cytogenetic response in
  lenalidomide treatment in MDS
  with 5q31 deletion

Plt count < 100 000 was             [chi square] test
  significantly associated with       3.6 versus 1.4
  IPSS categories, OS, and AML
  evolution in MDS

Plt counts have prognostic          Not given,
  effect in idiopathic                references quoted
  myelofibrosis
Peripheral blood parameters         <.01
  Plt, MCV, reticulocyte count,
  and percentage of lymphocytes
  are significantly different in
  severe AA versus hypoplastic
  MDS in adults
In MDS, significantly different     <.001
  survival and evolution to AML
  was associated with Plt < 100
  000
Absolute neutrophil count >         [chi square] test
  1500 was significantly              3.9 versus 0.9
  associated with IPSS
  categories, OS, and AML
  evolution in MDS
In MDS, significantly different     <.001
  survival and evolution to AML
  was associated with absolute
  neutrophil count < 0.8
Reticulocyte count is               <.01
  significantly different in
  severe AA as compared with
  nonsevere AA and MDS
RDW is significantly different      <.05
  in severe and nonsevere AA
  versus hypoplastic MDS

Table 6. Key Elements of Synoptic Reports for Bone Marrow (BM)
Aspirate Specimens

Element With Significant     Relevant Disease
Outcome Difference           or Diagnosis

Percentage of blasts         ALL, AML, MDS, MPN, AA

Dysplasia                    MDS, MDS/MPN

Percentage lymphocytes,      NHL, CLL
  morphology
Percentage of plasma cells   Plasma cell myeloma

Element With Significant     Studies Reporting
Outcome Difference              Significant
                             Differences, No.

Percentage of blasts                 7

Dysplasia                            5

Percentage lymphocytes,              2
  morphology
Percentage of plasma cells           1

Element With Significant             Source, y
Outcome Difference

Percentage of blasts         Basso et al, (29) 2009
                             Gandemer et al, (23) 2009
                             Jabbour et al, (32) 2006
                             Kao et al, (24) 2008
                             Lugli et al, (34) 2005
                             Rowe et al, (35) 2010
                             Wang et al, (26) 2011
Dysplasia                    Baumann et al, (20) 2012
                             Lugli et al, (34) 2005
                             Wang et al, (26) 2011
                             Liu et al, (36) 2009
                             Thiele et al, (37) 2011
Percentage lymphocytes,      Lombardo et al, (33) 2002
  morphology                 Musolino et al, (38) 2010
Percentage of plasma cells   Fernandez de Larrea et al,
                               (31) 2011

Abbreviations: 95% CI, 95% confidence interval; AA, aplastic anemia;
ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia;
BACOP, bleomycin, epidoxorubicin, cyclophosphamide, vincristine, and
prednisone; CLL, chronic lymphocytic leukemia; CML, chronic myeloid
leukemia;  CR, complete remission; ET, essential thrombocythemia;
IPSS, International Prognostic Scoring System; MDS, myelodysplastic
syndrome; MPN, myeloproliferative syndrome; NHL, non-Hodgkin
lymphoma; NPV, negative predictive value; OS, overall survival; PPV,
positive predictive value; RFS, relapse-free survival; T-ALL, T-cell
lymphoblastic leukemia.

Table 6. Extended

Results Summary                     Comparison Favors/Shows
                                    Benefit/Difference for
                                    (Outcome)

