Report of the Clinical Practice Task Force Survey of the Clinical Cytometry Society

Transcription

1 Cytometry (Communications in Clinical Cytometry) 46: (2001) Forum Report of the Clinical Practice Task Force Survey of the Clinical Cytometry Society J. Philip McCoy, Jr. 1 and Bruce H. Davis 2 * 1 Department of Pathology, Cooper Hospital/UMC, UMDNJ-RWJ at Camden, Camden, New Jersey 2 Department of Pathology, Maine Medical Center, Portland, Maine Among the goals of the Clinical Practice Task Force of the Clinical Cytometry Society is to establish a complete and accurate database of patterns of practice in clinical cytometry and to assist in consensus development on medical applications of cytometry (1 6). As one step in accomplishing this goal, the Task Force conducted an international survey of practitioners of clinical cytometry. The purpose of this survey was to obtain contemporary data regarding the clinical practice of diagnostic cytometry, including scope of clinical utilization, patterns of reagent use, credentials of laboratory personnel, impact of regulatory compliance, and regional reimbursement experiences. These data update and augment information from surveys previously conducted on the practice of clinical flow cytometry (7 10) and will support the development of consensus on a variety of issues. These issues range from the construction of appropriate panels for the analysis of leukemias and lymphomas to the establishment of fair reimbursement for clinical flow cytometric services. Concomitant studies, such as one examining Medicaid and Medicare reimbursements for flow cytometric services (10), complement the current endeavor. METHODS The survey was distributed in April and May, The distribution was by , telefax, and Postal Service. Approximately 600 surveys were distributed, primarily to members of the Clinical Cytometry Society. Survey distribution also was conducted at the CCS Hematolymphoid Consensus meeting held in Montpellier, France during May, 2000 (6), and available over the internet through the internet based Purdue cytometry bulletin board. All completed surveys were received by December, Data were entered into an Excel spreadsheet for subsequent analysis. RESULTS Respondents One hundred seventeen completed surveys were received. Eighty four (71.8%) of the responses were from flow cytometry laboratories located within the United States, representing 33 states. Two responses (1.7%) were received from Canadian laboratories, twenty three (19.7%) from European laboratories, and two (1.7%) from Asian laboratories. Additionally, three responses were received from the Middle East, two from Australia, and one from Brazil. The types of these laboratories are illustrated in Figure 1. Eighty five respondents (72%) reported that diagnostic activities were the primary function of the laboratory, with forty of these laboratories (34% of the total respondents) reporting a minor research endeavor. Fifteen laboratories (13%) reported performing diagnostic services and research in roughly equal proportions, and only eight (7%) described themselves as largely research laboratories with a minor effort committed to diagnostic services. Seven respondents (6%) reported research as the primary effort, and were asked not to answer the remaining questions in the survey. Credentials and Certification The majority of individuals directing laboratories which perform clinical flow cytometry testing are physicians. Eighty six respondents (74%) reported the director of the laboratory held an M.D. (or similar) degree. Seventy one (61%) laboratories indicated that the physician director was a pathologist, while fifteen (13%) reported a non-pathologist physician directed the laboratory. Individuals holding a Ph.D. degree and board certification or regional license were the laboratory directors for twenty one (18%) of the responding laboratories. Six laboratories (5%) indicated having a director with a Ph.D. without additional clinical qualification and one laboratory (1%) reported having a nondoctoral scientist as the director. The predominant mode of laboratory inspection and certification was through the College of American Pathologists (CAP), as seventy nine (68%) of the responding Members of the Clinical Task Force: Bruce H. Davis, M.D., Portland, ME, Carlton Stewart, Ph.D, Buffalo, NY, J. Philip McCoy, Ph.D., Camden, NJ, John Carey, M.D., Detroit, MI, Jeannine Holden, M.D., Atlanta, GA, Brent Wood, M.D., Ph.D., Seattle, WA, Wlodek Szczarkowski, M.D., Brentwood, TN, Raul Braylan, M.D., Gainesville, FL, Charles Goolsby, Ph.D., Chicago, IL, MaryAlice Stetler-Stevenson, M.D., Ph.D., Bethesda, MD, Curtis Hanson, M.D., Rochester, MN, Frances Lacombe, M.D., Pessac, France, Anna Porwit, M.D., Stockholm, Sweden, Michael Borowitz, M.D., Ph.D., Baltimore, MD, Joseph A. DiGiuseppe, M.D., Ph.D., Hartford, CT. *Correspondence to: Bruce Davis, Maine Medical Center Research Institute, 81 Research Drive, Scarborough, ME davisb@mmc.org Received 13 March 2001; Accepted 18 April Wiley-Liss, Inc.

