CHEMMATE LAMBDA

{0}------------------------------------------------ KP73542 #### 510(k) Summary OCT - 3 1997 Date: September 29, 1997 VENTANA MEDICAL SYSTEMS, INC. 3865 North Business Center Drive Tucson, Arizona 85705 Telephone: (520) 887-2155 (520) 887-2558 Facsimile: Stephen A. Tillson, Ph.D. Contact: Vice President Scientific Affairs/ Quality Assurance 2028492 Registration #: ChemMate™ Lambda Trade Name: Class II FOR IN VITRO DIAGNOSTIC USE. Intended Use: ChemMate™ Lambda (rabbit polyclonal anti-Human Lambda light chains) is intended for laboratory use to qualitatively identify by light microscopy human lambda light chains in immunodlobulin secreting plasma cells and plasmacytoid B lymphocytes in normal and pathological paraffin embedded tissues processed in zinc formalin, neutral buffered formalin, Bouin's or B5 fixative. 11.19.20 Positive results aid in differential diagnosis, classification and immunophenotyping of lymphomas and must be interpreted by a pathologist within the context of clinical data, gross and microscopic morphological criteria and multiple chemical and immunohistochemical stains. This antiserum has been optimally prediluted for use with the ChemMate™ SDK605 or SDK305 Secondary Detection - Peroxidase/DAB kit. Additionally, the prediluted ChemMate™ Lambda antibody, as well as the ChemMate™ SDK605 and SDK305 Secondary Detection - Peroxidase/DAB kit, have been optimized for use with the TechMate™ for automated immunohistochemical staining. {1}------------------------------------------------ # 510K SUMMARY OF SAFETY AND EFFECTIVENESS #### SUMMARY AND EXPLANATION ChemMate™ Lambda is comprised of a rabbit polyclonal antibody to human lambda light chains. The antibody reacts with free lambda light chains as well as lambda chains in intact immunoglobulin molecules. In a large study involving paraffin-embedded tissues as well as frozen tissues and acetone fixed cryostat sections. Picker et al. demonstrated that 24 of 31 non-malignant, lymphoid hyperplasia cases, diagnosed by histologic criteria, co-expressed both lambda and kappa light chains. Six of these cases were uninterpretable, and one was light chain restricted. Further investigation of the light chain restricted case by Southern Blot analysis showed no clonal rearrangement of Iq genes, leading the authors to conclude that the results of this case were false positive. Positive cells included cells of primary follicles, mantle zones and dendritic reticulum cells. Most cells of germinal centers appeared negative. Additionally, 198 of 297 B-cell neoplasms were shown to be light chain restricted with 71 cases expressing lambda and 127 cases expressing kappa. Of the remaining 99 cases, 74 were light chain negative and 25 were uninterpretable.1 Hitzman et al. confirmed the usefulness of immunoperoxidase staining of formalin-fixed paraffin-embedded bone marrow sections with antibodies aqainst lambda (and kappa) light chains. Additionally, the value of utilizing these antibodies in the characterization of lymphoproliferative disorders was demonstrated. Results supported the premise that reactive plasmacytosis or lymphoid hyperplasia is generally characterized by polyclonal proliferations of cells positive for both lambda and kappa immunoglobulins and that B-cell neoplasms typically express either lambda or kappa intracellular immunoglobulins. In 10 reactive cases (5 plasmacytosis and 5 lymphocytosis cases), all were positively labeled by both lambda and kappa antibodies. In 76 bone marrow mveloma cases. 68 were monotypic (26 expressing lambda and 42 expressing kappa), one case was negative for both and 7 cases were biclonal. Of 8 lymphoma cases tested, 5 were monotypic (2 expressing lambda and 3 expressing kappa) and 3 were negative, including both of the poorly differentiated lymphocytic lymphomas. Six metastatic tumors with various origins were all negative for both lambda and kappa.2 And, in a study involving plasmacytomas, Petruch, et al. reported that of the 46 plasmacytomas containing neoplastic plasma cells, 22 expressed lambda light chains while the other 24 expressed kappa light chains.3 Harris et al.4 further substantiated the immunoreactivity of lambda and kappa in a study involving frozen sections of malignant lymphomas. They reported {2}------------------------------------------------ that 15 out of 15 cases of nodular lymphoma were single light chain positive for either lambda (7 cases) or kappa (8 cases). Results of reactive lymph nodes did not reveal a monotypic phenotype, but instead revealed a dual expression of lambda and kappa labeling. This difference in staining allowed the differentiation of neoplastic and reactive tissues. In 31 cases of diffuse Ivmphoma. 