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Aberrant myeloid marker expression in precursor B-cell and T-cell leukemias
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Experimental and Molecular Pathology 83 (2007) 471 – 473 www.elsevier.com/locate/yexmp
Aberrant myeloid marker expression in precursor B-cell and T-cell leukemias Jeanann L. Suggs ⁎, Julius M. Cruse, Robert E. Lewis Department of Pathology, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216, USA Received 20 August 2007 Available online 7 September 2007
Abstract The World Health Organization (WHO) characterization of the immunophenotype of precursor B-cell acute lymphoblastic leukemia (pre-B ALL) includes the possible expression of myeloid cluster of differentiation (CD) markers CD13 and CD33. In precursor T-cell acute lymphoblastic leukemia (pre-T ALL), myeloid markers CD13 and CD33 are frequent while CD117 is rare. In the present investigation, 71 cases of confirmed pre-B ALL were evaluated for the presence of CD13 and CD33. Of the 19 (27%) cases that positively expressed myeloid markers, 10 (53%) expressed CD13, 17 (89%) expressed CD33, and 1 (5%) expressed CD117. Eight (42%) expressed both CD13 and CD33, and 1 (5%) expressed CD13, CD33, and CD117. Twenty-one cases of confirmed pre-T ALL were analyzed for myeloid markers CD13, CD33, CD117, and MPO. Of the 6 (29%) expressing myeloid markers, 4 (67%) were positive for CD13, 4 (67%) for CD33, 3 50(%) for CD117, and 1 (17%) for MPO. One (17%) was positive for both CD13 and CD117; one (17%) for CD13 and CD33; one (17%) for CD13, CD33 and CD117; and one (17%) for CD13, CD33 and MPO. These markers portend a poor prognosis compared to ALL cases without myeloid antigens, and a poor response to drug therapies targeting conventional ALL. Future studies will be directed to correlation of these markers with prognosis and therapeutic response, as well as whether drug therapies targeting myeloid antigens could be of use in treatment. © 2007 Elsevier Inc. All rights reserved.
Introduction Acute lymphoblastic leukemia, or ALL, is the most common type of leukemia affecting individuals less than 19 years old. ALL causes an uncontrolled proliferation of immature lymphoblasts resulting in a decrease in the number of functioning cells derived from the bone marrow. Two subsets of ALL are precursor B-cell ALL and precursor T-cell ALL. The World Health Organization (WHO) describes precursor pre-B ALL lymphoblasts as having negative expression of MPO but positive expression of TdT. Myeloid markers CD13 and CD33 may be expressed. CD19 and CD79a are almost always positively expressed. WHO states that most pre-B ALL cases will positively express CD10, while CD20 has variable expression. This disease is reported as affecting mostly males (Jaffe et al., 2001). Pre-T ALL is also described by WHO as being a disease of adolescents found more commonly in males. The lymphoblasts in pre-T ALL are described as TdT positive. Additionally, CD10, CD79a, and cCD3 may be expressed. WHO states my⁎ Corresponding author. Fax: +1 601 984 1835. E-mail address: [email protected] (J.L. Suggs). 0014-4800/$ - see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.yexmp.2007.08.012
eloid markers CD13 and CD33 are often expressed, but CD117 is rare (Jaffe et al., 2001). Materials and methods Seventy-one cases of confirmed pre-B ALL and 21 cases of confirmed pre-T ALL were evaluated for immunophenotypic markers at the University of Mississippi Medical Center. These cases date back to October 2002 (pre-B ALL)
Fig. 1. Positive expression of myeloperoxidase (MPO) in pre-B ALL.