2 178 MCCOY AND DAVIS FIG. 1. Distribution of types of flow cytometry laboratories responding to survey. laboratories identified CAP as the organization performing these tasks. The American Society for Histocompatibility and Immunohematology (ASHI) served as the inspecting and certifying agency for five (4%) of the responding laboratories. Eleven laboratories (9%) indicated inspection and certification by governmental agencies. Other agencies inspected and certified twenty other responding laboratories (17%), and fourteen laboratories (12%) reported that laboratory inspections were not required. Of the fourteen laboratories indicating that no inspection was required, thirteen were from outside of the United States. Laboratory Size and Volume of Specimens Tables 1 and 2 display the annual number of tests performed by responding laboratories. When queried regarding anticipated changes in workload, most laboratories projected an increase. Thirty one laboratories (28%) anticipated a modest 10% increase in workload, while thirty six (33%) foresaw a 10 25% increase. Sixteen respondents (15%) projected an increase of more than 25%. Only three (3%) laboratories foresaw a decrease in workload. Twenty three laboratories (22%) reported either no anticipated change or did not know if a change would occur. Table 1 Number and of Type of Tests Performed Annually Annual # tests for each assay Number and (%) of responding laboratories CLL ALL DNA (11%) 16 (16%) 3 (5%) (14%) 25 (25%) 16 (26%) (13%) 16 (16%) 12 (19%) (32%) 30 (29%) 23 (37%) (30%) 15 (15%) 8 (13%) Financial Information An attempt was made to collect information concerning the billing and payments received for each laboratory performing diagnostic flow cytometric testing. Over one third of the responding laboratories (36 out of 107) were unable to determine their total laboratory billing and nearly half (53 out of 107) were unable to provide information regarding the total payments received by the laboratory. The number of full time laboratory personnel required by laboratories for diagnostic flow cytometric testing and the dollar amount billed by corresponding laboratories is shown in Table 3. Table 4 illustrates the estimated total billing and payments received reported by each of the responding laboratories. Laboratories were asked to identify the largest payer of diagnostic services and the percentages of payments received from managed care, Medicare, and private insurance; this information was largely of relevance only for the U.S. based laboratories. These responses are shown in Figures 2 and 3. Figure 4 displays the average reimbursement (combined technical and professional) received for each immunophenotyping study (each CPT billed). Laboratories were also queried about expenditures, and roughly 55% (56 out of 102) of the respondents indicated that $100,000 or less was spent on reagents and supplies. Twenty eight percent (29/102) of the responding laboratories spent $200,000 to $300,000 per annum on reagents and supplies while 10% (10/ 102) spent between $300,000 and $500,000. Only 7% (7/102) laboratories indicated spending more than $500,000 on reagents and supplies, and six of these spent more than $750,000. Total laboratory expenses were $200,000 or less for 50 (49%) of the responding laboratories, $200, ,000 for 17 (17%), and between $300,000 and $500,000 for 20 (20%). Eleven (11%) laboratories reported total expenditures between Annual # tests Table 2 Annual Number of Tests Total clinical samples Number and (%) of responding laboratories Samples for lymph subset analysis 50 2 (2%) 11 (10%) (19%) 9 (9%) (17%) 11 (10%) (30%) 15 (14%) (17%) 24 (23%) (18%) 35 (33%)

3 CLINICAL CYTOMETRY PRACTICE SURVEY 179 Table 3 The Number of FTEs Versus the Amount Billed for Clinical Services for Responding Laboratories $ Amount billed Number of full time employees to6 7to K K K K K K K Unknown Total FTEs $500,000 and $750,000 while 4 (4%) indicated expenditures greater than $750,000. In response to a question asking if financial pressures have led to consideration of closure of the flow cytometry laboratory in the past one to two years, 18 out of 108 (17%) responding laboratories indicated that they had. Clinical Practice of Immunophenotyping Table 5 displays the number of laboratories performing various tests by flow cytometry. None of the 107 responding laboratories indicated performing one color analysis of immunophenotyping. Twenty seven respondents (25%) reported performing two color analysis while 54 laboratories (50%) performed three color analysis. Twenty six laboratories (25%) conducted four color analysis and no respondents indicated using five or more colors for routine analysis of clinical specimens. Less than one half (45 out of 105) of the laboratories responding reported performing any type of quantitative assessment of antigen expression in clinical testing, and most of these applications were limited. Only nineteen of these laboratories indicated using standardized units such as ABC (antigen binding capacity) or MESF (mean equivalents of soluble fluorescein) to express antigen quantitation. For preparation of blood and bone marrow for immunophenotyping, the majority of responding laboratories (68 