Residual disease of BM blasts       BM blasts: <0.1%, <10%,
  in d 15 childhood ALL is            [greater than or equal to] 10%
  predictive of relapse               measured by flow cytometry was
                                      associated with 5-y cumulative
                                      relapse in 7.5%, 17.5%, and
                                      47.2%, respectively
BM blast percentage at d 21 is      95% CR [less than or equal to]
  associated with prognosis           5% blasts; 75% CR > 5% blasts
Marrow involvement in T-ALL         OS BM+, 85%; OS BM-, 37%
  associated with OS; CR defined
  as [less than or equal to] 5%
  blasts
Uses IPSS cytogenetic group         Significant correlation with
  blast percentage definitions        blast percentage and cytopenias
BM blast percentage is              BM blast percentage associated
  morphologic indicator of            with cytogenetic response
  response in CML
BM blast percentage as response     Various, including >10% blasts
  criterion, residual disease         d-6 CR, 54%; <10% blasts d-16
  postinduction portends worse        CR, 84%
  prognosis, but similar
  long-term outcome with 1 or 2
  cycles to CR
[CD34.sup.+] blasts lower in AA     Severe AA, 0; nonsevere AA,
  than in hypocellular MDS            0.12; MDS, 2.2
MDS Morphologic criteria can        Patchy erythropoiesis with
  distinguish refractory              defective maturation and
  cytopenia of childhood versus       micromegakaryocytes were the
  severe AA with high                 most significant discriminators
  interobserver reliability           (no statistical values
                                      provided)
Decrease of abnormal                Reduction of abnormal
  megakaryocytes correlates with      megakaryocytes to <10%,
  cytogenetic response of CML on      significantly correlates with
  imatinib treatment                  cytogenetic response
Dyserythropoiesis is a key          Erythropoietic pathologic
  finding in MDS in distinction       hemogenesis in 0% of severe AA
  to severe AA                        versus 95.5% of MDS
Incidence of specific dysplasia     Incidence of specific dysplasia
  for granulocyte and                 for granulocyte and
  megakaryocyte lineage was           megakaryocyte lineage was
  significantly different for         significantly different for
  abnormal karyotype MDS versus       abnormal karyotype MDS versus
  normal karyotype MDS or non-MDS     normal karyotype MDS or non-MDS
  cytopenias                          cytopenias
Morphologic BM features             Megakaryocyte morphologic
  distinguish ET versus early         features, increased
  primary myelofibrosis               granulopoiesis and
                                      erythropoiesis can distinguish
                                      ET versus primary myelofibrosis
                                      with high interobserver
                                      concordance
Response rate and RFS in            Response rate and RFS in
  follicular lymphoma treated         follicular lymphoma treated
  with BACOP was significantly        with BACOP was significantly
  different in patients with BM       worse in patients with BM
  involvement                         involvement
BM aspirate staging correlates      BM aspirate staging
  with BM biopsy but has a            significantly correlates with
  different sensitivity,              BM biopsy results; BM aspirate
  specificity, NPV, and PPV when      PPV is 82% and NPV is 85% in
  compared with BM biopsy             indolent NHL versus 29% PPV and
                                      89% NPV in aggressive NHL
BM plasma cells > 1.5% after        BM plasma cells > 1.5% after
  autologous transplantation had      autologous transplantation had
  an increased risk of                an increased risk of
  progression                         progression

Results Summary                     P Value

Residual disease of BM blasts       <.001
  in d 15 childhood ALL is
  predictive of relapse

BM blast percentage at d 21 is      <.001
  associated with prognosis
Marrow involvement in T-ALL         .01
  associated with OS; CR defined
  as [less than or equal to] 5%
  blasts
Uses IPSS cytogenetic group         <.001
  blast percentage definitions
BM blast percentage is              .001
  morphologic indicator of
  response in CML
BM blast percentage as response     None given, reference
  criterion, residual disease         cited
  postinduction portends worse
  prognosis, but similar
  long-term outcome with 1 or 2
  cycles to CR
[CD34.sup.+] blasts lower in AA     <.05
  than in hypocellular MDS
MDS Morphologic criteria can        [kappa] = 0.79, indicates
  distinguish refractory              substantial interobserver
  cytopenia of childhood versus       agreement
  severe AA with high
  interobserver reliability

Decrease of abnormal                <.001
  megakaryocytes correlates with
  cytogenetic response of CML on
  imatinib treatment
Dyserythropoiesis is a key          None given
  finding in MDS in distinction
  to severe AA
Incidence of specific dysplasia     <.05
  for granulocyte and
  megakaryocyte lineage was
  significantly different for
  abnormal karyotype MDS versus
  normal karyotype MDS or non-MDS
  cytopenias
Morphologic BM features             Concordance [kappa] = 0.739
  distinguish ET versus early         (P<.001), 95% CI,
  primary myelofibrosis               0.651-0.827

Response rate and RFS in            Response rate difference,
  follicular lymphoma treated         <.001; RFS, <.001
  with BACOP was significantly
  different in patients with BM
  involvement
BM aspirate staging correlates      <.001 for correlation of
  with BM biopsy but has a            BM aspirate and biopsy
  different sensitivity,
  specificity, NPV, and PPV when
  compared with BM biopsy

BM plasma cells > 1.5% after        .02
  autologous transplantation had
  an increased risk of
  progression

Table 7. Key Elements of Synoptic Reports for Bone Marrow (BM) Core
Biopsies

Element With     Relevant      Studies              Source, y
Significant     Disease or    Reporting
Outcome         Diagnosis    Significant
Difference                   Differences,
                                 No.