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J.L. Suggs et al. / Experimental and Molecular Pathology 83 (2007) 471–473
Table 1 Pre-B ALL immunophenotypes Total % All participants Positive Negative Less than 19 years Positive Negative 19 years–35 years Positive Negative Greater than 35 years Positive Negative
Male %
MPO
TdT
CD13 or CD33
CD19
CD79a
CD10
CD20
2 69
63 8
19 52
67 2
68 3
62 6
31 34
0 45
43 2
10 35
45 0
45 0
42 2
22 20
0 11
8 3
5 6
10 1
9 2
11 0
3 8
2 13
12 3
4 11
12 1
14 1
9 4
6 6
58%
63%
15%
21%
60%
55%
53%
and March 2003 (pre-T ALL). Bone marrow aspirates, as well as peripheral blood collected in EDTA, were analyzed by flow cytometry (Epics XL and FC500, Beckman and Coulter, Miami, FL) using standard techniques involving fluorochrome labeled monoclonal antibodies.
Results Of the 71 cases of pre-B ALL studied, 45 patients were less than 19 years old, and 15 patients were greater than 35 years old. Only 2 cases (3%) exhibited positive MPO expression (Fig. 1). TdT expression was negative in 8 cases (11%). CD13 or CD33 was positive in 19 cases (27%). CD19 was positive in 67 cases (97%), while CD79a was positive in 68 cases (96%). CD10 was positive in 62 cases (91%). CD20 was positive in only 31 cases (48%). In depth review of immunophenotype according to age groups can be found in Table 1. Of the 21 cases of pre-T ALL reviewed, seven patients (33%) were aged less than 13. Eight patients (38%) were aged greater than 25. TdT was found to be negative in 2 cases (10%) (Fig. 2). CD10 was found to be positive in 9 cases (43%), CD79a was positive in 11 cases (52%), and cCD3 was found to be positive in 20 cases (100%). Myeloid markers CD13 and CD33 were found to be positive in 5 cases (24%), while CD117 was positive in 3 cases (14%) (Fig. 3). Breakdown of expression according to age divisions can be found in Table 2.
Fig. 2. Negative expression of terminal deoxynucleotidyl transferase (TdT) in pre-T ALL.
Discussion Several criteria described by WHO to characterize pre-B ALL were supported by this study. The majority of cases (53%) included patients aged less than 14 years old, and 58% of this age group was male. The high percentage of positive expression for CD19, CD10, and CD79a, as well as the variable expression of CD20, again supports WHO criteria. The high incidence of CD19 (97%) suggests that CD19 might be useful as a therapeutic target for pre-B ALL. Contradictory to WHO criteria, our study did not find MPO expression to be negative in all pre-B ALL cases. Two cases (3%) of older males (age 41 and age 45) had positive expression of MPO. Also contradictory was the finding of positivity for TdT within the pre-B ALL population. Eight cases (11%) did not express TdT, including two females (aged 8 years and 45 years) and six males (aged 7 months, 20 years, 24 years, 30 years, 37 years, and 39 years). The suggestion by WHO that CD13 and CD33 may be present is upheld, as our study found positive expression in 27% of cases. The possible presence of these myeloid variations within the immunophenotype of this disease should be acknowledged, as different treatment options may exist for these different disease manifestations. In these cases, therapies useful in treating myeloid leukemias might be of use, despite the lymphoid leukemia diagnosis. In pre-T ALL, however, the opposite was true for inclusion of myeloid markers in disease. WHO describes the
Fig. 3. Positive expression of CD117 in pre-T ALL.