laboratories out of 109 responses [62%]) used red blood cell lysis followed with a wash. Twenty six laboratories (24%) reported using red blood cell lysis without a subsequent wash, and fifteen (14%) performed density gradient separation such as ficoll hypaque. Use of density gradient separation in immunophenotyping was reported primarily by non-u.s. laboratories. Response to a question concerning gating for the analysis of immunophenotyping revealed that twenty seven out of 108 responding laboratories (25%) used light scatter parameters alone, while forty three laboratories (40%) used a combination of CD45 and light scatter. The use of CD45, scatter, and lineage markers for gating was reported by 20 laboratories (19%). Gating using CD45 in combination with scatter and/or viability staining was reported by 5 respondents (5%) and gating using CD45, scatter, lineage, and/or viability was indicated by 13 (12%) of the responding laboratories. For preparation of immunophenotyping reports, thirty three of the 109 responding laboratories (30%) indicated that list mode file were reviewed by technologists while fifty seven (52%) reported that the files were reviewed by both a technologist and the person issuing the report. The list mode files were reviewed only by the person issuing the report in thirteen laboratories (12%) and no review was performed in 6 (6%) of the responding laboratories. Figure 5 illustrates the extent to which laboratories reported correlating flow cytometric findings with other laboratory findings or patient information prior to issue an interpretive report. Sixty laboratories indicated that the immunophenotyping reports existed as stand alone documents while 42 respondents integrated the immunophenotyping into a lymph node or bone marrow pathology report. A summary of morphological findings was included in the reports by 43 responding laboratories and an interpretative diagnosis was included by eighty one. Thirty six laboratories report immunophenotypic findings as percentages while seventy one provide a description of the abnormal population. Use of Monoclonal Antibodies A major component of the Survey was to ascertain the value laboratories placed on a number of monoclonal antibodies in the study of various diseases. Respondents were asked to indicate whether specific monoclonal antibodies were A) routinely used, B) occasionally used, C) rarely used, D) not used, or E) not familiar with antigen or not evaluated in the study of ten categories of Table 4 The Amount Billed Versus the Payments Received for Responding Laboratories. Note One Lab Reported Collecting More ($300, ,000) Than the Amount Billed ($200, ,000) $ Amount billed $ Received 100k k k k k k 1000k 100k k k k k k k

4 180 MCCOY AND DAVIS FIG. 2. Distribution of single largest payer of diagnostic services among the survey respondents. diseases. To distill the data received into a simple, readable format, the following analysis approach was used: Answers were assigned the following weight: A 2; B 1; C 1; D 2; E 0. The number of responses received for each answer was multiplied by the weighting factor, then the sum of all weighted responses was obtained. A positive sum was assigned a, indicating that the monoclonal antibody was considered useful in the evaluation of the specific disease. The results of this analysis are shown in Table 6. DNA Analysis Laboratories were asked to indicate which conditions were examined for DNA content and whether flow cytometry or image analysis was used in these studies. The responses are shown in Figure 6. Among the sixty two laboratories that indicated DNA analyses were performed, eight (13%) reported analyzing more than 500 specimens per year. Twenty three laboratories (37%) analyzed between 100 and 500 specimens per year. Nineteen laboratories, nearly one third of those performing DNA analyses, evaluated 50 specimens or less per year. DISCUSSION The current survey revealed the current practices in clinical cytometry on an international scale. The one major difference between the laboratories within the United States and those outside was the need for periodic laboratory inspection by accrediting organizations. In the United States, inspections are mandated for clinical laboratories by the Clinical Laboratory Improvement Act of 1988 (CLIA 88) and subsequent amendments and revisions to this law, while such regulations are variable in other countries. It is curious that one clinical laboratory within the United States claimed no inspections were necessary, as this apparently is in violation of CLIA 88. Responses to other questions indicated very little difference in clinical practices between laboratories located inside the United States versus those outside, except for the greater frequency of use of density gradient separation outside the United States and contrary to previous consensus recommendations (3). FIG. 3. Distribution of percentages of payments received from managed care, Medicare, and private insurance as reported by the responding laboratories in the United States. FIG. 4. Reported average global reimbursement (combined technical and professional) received for each monoclonal antibody marker (each CPT unit) in an immunophenotyping study.