Fibrosis        MPN, MDS          6         Barbui et al, (44) 2012
                                            Campbell et al, (45) 2009
                                            Hultdin et al, (47) 2007
                                            Kvasnicka and Thiele, (25)
                                              2006
Cellularity     MPN, AA,          3         Lugli et al, (34) 2005
                  MPD                       Greenberg et al, (27) 2012
                                            Wang et al, (26) 2011
                                            Thiele et al, (37) 2011
                                            Lugli et al, (34) 2005
Cellularity/    NHL and           3         Lombardo et al, (33) 2002
  involvement     Hodgkin                   Gallamini et al, (46) 2004
  by lymphoma     lymphoma                  Takasaki et al, (48) 2007
Blast %         AML               1         Rowe et al, (35) 2010

Abbreviations: 95% CI, 95% confidence interval; AA, aplastic anemia;
AML, acute myeloid leukemia;  ATLL, adult T-cell leukemia/lymphoma;
BM, bone marrow; CML, chronic myeloid leukemia;  ET, essential
thrombocythemia; HR, hazard ratio; HYA, hyaluronan acid; IMF,
idiopathic myelofibrosis; MDS, myelodysplastic syndrome; MPN,
myeloproliferative neoplasms; NHL, non-Hodgkin lymphoma;  PCV,
polycythemia vera; PMF, prefibrotic primary myelofibrosis; RFS,
relapse-free survival.

Table 7. Extended

Results Summary                          Comparison Favors/Shows
                                         Benefit/ Difference for
                                                (Outcome)

Fibrosis at diagnosis in PCV        Palpable splenomegaly,
  significantly associated with       thrombosis 1.1 versus 2.7 per
  splenomegaly, decreased             100 patient-y; postpolycythemic
  thrombosis, postpolycythemic        myelofibrosis 2.2 versus 0.8
  myelofibrosis                       per 100 patient-y
Elevated reticulin fibrosis at      Arterial thrombosis HR 1.8, 95%
  presentation of ET predicted        CI, 1.1 to 2.9; major
  higher rates of arterial            hemorrhage HR, 2.0; 95% CI,
  thrombosis, major hemorrhage        1.0-3.9; myelofibrotic
  and myelofibrotic                   transformation HR, 5.5; 95% CI,
  transformation                      1.7-18.4
After 2 y of anagrelide             Reticulin and HYA scores were
  therapy, the reticulin and HYA      significantly higher than
  scores were significantly           before treatment
  higher than before treatment (P
  = .02 and P = .002,
  respectively); indicating
  progression of disease
Included [greater than or equal     Patients with ET has better
  to] grade 2 fibrosis or cases       survival than those with
  with increase of 1 grade in <12     prefibrotic and early IMF
  mo follow-up; survival rates in     (IMF0, IMF1)
  IMF: prefibrotic and early
  fibrotic stages of IMF display
  significantly higher 5- and
  10-y relative survival rates
  than advanced (classical)
  stages with prominent
  myelofibrosis (IMF-2/3 or
  myeloid metaplasia).
  Myelofibrosis survival rates in
  polycythemia rubra vera:
  10%-20% of patients present
  with mild to moderate reticulin
  fibrosis at onset; development
  of marked collagen
  myelofibrosis occurred in <20%
  of patients and displayed
  strong time-related progression
Reduction of fibrosis               Fibrosis [less than or equal
  significantly associated with       to] grade 2 associated with
  cytogenetic response                higher rate of complete or
                                      other cytogenetic response
Significantly different             Patients with associated BM
  survival and evolution to AML       fibrosis had poorer survival
  were associated (P < .001) with     and higher incidence of
  marrow fibrosis                     transformation to AML than
                                      those who did not have
                                      associated bone marrow fibrosis
Cellularity of <20%-30% is          Hypoplastic MDS requires BM
  defining hypoplastic MDS            biopsy cellularity <30% age <60
                                      y, <20% age [greater than or
                                      equal to] 60 y
Cellularity determination can       Normal or slightly increased
  help, in addition to other          cellularity present in ET is
  morphologic features, to            significantly different from
  distinguish between ET and          marked increase in age-matched
  early PMF.                          cellularity in early
                                      prefibrotic stage of PMF with
                                      high diagnostic concordance of
                                      74%
Normalization of cellularity        Age-adjusted normal cellularity
  was significantly associated        was significantly associated
  with cytogenetic response in        with complete or other
  CML on imatinib treatment           cytogenetic response
BM involvement by follicular        BM involvement by follicular
  lymphoma is significantly           lymphoma is significantly
  associated with adverse             associated with adverse
  response rate and RFS               response rate and RFS
BM involvement by peripheral        BM involvement by peripheral
  T-cell lymphoma is associated       T-cell lymphoma is associated
  with poorer outcome (increased      with worse outcome after
  relative risk 95% CI, 1.454; P      therapy and worse overall
  = .03) in multivariate analysis     survival
  and worse overall survival in
  univariate analysis (P < .001)
BM involvement is strongly          Presence of BM involvement in
  associated with adverse outcome     ATLL is associated with
  in ATLL (HR, 1.9)                   increased risk of death when
                                      compared with patients with no
                                      marrow involvement
BM blast percentage as response     Significant improvement of
  criterion for AML, residual         complete remission if patients
  disease postinduction portends      with residual leukemia after
  worse prognosis, but similar        first induction received second
  long-term survival if complete      induction chemotherapy
  remission is achieved with 2
  cycles of induction
  chemotherapy