24 exhibited monotypic staining for lambda(10 cases) or kappa(14 cases). 5 cases were negative for both and 2 cases were uninterpretable. In 18 cases of diffuse large cell lymphomas, lambda or kappa labeled all 16 Bcell cases (7 expressing lambda and 9 expressing kappa). Two T-cell cases were negative for both kappa and lambda.4 Findings reported by Mori et al. further expanded the immunoreactivity profile thus far presented for lambda (and kappa). In their study involving four cases of paraffin-embedded mantle zone lymphomas, immunohistochemistry was used to substantiate immunoglobulin phenotypes. Results revealed that all cases were monoclonal. 1 expressed lambda and 3 expressed kappa. These results were identical to those obtained from clinical serum findings. The immunoqlobulin phenotype of the plasma cells surrounding the neoplastic nodules of the mantle zone lymphomas were also analyzed. In 2 cases, the plasma cells surrounding the nodules possessed the same monoclonal immunoglobulins as the neoplastic cells in the nodules. In the other 2 cases, some of the plasma cells surrounding the nodules were polyclonal, but most possessed the same monoclonal immunoglobulin as the cells of the nodules. § In a study conducted by Meis et al.6 in which lambda was also used as part of a panel of antibodies, formalin-fixed, paraffin-embedded Hodgkin's and non-Hodgkin's lymphomas were evaluated. In 15 cases of Hodgkin's disease, the cvtoplasm of Reed-Sternberg cells reacted positively in eight cases. Five of the eight cases were polyclonal, expressing both lambda and kappa light chains. In 10 cases of T-cell Ivmphoma, only one case was positive. exhibiting polyclonal expression of both lambda and kappa. It was suggested that the polyclonal large lymphocytes that were positive in this case might be attributed to the presence of neoplastic transformed B-lymphocytes, as opposed to the true conserved T-cell lineage cells. Seven of 10 B-cell lymphomas reacted positively for lambda and/or kappa. Of these, 1 case was polyclonal, 2 were lambda monotypic and 4 were kappa monotypic. All six monoclonal cases were large cell B-cell lymphomas. Cytoplasmic and membranous staining of varying intensities was seen in these cases. The one polyclonal case, a B-cell immunoblastic sarcoma (large cell B-cell lymphoma), showed light cytoplasmic staining of only rare tumor cells. In two histiocytic lymphoma cases the cytoplasm of rare tumor cells was diffusely stained for both lambda and kappa. The author cautioned that the immunostaining of lambda (and kappa) light chains is not always specific. All of the data must be considered when developing a differential diagnosis.8 {3}------------------------------------------------ #### Hodakin's Disease In a study by Rabia and Kahn' involving immunoperoxidase labeling of lambda (and kappa) among a panel of other antibodies, 15 formalin and B-5 fixed and 5 formalin fixed cases of Hodgkin's disease were evaluated. Results with lambda and kappa revealed polytypic labeling of Reed-Sternberg cells and their monoclonal variants in 19 of the 20 cases. Such findings have lead some investigators to suggest that they are transformed lymphocytes of B-cell lineage. The remaining case demonstrated monoclonal labeling. Reactive plasma cells in all cases labeled polytypically for lambda and kappa and showed more intense cytoplasmic labeling than neoplastic cells. Most Bcell neoplasms possess monoclonal lambda or kappa light chains. Immunoelectronmicroscopy, however, has shown the presence of lambda (and kappa), along with albumin, diffusely in the cytoplasm of Reed Sternberg cells not associated with organelles involved with protein synthesis and storage. These low molecular weight proteins may be able to cross the cell membrane whereas larger molecules may not.8 Kadin, et al. demonstrated polvclonal Ig on the plasma membrane of Reed Sternberg cells and its internalization as well. The authors suggest this may be facilitated via Fc or complement receptors, followed by endocytosis. As a result of these observations, the B-cell origin of the Reed-Sternberg cell is not firmly established. 