5 CLINICAL CYTOMETRY PRACTICE SURVEY 181 Table 5 Type of Testing Performed by Laboratories Number of Test laboratories Leukemia/Lymphoma immunophenotyping 89 Fetal red cell detection for fetomaternal hemorrhage 8 Fetal red cell counts 3 HLA-B27 screening 25 P1A1 Platelet antigen status 5 Platelet associated antibody assay 16 Platelet activation assays 5 Reticulated platelet assay 7 OKT-3 monitoring 37 CD34 counting 49 Reticulocyte analysis, including IRF or RMI 5 Reticulocyte analysis, NOT including IRF or RMI 4 Flow cross-match for transplantation purposes 10 Flow cross-match for infertility purposes 2 Others (specify): 47 Previous surveys (9,10) noted increasing workloads for clinical flow cytometry laboratories. The current data suggest that this trend will continue, as most respondents projected increasing workloads in the foreseeable future. While laboratories predicted increased workloads, surprisingly few were able to provide information regarding revenue. The irony of this lack of information is that most laboratories are expected to operate in a cost-effective manner, but apparently with a lack of information concerning laboratory revenue. It is unclear how decisions such as the number of monoclonal antibodies to use to analyze leukemias and lymphomas are made with incomplete information concerning reimbursement for these tests. The present survey attempted to ascertain which monoclonal antibodies were deemed important by the respondents in the evaluation of a number of diseases. The number of antibodies generally agreed to be important ranged from 20 in lymphoma to 21 in acute lymphocytic leukemia and 24 in acute myeloid leukemia. These numbers are slightly higher than found in a previous survey (10). However these results are similar to more recent consensus recommendations (6). Of particular interest in the current study are several antibodies which not widely accepted as useful for particular diseases, despite published data to this end. Examples of this included the use of CD64 as an indicator of monocytic differentiation in AML and cytoplasmic CD79a in B cell ALL (11). Quantitative immunophenotyping by flow cytometry remains a slowly evolving area of clinical cytometry. Only 43% of the responding laboratories indicated performing quantitative analyses, compared to 71% in a survey published in The frequency of laboratories reporting quantitation using MESF units increased from less than 4% in the previous survey to 10% in the current study. A recent US Canadian Consensus Conference on the immunophenotyping of leukemias and lymphomas (5) stressed the importance of quantitation in certain diseases, yet acceptance and implementation of this practice in a standard fashion has been extremely slow. The use of reporting percent positive in leukemia and lymphoma phenotyping, a vestige from the cytometry practice of lymphocyte subset counting, is still practiced by the significant minority (35%) of laboratories, again despite consensus recommendation to the contrary (4). As might be expected, the use of four color immunophenotyping and of CD45 in gating leukemias has increased since a previous survey. The reporting of the immunophenotyping of leukemias and lymphomas is generally, but not universally, in concert with the recommendations of the US Canadian Consensus Conference (6). Findings at odds with the recommendations of the consensus conference include that no review of list mode files is conducted in 6% of the responding laboratories and 36% laboratories report percentage of positive cells without including a description of the abnormal population. Compared with previous data, however, there appears to be a growing compliance with the consensus recommendations. Yet these differences in reported practice patterns and consensus expert recommendations raise the question of whether the laboratory accreditation process is effective in optimizing laboratory practice, at least in areas of specialized testing, such as clinical cytometry. Finally, the study of DNA/cell cycle analysis by flow cytometry continues to languish. The analysis of breast tissue remains the primary use of DNA analysis, as observed previously. The number of specimens analyzed for DNA content, as well as the number of laboratories performing this test, remains substantially less than reported for immunophenotyping. Presumably, this is the direct result of reports questioning the clinical utility of such testing (12). In summary, this survey revealed interesting aspects in the continuing evolution of the practice of clinical cytometry. In general there is more standardization in methods and interpretation than ever before. However, some controversy remains in the selection of monoclonal antibodies for routine diagnostic use and in how to FIG. 5. Number of respondents correlating flow cytometric findings with other laboratory findings or patient information prior to issue an interpretive report.