J.L. Suggs et al. / Experimental and Molecular Pathology 83 (2007) 471–473
473
Table 2 Pre-T ALL immunophenotypes Total % All participants Positive Negative Less than 13 years Positive Negative 13 years–25 years Positive Negative Greater than 25 years Positive Negative
Male %
TdT
CD13 or CD33
CD10
CD79a
cCD3
CD117
19 2
5 16
9 12
11 10
20 0
3 18
6 1
0 7
3 4
4 3
7 0
0 7
6 0
2 4
3 3
1 5
6 0
2 4
7 1
3 5
3 5
6 2
7 0
1 7
76%
33%
29%
38%
71%
83%
75%
presence of CD13 and CD33 as often expressed, but this study revealed only expression in only 24% of cases reviewed. WHO considers CD117 a rarely expressed myeloid marker, although this study found it positively expressed in 14% of pre-T ALL cases. CD10 was positively expressed in only 43% of the pre-T ALL cases in this study. CD79a was found to be present in over 52% of the pre-T ALL cases studied here. TdT, considered by WHO to always be found in pre-T ALL, was absent in two cases (10%) in this study. These contradictory incidences of immunophenotypic markers suggest the need for a larger study of ALL cases to determine if new diagnostic criteria are necessary to allow for more flexible guidelines in disease determination. However, it is important that these immunophenotypes are utilized for more than simply diagnosis of disease. Perhaps even more important than tools for diagnostic evaluation, these markers may serve as novel approaches to clinical disease management. Research studies have begun testing the efficacy of anti-CD19 immunotoxins in treating murine disease (Herrera et al., 2006). Due to the high percentage of CD19 expression in these cases, therapy of this nature might be of use in treating pre-B ALL. Other possible monoclonal antibody (MoAb) targets for these diseases include CD20 or CD33 (Abutalib and Tallman, 2006; Li and Zhu, 2007). Rituximab, an anti-CD20 MoAb, has been clinically tested in mature B-ALL and other lymphomas (Lewis et al., 2006). Although only 48% of the pre-B ALL cases were positive for CD20, this subset might be susceptible to treatment regimens targeted at CD20. Conclusions These study results upheld several diagnostic criteria suggested by WHO, including positive expression of CD19, CD79a, and CD10, and variable expression of CD20 in pre-B ALL. Also upheld were the criteria of possible CD10 and CD79a criteria in pre-T ALL. However, several stringent diagnosis criteria were rebuked in some cases of ALL examined. TdT was found to be negative in some cases within
both subsets. Additionally, pre-B ALL cases were found to demonstrate positive MPO expression (3%). Several pre-T ALL cases (14%) were found to be CD117 positive, a rare finding according to WHO. As for the myeloid markers CD13 and CD33, it is interesting to see positivity in only 24% of pre-T ALL cases, as the WHO diagnosis criteria maintain it is ‘often’ found (Jaffe et al., 2001). As for pre-B ALL, CD13 and CD33 may be present, according to WHO, and our study revealed positivity in 27% of cases. It is these results that lead to the conclusion that the criteria for pre-B and pre-T ALL should not be considered stringent when used for diagnosis of disease. Furthermore, the variability of disease immunophenotyping should be analyzed for alternative targeted drug therapy, such as monoclonal antibodies directed against CD33, CD20, or CD19. Acknowledgments The authors express sincere appreciation to Mrs. Patsy Foley, B.S., MT (ASCP), CHT, CHS (ABHI); Ms. Susan Touchstone, B.S., MT (ASCP), SBB (AABB), CHT, CHS (ABHI); and Mr. John Coker, B.S., MT (NCA) for their skilled technical expertise in flow cytometric analysis.
References Abutalib, S.A., Tallman, M.S., 2006. Monoclonal antibodies for the treatment of acute myeloid leukemia. Curr. Pharm. Biotechnol. 7 (5), 343–369 (Oct). Herrera, L., Stanciu-Herrera, C., Morgan, C., Ghetie, V., Vitetta, E.S., 2006. Anti-CD19 immunotoxin enhances the activity of chemotherapy in severe combined immunodeficient mice with human pre-B acute lymphoblastic leukemia. Leuk. Lymphoma 47 (11), 2380–2387 (Nov). Jaffe, E.S., Harris, N.L., Stein, H., Vardiman, J.W. (Eds.), 2001. World Health Organization classification of tumours. Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. IARC Press, Lyon. Lewis, R.E., Cruse, J.M., Sanders, C.M., Webb, R.N., Tillman, B.F., Beason, K.L., Lam, J., Koehler, J., 2006. The immunophenotype of pre-TALL/LBL revisited. Exp. Mol. Pathol. 81 (2), 162–165 (Oct). Li, Y., Zhu, Z., 2007. Monoclonal antibody-based therapeutics for leukemia. Expert Opin. Biol. Ther. 7 (3), 319–330 (Mar).
