From: Richard McFarland (mcfarland.richard@pathology.swmed.edu)
Date: Mon Nov 09 1998 - 17:15:02 EST
> > The deadline for receipt of comments on the proposed regulations >is 11/11/98. This means that letters must be sent by overnight mail by >noon 11/10!!! Below is a copy of a letter that is being sent from a >pathologist at our institution. This may provide you with helpful >information and concrete arguments to use. If you absolutely can't mail >your letter by noon tomorrow, the FAX number is 202-690-5863. However, >this fax line may be jammed on 11/10, making it impossible for your >comments to be heard - so rely on it only as a last resort! > >SAMPLE LETTER >Judy Ballard and Nancy Rubenstein >Facilitators, Negotiated Rulemaking Committee >DHHS Departmental Appeals Board >Hubert H. Humphrey Building, Room 637D >200 Independence Avenue, S.W. >Washington, D.C. 20201 > >Dear Ms. Ballard and Ms. Rubenstein: > > As a pathologist practicing flow cytometry, I am writing to >express my concerns regarding the "Recommended Medicare National Coverage >Policy for Flow Cytometry". > For clarity, I have reprinted the document text below, and >inserted my comments in the areas to which they pertain (references on >last page). > >DESCRIPTION >Flow cytometry is a technique to analyze single cell suspensions from a >variety of sources including blood, bone marrow, body fluids, lymph nodes, >and other tissues. A variety of cell surface and intracellular antigens >are detected with the use of fluorescent probes and fluorescently-labeled >antibodies. Flow cytometers contain lasers, fluidics, and optical >detection systems to rapidly and sensitively detect fluorescent signals >from a large number of cells. Detection of specific protein antigens and >quantitation of cellular DNA can be useful in the diagnosis, monitoring of >response to therapy, analysis of relapse, detection of minimal residual >disease, and as indicators to predict prognosis in a wide variety of >disease states. >HCPCS CODES (Alpha numeric CPT © AMA): >Code: Descriptor: >88180 Flow cytometry; each cell surface marker >88182 Cell cycle or DNA analysis > >Comments: > CPT code number 86361, which is not on the above list, should be >used for CD4 absolute numbers. Both the percentage and absolute numbers >of CD4+ CD3+ cells should be reported (1). > >INDICATIONS: >1. HIV Infection. Determination of the numbers of lymphocytes in the >peripheral blood is useful for the diagnosis and monitoring of patients >with HIV infections. Testing of other body fluids and tissues may also be >useful in selected clinical conditions. The most clinically relevant >marker to be measured is the number of CD4+ lymphocytes, [But there have >been questions raised that the standard of practice should include CD3, >CD8, CD16 and/or CD56, and CD18 with CD 45 and CD 14 used as part of the >analysis gating strategy. Please address comments to this.]. The >lymphocyte analysis is initially done as part of the diagnostic workup and >monitoring in stable individuals at no greater than 3-month frequency >intervals. Prior to initiation of anti-viral therapy the test may be >performed on two different occasions to ensure accuracy of the results and >establishing good baselines. Once therapy has begun, follow-up tests may >be done at 1 month, and then done every 3-4 months thereafter. Testing may >also be appropriate when a significant change has taken place in the >patient's clinical condition. > >Comments: > I agree that the most clinically relevant number to report is the >CD4+ lymphocytes, but the population must be confirmed to be CD3+ and >CD8-. The use of CD45 as an additional marker is critical in the strategy >of gating the appropriate population (1). Our lab runs a single tube four >color analysis to include 3/4/8/45. Reimbursement should compensate for >at least 4 antibodies. > >2. Leukemia or Lymphoma. For hematopoietic neoplasms (leukemias and >lymphomas) immunophenotyping is an important adjunct in primary diagnosis, >staging, assessing prognosis, and, in turn, formulating an optimal >treatment plan. Furthermore, it occasionally serves as a tool in >monitoring response to therapy. >Primary Diagnosis and Staging: The characterization of cell surface >markers is appropriate in suspected hematopoietic neoplasm, especially >where first-line diagnostic methods fail to establish a diagnosis. In many >cases, a panel of up to 12 antibodies (professional and technical >components) will be adequate for the diagnosis of acute leukemia. In cases >of lymphoma, a panel of 12 antibodies (for the professional and technical >components) and up to an additional 6 antibodies for the technical >component will be considered adequate for the diagnosis. Documentation >regarding medical necessity is to be provided for the use of additional >antibodies. However, simple diagnosis such as uncomplicated CLL may >require only 6 markers for diagnosis. > >Comments: > I strongly disagree with a limit of 12 or 18 antibodies for the >diagnosis of leukemias and lymphomas. Any individual malignant population >can probably be sufficiently defined by describing its level of expression >of 12 separate antigens, as in the tables in the article cited in the >recommended policy (2). However, examination of the tables in this >article shows that the antigens described are different for each disorder >listed. These neoplasms were certainly not detected using panels >containing only the markers shown for each process! In that case the >nature of the neoplastic process would already have to have been known in >order to have selected the appropriate 12 antibodies. In practice, this >is obviously not the case. The indication for biopsy/marrow aspiration, >etc., is often something like lymphadenopathy or cytopenia, and a large >number of disorders are within the differential diagnosis. > The US-Canadian Consensus Conference has published recommendations >regarding the immunophenotypic analysis of hematologic neoplasia by flow >cytometry (3,4). This consensus conference included clinical >hematopathologists, hematologists and laboratory scientists representing >academic institutions, federal agencies, large hospitals and commercial >diagnostic laboratories. Corporate representatives, members of regulatory >agencies and observers from European Countries were also present. As a >result of the conference, 5 consensus documents were produced. I think it >is appropriate to give more weight to the findings and opinions of this >Consensus Conference than to a review article written by only two authors. > The consensus document that deals with selection of antibody >combinations (4) provides lists of "core" and "supplemental" antibodies >useful in immunophenotyping. Although the lists of "core" antibodies can >be seen to contain only 12 antibodies, it is stated in the text that "a >screening panel serves only as an initial evaluation step that precedes >the use of a more extensive set of antibodies necessary to complete the >analysis". The consensus paper also states that "in general, the larger >the number of reagents, the higher the sensitivity of abnormal cell >detection and the better the ability of delineating phenotypes that may be >useful in disease monitoring" and "neoplastic cells often exhibit >abnormalities in antigen expression, a feature that may be overlooked if >an inadequate number of antibodies is used. A restricted panel may also >limit the ability of recognizing minimal neoplastic involvement." In >addition, the conclusions state that "The panels should be designed to >resolve normal as well as malignant cells because normal cells act as >internal reference standards. > In the consensus document, the Conference Committee quoted studies >showing that the average number of reagents routinely used by North >American laboratories engaged in the analysis of hematopoietic neoplasia >is 19 and 16 for acute leukemia and lymphoma analysis, respectively (5). >In Europe the number of antibodies recommended is even higher (6). The >conclusion of the Consensus Conference is that "An adequate >characterization of the cellular components in a sample requires at least >these many reagents or even larger panels, which unfortunately affect test >cost. However, such a characterization is often of significant clinical >value." > Also, this method of reimbursement does not take into account the >fact that antibodies cannot be used individually or in arbitrary >combinations, and to set up an effective panel requires specific >combinations. One reason for this is because the "highest intensity >fluorochromes for the lowest epitope densities should be used" (4). Also, >"a certain degree of redundancy in antibody specificity is always >desirable" (4) because "neoplastic cells often lack antigens expected to >be present on normal cells or are expressed in an aberrant manner" (4) >The same antibody often needs to be used more than once, in order to >combine it with different markers, and the laboratory absorbs the cost of >this duplication, as well as absorbing the cost of the isotypic control >antibodies used for each specimen. > As a reimbursement policy, I think it would be appropriate that >any antibodies beyond a certain number (maybe 12 or 16) be reimbursed at a >lower rate, but I think that, based on the above arguments, it is poor >diagnostic practice to systematically limit every case to a very >restricted panel of antibodies. > >They can also assist in staging of a patient (with the exception of >Hodgkin's Disease) to confirm a primary diagnosis of a secondary site. >Immunophenotyping is not usually part of evaluation of patients with >granulocytosis, nor is it medically necessary for the diagnosis of chronic >myelogenous leukemia (CML) which is not undergoing blastic transformation >(i.e., blast counts of greater than 5% in the bone marrow differential and >in the peripheral blood). >Prognostic Markers: After a diagnosis has been established, a panel of >cell surface markers can provide clinicians with useful prognostic >information for an individual patient. For