6 182 MCCOY AND DAVIS Table 6 Utility of Monoclonal Antibodies in Various Hematolymphoid and Immunodeficiency Diseases Antigen CLPD Lymphoma ALL AML MDS Myeloma ID PMN LD PNH CD1 CD2 CD3 CD4 CD5 CD7 CD8 CD9 CD10 CD11a CD11b CD11c CD13 CD14 CD15 CD16 CD18 CD19 CD20 CD22 CD23 CD24 CD25 CD30 CD32 CD33 CD34 CD35 CD36 CD38 CD40 CD41 CD42 CD45 CD55 CD56 CD57 CD59 CD61 CD64 CD65 CD69 CD71 CD79a CD79b CD95 CD103 CD117 CD138 MPO IgM IgG IgA light chains FMC7 HLADr BCL-2 TdT approach quantitation. Possibly the most interesting data from the current study are those indicating a widespread lack of knowledge by flow cytometry laboratories regarding laboratory revenue. This information would seem highly desirable in order for a laboratory to design cost-effective panels for immunophenotyping leukemias and lymphomas, and to assess the economic impact of analyzing replicate markers (such as the use of CD45 in every tube for gating). Continuing efforts should be made toward gathering consensus on the

7 CLINICAL CYTOMETRY PRACTICE SURVEY LITERATURE CITED 183 FIG. 6. Reported use of technique for clinical DNA content and cell proliferation measurements, flow cytometry (FCM) or image analysis (Image), in human malignancies of breast carcinoma (Br), colon carcinoma (Co), acute lymphocytic leukemia (ALL), lymphoma (LYM), multiple myeloma (MM), immune deficiency lymphocyte mitogen stimulation assays (ID), bladder carcinoma (BC), prostate carcinoma (PC), soft tissue tumors (STT), neuroblastoma (Ne), renal carcinoma (RC), brain tumors (BT), lung tumors (Lu), ENT tumors (ENT), other conditions (Other). utility of monoclonal antibodies and in elucidating the economics of clinical flow cytometry. ACKNOWLEDGMENTS The Clinical Practice Task Force of the Clinical Cytometry Society would like to thank Abbott Diagnostics, Beckman Coulter, Becton Dickinson, Caltag Laboratories, Esoterix (formerly Cytometry Associates), Impath, Mayo Medical Laboratory, Trillium Diagnostics and Verity Software House for providing support for this project. We would also like to thank the many respondents who dedicated the time necessary to complete the survey. 1. Braylan RC, Borowitz MJ, Davis BH, Stelzer GT, Stewart CC. U.S. Canadian consensus recommendations on the immunophenotypic analysis of hematologic neoplasia by flow cytometry. Cytometry 1997;30: Davis BH, Foucar K, Szczarkowski W, Ball E, Witzig T, Foon KA, Wells D, Kotylo P, Johnson R, Hanson C, Bessman D. US Canadian consensus recommendations on the immunophenotypic analysis of hematologic neoplasia by flow cytometry: Medical indications. Cytometry 1997;30: Stelzer GT, Marti G, Hurley A, McCoy JP, Lovett EJ, Schwartz A. Consensus Conference on the Flow Cytometric Analysis of Leukemia and Lymphoma: Report of the Committee on the Standardization and Validation of Laboratory Procedures. Cytometry 1997; 30(5): Braylan RC, Atwater SK, Diamond L, Hassett JM, Johnson M, Kidd PG, Leith C, Nguyen D. U.S. Canadian consensus recommendations on the immunophenotypic analysis of hematologic neoplasia by flow cytometry: Data reporting. Cytometry 1997;30(5): Stewart CC, Behm FG, Carey JL, Cornbleet J, Duque RE, Hudnall S, Hartubise PE, Loken M, Tubbs RR, Wormsley S. U.S.-Canadian consensus recommendations on the immunophenotypic analysis of hematologic neoplasia by flow cytometry. Selection of antibody combinations. Cytometry 1977;30(5): Braylan RC, Orfao A, Borowitz MJ, Davis BH. Optimal number of reagents required to evaluate hematolymphoid neoplasias. Results of an international consensus meeting. Cytometry 2001; in press. 7. Hassett J, Parker J. Laboratory practices in reporting flow cytometry phenotyping results for leukemia/lymphoma specimens: results of a survey. Cytometry 1995;22(4): McCoy JP, Overton WR. A survey of current practices in clinical flow cytometry. Am J Clin Pathol 1996;106(1): McCoy JP, Keren DF. Current practices in clinical flow cytometry: a practice survey by the American Society of Clinical Pathologists. Am J Clin Pathol 1999;111: McCoy JP. Medicaid and medicare reimbursement for flow cytometry. Am J Clin Pathol 2001; in press. 11. Bene MC, Castoldi G, Knapp W, Ludwig WD, Matute E, Orfao A, van t Veer MB. Proposals for the immunological classification of acute leukemias. Leukemia 1995;9: Clinical practice guidelines for the use of tumor markers in breast and colorectal cancer. J Clin Oncol 1996;14: