(Terminal deoxynucleotidyl transferase)
Terminal deoxynucleotidyl transferase (TdT) is an unusual deoxynucleotide polymerizing enzyme with a molecular weight of about 58 kDa found normally only in B- and T-cell lymphoblasts/prelymphocytes. The gene is located at 10q23-q24 and encodes a template-independent DNA polymerase that catalyzes the addition of deoxynucleotides to the 3'-hydroxyl terminus of oligonucleotide primers. TdT generates antigen receptor diversity by synthesizing non-germ line elements (N-regions) at the junctions of rearranged Ig heavy chain and T cell receptor gene segments. Alternatively spliced transcript variants encoding long and short isoforms of this gene have been described. Rare TdT-positive cells are regularly detected in thymus and bone marrow. Typically, TdT expression in the thymus is very variable from cell to cell since it is rapidly decreased in more mature T-cells. Tdt-positive cells may occasionally be found in tonsils, lymph nodes and extranodal lymphoid tissue. A subpopulation of haematogones (immature benign B-cell precursors in the bone marrow) forming linear arrangements also shows expression of TdT, which may reach significant numbers in the bone marrow biopsy with reactive changes (B-cell left shift), which is often more florid in children than in adults. However, even when markedly increased, TdT-positive haematogones should not form clusters larger than 5 cells in the bone marrow.
Uniform and strong expression is typical for pre-B and pre-T acute lymphoblastic leukemia/lymphoblastic lymphoma (ALL/LBL). Very weak expression is also sometimes seen in Burkitt lymphoma. All other mature (peripheral) malignant lymphomas are negative. Acute myeloid leukemia (AML) may show expression of TdT, which is not unusual finding in AML-M0 or AML with multilineage dysplasia, but rarely can be seen in other types of AML.
Immunohistochemical detection of TdT has value in classification of malignant lymphomas and acute leukaemias, particularly for the identification of pre-B and pre-T acute lymphoblastic leukemia/lymphoblastic lymphoma (ALL/LBL). The intensity of TdT expression is important since weak expression of TdT does not strongly support the diagnosis of ALL/LBL.
Normal thymus was found to be the most reliable and recommendable positive tissue control for TdT. In thymus virtually all cortical thymocytes must demonstrate an at least moderate distinct nuclear staining reaction, while the vast majority of medular thymocytes must be negative. Scattered thymocytes in the medular zone will be distinctively positive. Tonsil was less reliable as positive tissue control for TdT, as a false negative staining reaction of Pre-B-ALL and Thymoma could be seen, despite the perisinusoidal cells showed a strong and distinct nuclear staining reaction. The recommendation given by NordiQC in run 18, 2006 to use tonsil as single positive tissue control for TdT was thus unfortunately not correct. Tonsil can be used as negative tissue control for TdT - no staining reaction should be seen in mantle zone and germinal centre B-cells.
Selected references
Chang LM, Bollum FJ. Molecular biology of terminal transferase. CRC Crit Rev Biochem. 1986;21(1):27-52. Kang LC, Dunphy CH. Immunoreactivity of MIC2 (CD99) and terminal deoxynucleotidyl transferase in bone marrow clot and core specimens of acute myeloid leukemias and myelodysplastic syndromes. Arch Pathol Lab Med. 2006;130(2):153-7. Longacre TA, Foucar K, Crago S, Chen IM, Griffith B, Dressler L, McConnell TS, Duncan M, Gribble J. Hematogones: a multiparameter analysis of bone marrow precursor cells. Blood. 1989;73(2):543-52. McKenna RW, Asplund SL, Kroft SH. Immunophenotypic analysis of hematogones (B-lymphocyte precursors) and neoplastic lymphoblasts by 4-color flow cytometry. Leuk Lymphoma. 2004;45(2):277-85. McKenna RW, Washington LT, Aquino DB, Picker LJ, Kroft SH. Immunophenotypic analysis of hematogones (B-lymphocyte precursors) in 662 consecutive bone marrow specimens by 4-color flow cytometry. Blood. 2001;98(8):2498-507. Meru N, Jung A, Baumann I, Niedobitek G. Expression of the recombination-activating genes in extrafollicular lymphocytes but no apparent reinduction in germinal center reactions in human tonsils. Blood. 2002;99(2):531-7. Rimsza LM, Viswanatha DS, Winter SS, Leith CP, Frost JD, Foucar K.Benign hematogone-rich lymphoid proliferations can be distinguished from B-lineage acute lymphoblastic leukemia by integration of morphology, immunophenotype, adhesion molecule expression, and architectural features. Am J Clin Pathol. 2000;114(1):66-75. Rimsza LM, Viswanatha DS, Winter SS. et al. The presence of CD34+ cell clusters predicts impending relapse in children with acute lymphoblastic leukemia receiving maintenance chemotherapy. Am J Clin Pathol 1998;110:313–320. Sening W, Lisner R, Niedobitek G. Rare detection of phenotypically immature lymphocytes in Hashimoto thyroiditis and rheumatoid arthritis. J Autoimmun. 2004;22(2):147-52. Strauchen JA, Miller LK. Lymphoid progenitor cells in human tonsils. Int J Surg Pathol. 2003;11(1):21-4. Strauchen JA, Miller LK.Terminal deoxynucleotidyl transferase-positive cells in human tonsils. Am J Clin Pathol. 2001;116(1):12-6. Thai TH, Kearney JF. Distinct and opposite activities of human terminal deoxynucleotidyltransferase splice variants J. Immunol. 2004;173(6):4009-4019. Torlakovic E, Tenstad E, Funderud S, Rian E. CD10+ stromal cells form B-lymphocyte maturation niches in the human bone marrow. J Pathol. 2005;205(3):311-7. Toth B, Wehrmann M, Kaiserling E, Horny HP. Immunophenotyping of acute lymphoblastic leukaemia in routinely processed bone marrow biopsy specimens. J Clin Pathol. 1999;52(9):688-92.
11.04.14 - ET/MV/LE