9 The use of immunoperoxidase labeling for lambda (and kappa) for determining the phenotype of specific cells should be accompanied by caution and careful consideration of the entire morphological and clinical picture, particularly since the presence of lambda or kappa may be as result of passive diffusion into neoplastic cells or as result of membrane damage or active phagoctyosis.7 In summary, the use of immunoperoxidase labeling for lambda with kappa in a panel of antibodies is a useful tool in the differentiation and immunophenotyping of lymphomas. However, the results should be interpreted within the context of clinical data, gross and microscopic morphological criteria and multiple chemical and immunohistochemical stains. This differential approach is of particular need since it has been established that the presence of lambda (and/ or kappa) may not be solely attributable to specific staining, but may in fact be result of passive diffusion into neoplastic cells or as result of membrane damage or active phagoctyosis. {4}------------------------------------------------ ## Product Specific Limitations: - 1. In poorly fixed tissue specimens, nonspecific staining of non-lymphoid tissues may be observed, particularly epithelium and smooth muscle. - 2. Rare cases of T-cell lymphoma have been reported to stain positively for lambda and kappa light chains polytypically.6.10 - 3. In Hodgkin's disease, some Reed-Sternberg cells have been reported as staining positively for lambda and/or kappa light chains.6 - 4. The use of immunoperoxidase labeling for lambda (and kappa) for determining the phenotype of specific cells should be accompanied by caution and careful consideration of the entire morphological and clinical picture, particularly since the presence of lambda or kappa may be as result of passive diffusion into neoplastic cells or as result of membrane damage or active phagoctyosis.6 - 5. Lambda and/or kappa-positive B-cells may be present in tissues other than those of lymphoid origin11. Though these reactions are positive for lambda, interpretation should always be considered within the context of the predominant cell type of the tissue in question. #### Performance Characteristics: Reproducibility: ChemMate™ Lambda and ChemMate™ Negative Control Reagent have been tested on serial sections of 281 tissue specimens (both normal and tumor specimens were included in the study). Runs were performed a total of three times, with each run being performed on a different day. Consistent staining results were obtained. Immunoreactivity: Lambda and Kappa polytypic expression has been reported in non-malignant lymphoid hyperplasia with positive cells including cells of primary follicles, mantle zones and dendritic reticulum cells. Additionally, lambda reactivity has been reported in B-cell lymphomas, typically as monotypic, and exceptionally as polytypic expression10. Some plasmacytomas have been reported as being reactive for lambda. For a more comprehensive review of reported lambda immunoreactivity, please refer to the Summary and Explanation and Product Specific Limitations sections. {5}------------------------------------------------ ## References: - 1. Picker L. et al. Immunophenotvpic criteria for the diagnosis of non-Hodgkin's lymphoma. Am J Path. 1987, 128:181 - 2. Hitzman J. et al. Immunoperoxidase staining of bone marrow sections. Cancer. 1981, 48:2438 - 3. Pertruch U, et al. Frequent expression of haemopoietic and nonhaemopoietic antigens by neoplastic plasma cells. An immunohistochemical study using formalin-fixed, paraffin-embedded tissue. Histopath. 1992, 20:35 - 4. Harris N, et al. Demonstration of immunoglobulin in malignant lymphomas. Am J Clin Path. 1982, 78:14 - 5. Mori N, et al. Immunohistochemical study of mantle zone lymphoma. Am J Clin Path. 1988, 89:143 - 6. Meis J. et al. A comprehensive marker study of large cell lymphoma. Hodgkin's disease and true histiocytic lymphoma in paraffin-embedded tissue. Am J Clin Path. 1986, 86:591 - 7. Rabia M and Kahn L. Immunohistochemistry of Hodgkin's disease. Cancer. 1983, 52:2064 - 8. Popperna S, et al. The significance of intracytoplasmic proteins in Reed-Sternberg cells. Cancer. 1978, 42:1793 - 9. Kadin ME, et al. Exogenous immunoglobulin and the macrophage origin of Reed-Sternberg cells in Hodgkin's disease. N Engl J Med. 1978, 299:1208 - 10. Cleary ML, et al. Monoclonality of Ivmphoproliferative lesions in cardiactransplant recipients. NEJM 1984; 310:477 - 11. Ernst PB, et al. Immunity in mucosal tissues. Basic and Clinical Immunology, 6th edition, chapter 12. Stites, DP, et al. Editors. Norwalk, CT, Appleton & Lang Press, 1987:159 {6}------------------------------------------------ #### DEPARTMENT OF HEALTH & HUMAN SERVICES Image /page/6/Picture/1 description: The image shows the logo for the Department of Health & Human Services USA. The logo is a circular seal with the words "DEPARTMENT OF HEALTH & HUMAN SERVICES · USA" arranged around the perimeter. Inside the circle is a stylized image of an eagle. Food and Drug Administration 2098 Gaither Road Rockville MD 20850 Stephen A. Tillson, Ph.D. Vice President Scientific Affair/ Quality