example, patients with CD20 >positive lymphoma are candidates for anti CD20 antibody (Ritixumab) >treatment. Also CD10 (CALLA) and CD34 negative leukemia are known to have >a poor prognosis. > > The antibodies listed here are important in the diagnosis of the >disorders mentioned and should therefore be run in the original panel. It >is important for the original panel to be as complete as possible because >"This procedure saves time, and additional staining is only rarely >required." (4) Neoplastic cells are fragile and degenerate over time. >Thus, it is best to do all the necessary stains on the fresh specimen >instead of performing a very limited panel and then doing extra markers, >which delays diagnosis and can put the specimen in jeopardy of degradation > > >Monitoring Response to Therapy: Presently this is an infrequent >application of flow cytometry and is at carrier discretion. > >3. Organ Transplants. Postoperative monitoring of covered organ >transplants may be done by analysis of lymphocytes in the peripheral blood >or tissue of patients. Analysis of cells may be useful to indicate early >rejection, bone marrow toxicity during immunosuppressive therapies, and to >help in the differentiation of infections from transplant rejection. A >variety of cell surface markers and activation antigens can be used >depending on the clinical condition and the organ transplanted. Periodic >monitoring may be done at intervals determined by organ-specific >protocols. Testing may also be done when the clinical condition is >indicative of possible acute or increased severity of chronic rejection >episodes. Peripheral blood testing may also be done to monitor >effectiveness of anti-rejection immunosuppressive therapy which may >include OKT3, anti-thymocyte globulin, or other toxic agents. The number >of circulating T-cells is usually determined by measuring the cell surface >marker CD3. [Comments are invited to explain the medical necessity of >other markers, e.g., NK cell surface markers, CD4, 8, 19, 16, 56]. A >single test sample is usually sufficient; however, additional testing may >be necessary for further evaluation when patients show partial or no >response to the therapy. > >4. Carcinomas. DNA analysis of tumor for ploidy and percent-S-phase cells >may be helpful for patients with early stage carcinomas (ovarian, breast, >colon, endometrium, prostate, and carcinoma of unknown primary site). >Prognostic information obtained from DNA analysis may be useful in >directing treatment decisions in patients with localized disease (stages I >and II). Additionally, DNA ploidy and DNA index may have prognostic value >in predicting long-term, disease-free survival in advanced ovarian >carcinoma. DNA analysis is usually performed one time after an initial >diagnosis has been made. > >5. Primary & Secondary Immunodeficiencies. A variety of primary >immunodeficiency diseases have been identified in which surface or >cytoplasmic proteins are missing or have impaired function. Primary >immunodeficiencies usually occur in infants and young children and can be >a result of defects in T-cells, B-cells, granulocytes, or monocytes. The >selections of antibodies used should be based on the clinical >presentation, for the flow cytometry method can be used to detect >abnormalities of a variety of surface markers. The selection of antibodies >used should be based on the clinical presentation of each affected >individual and the abnormalities most likely to be present. Some flow >cytometry testing can be done to detect possible dysfunction present in >white blood cells. These defects usually cause primary immunodeficiency >and are detected in newborns and young children, but may occasionally >occur in teenagers or young adults. The flow cytometry testing may include >the analysis of PMN and monocyte generation of oxidative burst and >phagocytosis, analysis of T and B cell mitogen responses, analysis of NK >cell tumor cell lytic function, analysis of platelet activation antigens, >and the analysis of intracellular calcium and pH cell changes in cells. >The selection of testing should be based on the clinical presentation of >each affected individual and the abnormalities most likely to be present. >A variety of secondary immunodeficiencies have been identified in which >the patient presents with recurrent infectious diseases. The >immunodeficiency is related to the occurrence of another illness or >condition. Several of the more common diseases which can cause >immunodeficiencies are severe malnutrition, biotin, B12 or zinc >deficiency, lymphoma, myasthenia gravis, myeloma, radiation or >chemotherapy, chronic alcoholism, drug abuse, cancers, splenectomy, >chronic viral illnesses, and chronic disease. If a secondary >immunodeficiency is suspected, an analysis of quantity and types of >lymphocytes present in the blood can be performed to assess immune status. >This could include detection of B-cell, NK cell, and T-cell antigens >including CD4 and CD8. Flow cytometry testing for primary and secondary >immunodeficiencies is usually done as an aid to the initial diagnosis of >the patient but may also, in some conditions, be used to monitor the >disease or response to the therapy or following bone marrow >transplantation to assess reconstitution. > >Comments: > I agree with the recommendations on the use of flow cytometry for >immunodeficiency testing and I support consultation between the >pathologist and the clinician to best choose which markers and or tests >are required based on the clinical findings. > >6. Stem Cell Transplantation. Hematopoietic stem cells which are positive >for the CD34 surface protein are capable of reconstituting bone marrow >with all the important cellular elements. Measurement of the percent and >number of CD34+ cells in the peripheral blood prior to stem cell >collection can be done to determine the appropriate time for the pheresis. >The CD34+ measurement can also be done to determine the actual yield of >CD34+ cells in the pheresis product to ensure the presence of adequate >numbers of stem cells in the product. The analysis should include the CD34 >antibody but may also include several additional antibodies used to insure >the correctness of the analysis and minimize overestimation of the numbers >of stem cells present. > >Comments: > I agree with the recommendations regarding stem cells especially >regarding the inclusion of several other additional antibodies to insure >the correctness of the analysis and minimize overestimation, given the >critical importance of harvesting sufficient stem cells for these >patients. > >7.Paroxysmal Nocturnal Hemoglobulinuria. Paroxysmal nocturnal >hemoglobulinuria (PNH) is an acquired disease characterized by the >development of an abnormal clone of precursor cells in the bone marrow. >The cells produce abnormal white cells and red cells, which have abnormal >function and are susceptible to lysis. Analysis of this abnormality by >flow cytometry, in general, can be accomplished by analysis of two >antigens on the red or white cells. Further documentation may be supplied >to support medical necessity of up to four antigens. In general, this >testing would be done for diagnostic purpose only. > >Comments: > The experience in our lab has been that flow cytometry is a very >sensitive tool for the diagnosis of varying degrees of severity of PNH. >Because of the different patterns of GPI-linked antigens on various normal >cell populations (for example, only granulocytes and B-lymphocytes would >be expected to express CD24 - negativity is normal in other cell >populations), we include markers which will separate the various >populations. Our panel includes CD14, 59, 45, 33, 16, 55, 3, 24, 19. >Although a more limited panel may possibly be effective, there is not yet, >to my knowledge, sufficient data to support that conclusion. That may >change in the future, because this is a relatively new diagnostic modality >with which we have had limited experience. > >8. Other. Flow cytometry can also be used to directly demonstrate >anti-platelet, anti-granulocyte, lymphocyte, and red cell autoantibodies. >These antibodies can be found in a variety of autoimmune conditions and >cause anemia, leukopenia, or thrombocytopenia. Detection can be either >direct (patient cells) or indirect (patient serum) and use anti-human IgG >antibodies. The analysis may also include several additional antibodies >used to insure the correctness of the analysis for the cells of interest. > >Conclusion: > For these reasons, I think the proposed reimbursement policy would >lead to an unacceptably poor quality of flow cytometric diagnosis. >Accurate diagnosis is important in avoiding over-treatment, which can lead >to unnecessary morbidity and mortality and increased expense, or >under-treatment, which can lead to disease recurrence. > >Sincerely, > > > >Deborah B. Aquino >Assistant Professor of Pathology > >References: > >1. Centers for Disease Control and Prevention. 1997 Revised guidelines >for performing CD4+ T-cell determinations in persons infected with human >immunodeficiency virus (HIV). MMWR 1997;46:1-30. > >2. Jennings CD, Foon KA. Recent advances in flow cytometry: Application >to the diagnosis of hematologic malignancy. Blood 1997;90:2863-91. > >3. Braylan RC, et al. U.S.-Canadian consensus recommendations on the >immunophenotypic analysis of hematologic neoplasia by flow cytometry. >Cytometry 1997;30:213. > >4. Stewart CC, et al. U.S.-Canadian consensus recommendations on the >immunophenotypic analysis of hematologic neoplasia by flow cytometry: >Selection of antibody combinations. Cytometry 1997;30:231-5. > >5. Hassett J, Parker J. Laboratory practices in reporting flow cytometry >phenotyping results for leukemia/lymphoma specimens: Results of a survey. >Cytometry 1995;22:264-81. > >6. Rothe G, Schmitz G. Consensus protocol for the flow cytometric >immunophenotyping of hematopoietic malignancies: Working Group on Flow >Cytometry and Image Analysis. Leukemia 1996;10:877-95. > >
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