Experimental and Molecular Pathology 83 (2007) 471 – 473 www.elsevier.com/locate/yexmp
Aberrant myeloid marker expression in precursor B-cell and T-cell leukemias Jeanann L. Suggs ⁎, Julius M. Cruse, Robert E. Lewis Department of Pathology, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216, USA Received 20 August 2007 Available online 7 September 2007
Abstract The World Health Organization (WHO) characterization of the immunophenotype of precursor B-cell acute lymphoblastic leukemia (pre-B ALL) includes the possible expression of myeloid cluster of differentiation (CD) markers CD13 and CD33. In precursor T-cell acute lymphoblastic leukemia (pre-T ALL), myeloid markers CD13 and CD33 are frequent while CD117 is rare. In the present investigation, 71 cases of confirmed pre-B ALL were evaluated for the presence of CD13 and CD33. Of the 19 (27%) cases that positively expressed myeloid markers, 10 (53%) expressed CD13, 17 (89%) expressed CD33, and 1 (5%) expressed CD117. Eight (42%) expressed both CD13 and CD33, and 1 (5%) expressed CD13, CD33, and CD117. Twenty-one cases of confirmed pre-T ALL were analyzed for myeloid markers CD13, CD33, CD117, and MPO. Of the 6 (29%) expressing myeloid markers, 4 (67%) were positive for CD13, 4 (67%) for CD33, 3 50(%) for CD117, and 1 (17%) for MPO. One (17%) was positive for both CD13 and CD117; one (17%) for CD13 and CD33; one (17%) for CD13, CD33 and CD117; and one (17%) for CD13, CD33 and MPO. These markers portend a poor prognosis compared to ALL cases without myeloid antigens, and a poor response to drug therapies targeting conventional ALL. Future studies will be directed to correlation of these markers with prognosis and therapeutic response, as well as whether drug therapies targeting myeloid antigens could be of use in treatment. © 2007 Elsevier Inc. All rights reserved.
Introduction Acute lymphoblastic leukemia, or ALL, is the most common type of leukemia affecting individuals less than 19 years old. ALL causes an uncontrolled proliferation of immature lymphoblasts resulting in a decrease in the number of functioning cells derived from the bone marrow. Two subsets of ALL are precursor B-cell ALL and precursor T-cell ALL. The World Health Organization (WHO) describes precursor pre-B ALL lymphoblasts as having negative expression of MPO but positive expression of TdT. Myeloid markers CD13 and CD33 may be expressed. CD19 and CD79a are almost always positively expressed. WHO states that most pre-B ALL cases will positively express CD10, while CD20 has variable expression. This disease is reported as affecting mostly males (Jaffe et al., 2001). Pre-T ALL is also described by WHO as being a disease of adolescents found more commonly in males. The lymphoblasts in pre-T ALL are described as TdT positive. Additionally, CD10, CD79a, and cCD3 may be expressed. WHO states my⁎ Corresponding author. Fax: +1 601 984 1835. E-mail address: [email protected] (J.L. Suggs). 0014-4800/$ - see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.yexmp.2007.08.012
eloid markers CD13 and CD33 are often expressed, but CD117 is rare (Jaffe et al., 2001). Materials and methods Seventy-one cases of confirmed pre-B ALL and 21 cases of confirmed pre-T ALL were evaluated for immunophenotypic markers at the University of Mississippi Medical Center. These cases date back to October 2002 (pre-B ALL)
Fig. 1. Positive expression of myeloperoxidase (MPO) in pre-B ALL.