Results Summary                        P Value

Fibrosis at diagnosis in PCV        .01-.03
  significantly associated with
  splenomegaly, decreased
  thrombosis, postpolycythemic
  myelofibrosis
Elevated reticulin fibrosis at      <.001-.05
  presentation of ET predicted
  higher rates of arterial
  thrombosis, major hemorrhage
  and myelofibrotic
  transformation
After 2 y of anagrelide             .002
  therapy, the reticulin and HYA
  scores were significantly
  higher than before treatment (P
  = .02 and P = .002,
  respectively); indicating
  progression of disease
Included [greater than or equal     <.001
  to] grade 2 fibrosis or cases
  with increase of 1 grade in <12
  mo follow-up; survival rates in
  IMF: prefibrotic and early
  fibrotic stages of IMF display
  significantly higher 5- and
  10-y relative survival rates
  than advanced (classical)
  stages with prominent
  myelofibrosis (IMF-2/3 or
  myeloid metaplasia).
  Myelofibrosis survival rates in
  polycythemia rubra vera:
  10%-20% of patients present
  with mild to moderate reticulin
  fibrosis at onset; development
  of marked collagen
  myelofibrosis occurred in <20%
  of patients and displayed
  strong time-related progression
Reduction of fibrosis               .01
  significantly associated with
  cytogenetic response

Significantly different             <.001
  survival and evolution to AML
  were associated (P < .001) with
  marrow fibrosis

Cellularity of <20%-30% is          <.05
  defining hypoplastic MDS

Cellularity determination can       <.001
  help, in addition to other
  morphologic features, to
  distinguish between ET and
  early PMF.

Normalization of cellularity        .001
  was significantly associated
  with cytogenetic response in
  CML on imatinib treatment
BM involvement by follicular        .001 response
  lymphoma is significantly           rate and RFS
  associated with adverse
  response rate and RFS
BM involvement by peripheral        .03
  T-cell lymphoma is associated     <.001
  with poorer outcome (increased
  relative risk 95% CI, 1.454; P
  = .03) in multivariate analysis
  and worse overall survival in
  univariate analysis (P < .001)
BM involvement is strongly          .001
  associated with adverse outcome
  in ATLL (HR, 1.9)

BM blast percentage as response     <.001
  criterion for AML, residual
  disease postinduction portends
  worse prognosis, but similar
  long-term survival if complete
  remission is achieved with 2
  cycles of induction
  chemotherapy
COPYRIGHT 2016 College of American Pathologists
No portion of this article can be reproduced without the express written permission from the copyright holder.
Copyright 2016 Gale, Cengage Learning. All rights reserved.

Article Details
Printer friendly Cite/link Email Feedback
Title Annotation:Special Articles
Author:Sever, Cordelia; Abbott, Charles L.; de Baca, Monica E.; Khoury, Joseph D.; Perkins, Sherrie L.; Rei
Publication:Archives of Pathology & Laboratory Medicine
Date:Sep 1, 2016
Words:16425
Previous Article:Validating Laboratory Results in Electronic Health Records: A College of American Pathologists Q-Probes Study.
Next Article:How to Screen for Hereditary Cancers in General Pathology Practice.
Topics:

Terms of use | Privacy policy | Copyright © 2022 Farlex, Inc. | Feedback | For webmasters |