Assurance VENTANA MEDICAL SYSTEMS, INC. 3865 North Business Center Drive Tucson, Arizona 85705 Re : K973392 Trade Name: ChemMate™ Lambda Regulatory Class: II Product Code: DEM Dated: July 7, 1997 Received: July 9, 1997 Dear Dr. Tillson: We have reviewed your Section 510 (k) notification of intent to market the device referenced above and we have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to devices marketed in interstate commerce prior to May 28, 1976, the enactment date of the Medical Device Amendments or to devices that have been reclassified in accordance with the provisions of the Federal Food, Druq, and Cosmetic Act (Act). You may, therefore, market the device, subject to the general controls provisions of the Act. The general controls provisions of the Act include requirements for annual registration, listing of devices, good manufacturing practice, labelinq, and prohibitions against misbranding and adulteration. OCT - 3 1907 If your device is classified (see above) into either class II (Special Controls) or class III (Premarket Approval), it may be subject to such additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations, Title 21, Parts 800 A substantially equivalent determination assumes compliance to 895. with the current Good Manufacturing Practice requirement, as set forth in the Quality System Requlation (QS) for Medical Devices: General regulation (21 CFR Part 820) and that, through periodic (QS) inspections, the Food and Drug Administration (FDA) will verify such assumptions. Failure to comply with the GMP requlation may result in regulatory action. In addition, FDA may publish further announcements concerning your device in the Federal Register. Please note: this response to your premarket notification submission does not affect any obligation you might have under sections 531 through 542 of the Act for devices under the Electronic Product Radiation Control provisions, or other Federal Laws or Regulations. {7}------------------------------------------------ Paqe 2 Under the Clinical Laboratory Improvement Amendments of 1988 (CLIA-88), this device may require a CLIA complexity categorization. To determine if it does, you should contact the Centers for Disease Control and Prevention (CDC) at (770)488-7655. This letter will allow you to begin marketing your device as described in your 510(k) premarket notification. The FDA finding of substantial equivalence of your device to a legally marketed predicate device results in a classification for your device and thus, permits your device to proceed to the market. If you desire specific advice for your device on our labeling regulation (21 CFR Part 801 and additionally 809.10 for in vitro diagnostic devices), please contact the Office of Compliance at (301) Additionally, for questions on the promotion and 594-4588. advertising of your device, please contact the Office of Compliance at (301) 594-4639. Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR 807.97). Other general information on your responsibilities under the Act may be obtained from the Division of Small Manufacturers Assistance at its toll free number (800) 638-2041 or at (301) 443-6597 or at its internet address "http://www.fda.gov/cdrh/dsmamain.html" Sincerely yours, Steven Butman Steven I. Gutman, M.D., M.B.A. Director Division of Clinical Laboratory Devices Office of Device Evaluation Center for Devices and ........... Radiological Health Enclosure {8}------------------------------------------------ Page_1 of 1 _ 510(k) Number (if known): ____________________________________________________________________________________________________________________________________________________ ChemMate Lambda Device Name: Antibody Reagent ## Indications For Use: To qualitatively aid in the identification by light microscopy of human cells of lymphoid origin, by recognizing lambda light chains in immunoqlobulin secreting plasma cells and plasmacytoid B lymphocytes in normal and pathologic paraffin embedded tissues processed in neutral buffered formalin, 85, or Bouin's fixative. Positive results aid in the differential diagnosis, classification, and immunophenotyping of lymphomas and must be interpreted by a pathologist within the context of clinical data, gross and microscopic morphological criteria and multiple chemical and immunohistochemical stains. (PLEASE DO NOT WRITE BELOW THIS LINE-CONTINUE ON ANOTHER PAGE IF NEEDED) Concurrence of CDRH, Office of Device Evaluation (ODE) Peter E. Machin Division Sign-Off Bivision Sign-Off) Division of Clinical Laboratory Devices 510k) Number . **Prescription Use** (Per 21 CFR 801.109) OR Over-The-Counter. Use (Optional Format 1-2-96)