472
J.L. Suggs et al. / Experimental and Molecular Pathology 83 (2007) 471–473
Table 1 Pre-B ALL immunophenotypes Total % All participants Positive Negative Less than 19 years Positive Negative 19 years–35 years Positive Negative Greater than 35 years Positive Negative
Male %
MPO
TdT
CD13 or CD33
CD19
CD79a
CD10
CD20
2 69
63 8
19 52
67 2
68 3
62 6
31 34
0 45
43 2
10 35
45 0
45 0
42 2
22 20
0 11
8 3
5 6
10 1
9 2
11 0
3 8
2 13
12 3
4 11
12 1
14 1
9 4
6 6
58%
63%
15%
21%
60%
55%
53%
and March 2003 (pre-T ALL). Bone marrow aspirates, as well as peripheral blood collected in EDTA, were analyzed by flow cytometry (Epics XL and FC500, Beckman and Coulter, Miami, FL) using standard techniques involving fluorochrome labeled monoclonal antibodies.
Results Of the 71 cases of pre-B ALL studied, 45 patients were less than 19 years old, and 15 patients were greater than 35 years old. Only 2 cases (3%) exhibited positive MPO expression (Fig. 1). TdT expression was negative in 8 cases (11%). CD13 or CD33 was positive in 19 cases (27%). CD19 was positive in 67 cases (97%), while CD79a was positive in 68 cases (96%). CD10 was positive in 62 cases (91%). CD20 was positive in only 31 cases (48%). In depth review of immunophenotype according to age groups can be found in Table 1. Of the 21 cases of pre-T ALL reviewed, seven patients (33%) were aged less than 13. Eight patients (38%) were aged greater than 25. TdT was found to be negative in 2 cases (10%) (Fig. 2). CD10 was found to be positive in 9 cases (43%), CD79a was positive in 11 cases (52%), and cCD3 was found to be positive in 20 cases (100%). Myeloid markers CD13 and CD33 were found to be positive in 5 cases (24%), while CD117 was positive in 3 cases (14%) (Fig. 3). Breakdown of expression according to age divisions can be found in Table 2.
Fig. 2. Negative expression of terminal deoxynucleotidyl transferase (TdT) in pre-T ALL.
Discussion Several criteria described by WHO to characterize pre-B ALL were supported by this study. The majority of cases (53%) included patients aged less than 14 years old, and 58% of this age group was male. The high percentage of positive expression for CD19, CD10, and CD79a, as well as the variable expression of CD20, again supports WHO criteria. The high incidence of CD19 (97%) suggests that CD19 might be useful as a therapeutic target for pre-B ALL. Contradictory to WHO criteria, our study did not find MPO expression to be negative in all pre-B ALL cases. Two cases (3%) of older males (age 41 and age 45) had positive expression of MPO. Also contradictory was the finding of positivity for TdT within the pre-B ALL population. Eight cases (11%) did not express TdT, including two females (aged 8 years and 45 years) and six males (aged 7 months, 20 years, 24 years, 30 years, 37 years, and 39 years). The suggestion by WHO that CD13 and CD33 may be present is upheld, as our study found positive expression in 27% of cases. The possible presence of these myeloid variations within the immunophenotype of this disease should be acknowledged, as different treatment options may exist for these different disease manifestations. In these cases, therapies useful in treating myeloid leukemias might be of use, despite the lymphoid leukemia diagnosis. In pre-T ALL, however, the opposite was true for inclusion of myeloid markers in disease. WHO describes the
Fig. 3. Positive expression of CD117 in pre-T ALL.
J.L. Suggs et al. / Experimental and Molecular Pathology 83 (2007) 471–473
473
Table 2 Pre-T ALL immunophenotypes Total % All participants Positive Negative Less than 13 years Positive Negative 13 years–25 years Positive Negative Greater than 25 years Positive Negative
Male %
TdT
CD13 or CD33
CD10
CD79a
cCD3
CD117
19 2
5 16
9 12
11 10
20 0
3 18
6 1
0 7
3 4
4 3
7 0
0 7
6 0
2 4
3 3
1 5
6 0
2 4
7 1
3 5
3 5
6 2
7 0
1 7
76%
33%
29%
38%
71%
83%
75%
presence of CD13 and CD33 as often expressed, but this study revealed only expression in only 24% of cases reviewed. WHO considers CD117 a rarely expressed myeloid marker, although this study found it positively expressed in 14% of pre-T ALL cases. CD10 was positively expressed in only 43% of the pre-T ALL cases in this study. CD79a was found to be present in over 52% of the pre-T ALL cases studied here. TdT, considered by WHO to always be found in pre-T ALL, was absent in two cases (10%) in this study. These contradictory incidences of immunophenotypic markers suggest the need for a larger study of ALL cases to determine if new diagnostic criteria are necessary to allow for more flexible guidelines in disease determination. However, it is important that these immunophenotypes are utilized for more than simply diagnosis of disease. Perhaps even more important than tools for diagnostic evaluation, these markers may serve as novel approaches to clinical disease management. Research studies have begun testing the efficacy of anti-CD19 immunotoxins in treating murine disease (Herrera et al., 2006). Due to the high percentage of CD19 expression in these cases, therapy of this nature might be of use in treating pre-B ALL. Other possible monoclonal antibody (MoAb) targets for these diseases include CD20 or CD33 (Abutalib and Tallman, 2006; Li and Zhu, 2007). Rituximab, an anti-CD20 MoAb, has been clinically tested in mature B-ALL and other lymphomas (Lewis et al., 2006). Although only 48% of the pre-B ALL cases were positive for CD20, this subset might be susceptible to treatment regimens targeted at CD20. Conclusions These study results upheld several diagnostic criteria suggested by WHO, including positive expression of CD19, CD79a, and CD10, and variable expression of CD20 in pre-B ALL. Also upheld were the criteria of possible CD10 and CD79a criteria in pre-T ALL. However, several stringent diagnosis criteria were rebuked in some cases of ALL examined. TdT was found to be negative in some cases within
both subsets. Additionally, pre-B ALL cases were found to demonstrate positive MPO expression (3%). Several pre-T ALL cases (14%) were found to be CD117 positive, a rare finding according to WHO. As for the myeloid markers CD13 and CD33, it is interesting to see positivity in only 24% of pre-T ALL cases, as the WHO diagnosis criteria maintain it is ‘often’ found (Jaffe et al., 2001). As for pre-B ALL, CD13 and CD33 may be present, according to WHO, and our study revealed positivity in 27% of cases. It is these results that lead to the conclusion that the criteria for pre-B and pre-T ALL should not be considered stringent when used for diagnosis of disease. Furthermore, the variability of disease immunophenotyping should be analyzed for alternative targeted drug therapy, such as monoclonal antibodies directed against CD33, CD20, or CD19. Acknowledgments The authors express sincere appreciation to Mrs. Patsy Foley, B.S., MT (ASCP), CHT, CHS (ABHI); Ms. Susan Touchstone, B.S., MT (ASCP), SBB (AABB), CHT, CHS (ABHI); and Mr. John Coker, B.S., MT (NCA) for their skilled technical expertise in flow cytometric analysis.
References Abutalib, S.A., Tallman, M.S., 2006. Monoclonal antibodies for the treatment of acute myeloid leukemia. Curr. Pharm. Biotechnol. 7 (5), 343–369 (Oct). Herrera, L., Stanciu-Herrera, C., Morgan, C., Ghetie, V., Vitetta, E.S., 2006. Anti-CD19 immunotoxin enhances the activity of chemotherapy in severe combined immunodeficient mice with human pre-B acute lymphoblastic leukemia. Leuk. Lymphoma 47 (11), 2380–2387 (Nov). Jaffe, E.S., Harris, N.L., Stein, H., Vardiman, J.W. (Eds.), 2001. World Health Organization classification of tumours. Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. IARC Press, Lyon. Lewis, R.E., Cruse, J.M., Sanders, C.M., Webb, R.N., Tillman, B.F., Beason, K.L., Lam, J., Koehler, J., 2006. The immunophenotype of pre-TALL/LBL revisited. Exp. Mol. Pathol. 81 (2), 162–165 (Oct). Li, Y., Zhu, Z., 2007. Monoclonal antibody-based therapeutics for leukemia. Expert Opin. Biol. Ther. 7 (3), 319–330 (Mar).