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Hand mirror cell acute lymphoblastic leukemia with B lymphoid surface markers
498
Editorial correspondence
The Journal ~ Pediatrics March 1979
Table I. Comparison of serum levels in pregnant and nonpregnant women* Serum Nonpregnant women (16) Pregnant women (32)
Ig G (mg/dl) 1,506 _+ 252 1,229.8_+ 313.4 P < 0.01
I
[ t
lg A (mg/dl)
lgM emg/dl)
Ceruloplasmin r
Transferrin (mg/dl)
267 _+ 63.1
328 _+ 70.2
30.9 _+ 12.3
136.9 ___53.3
221.8 • 86.8 P < 0.20
269.3 • 76.9 P < 0.025
94.4 • 28.5 P < 0.001
358.2 • 107.6 P < 0.001
*Results given as mean +_ standard deviation. Table II. C o m p a r i s o n of colostrum a n d transitional milk levels*
ig 6
Ig A
Ig M
Serum
(mg/dl)
(mg/ dl)
(mg/ dl)
Ceruloplasmin (mg/dl)
Transferrin (mg/dl)
Colostrum (24) Milk (19)
47.3 _ 23.8 23.4 _+ 12.9 P < 0.001
354.2 • 99.2 216.3 • 79.7 P < 0.001
404.7 _+ 117 124.4 _+ 52.9 P < 0.001
6.4 _+ 1 5.0 • 0.4 P < 0.20
23.5 ___ 19.3 8.2 • 6.4 P < 0.005
*Results given as mean + standard deviation.
concentrations of antibodies, the milk antibody content reflecting the intestinal antibody response of the mother against microorganisms to which the infant in exposed after birth. The colostrum provides also ceruloplasmin and transferrin (lactoferrin) which are important protein fractions in phagocytosis. ~
S. (Hker Ones, M.D. Associate Professor of Pediatrics Section of Infectious Diseases and Clinical Immunology Facultv of Medicine of Istanbul University of Istanbul-~apa Turkey REFERENCES
1. Ogra SS, and Ogra PL: Immunologic aspects of human colostrum and milk. I. Distribution characteristics and concentrations of immunoglobulins at different times after the onset of lactation, J PEDIATR 92:546, 1978. 2. Frankel S, Reitman S, and Sonnenwirth AC: Gradwohl's clinical laboratory Methods and Diagnosis, ed 6, Saint Louis, 1963, The CV Mosby Co. 3. Mancini G, Carbonara AO, and Heremans JF. Immunochemical quantitation of antigens by single radial immunodiffuslons, Immunochemistry 2:235, 1965. 4. Ouchterlony O: Diffusion in gel methods for immunological analysis, Prog Allergy 5:1, 1958. 5. Hanson LA, and Winberg J: Breast milk and defense against infection in the newborn, Arch Dis Child 47:845, 1972 6. Ogra PL, and Karzon DT: The role of immunoglobulins in the mechanism of mucosal immunity to virus infection, Pediatr Clin North Am 17"385, 1970. 7. Tomasi TB, and Bienenstock JM: Secretory immunoglobulins, Adv Immunol 9:1, 1968. 8. Beisel WR, Pekarek RS, and Wannemacher RW Jr: In Hoekstra WG, Suttie JW, Ganther HE, and Mertz W, editors: Trace element metabolism in animals, Baltimore, 1974, University Park Press, p 217.
H a n d mirror cell acute lymphoblastic leukemia with B lymphoid surface markers To the Editor: Schumacher and Stass L' ~ have reported recently in this and other journals on the significance of"hand mirror" cells in acute lymphoblastic leukemia (ALL). The hand mirror cells in Schumacher's patient were unmarked or "null" cells. Recently we cared for a patient with the hand mirror variant of ALL whose blasts bore B lymphoid cell surface markers and who had a fulminating disease course. CASE REPORT
A 13-year-old white boy presented to Texas Children's Hospital with bone pain, anorexia, and fever. The spleen was palpable 2 cm below the left costal margin. The hemoglobin was 10.9 gm/dl, hematocrit 31.8%, platelet count 231,000/mm 3, and WBC count 6,700/mm:' with a differential leukocyte count of 48% neutrophils, 37% lymphocytes, 4% monocytes, and 11% eosinophils. Radial immuno-diffusion showed a decrease in IgA to 52 mg/dl (normal for age 81 to 232 mg/dl) but normal amounts of IgM and IgG. Bone marrow smears showed 84% blast forms, of which 71% were hand mirror cells. Cytochemical staining for pyronin methyl green, periodic acid-Schiff, chloroacetate and combined esterases, and peroxidase was negative, but 45% of the blasts exhibited small amounts of acid phosphatase. Surface marker determinations performed on Ficoll-triosil-separated marrow lymphoid cells (93% blasts) revealed the following: (1) 1.5% active E-R at 37~ and 4% total E-R at 4~ after overnight incubation; (2) 1.5% EAC-R; and (3) 74% of blasts demonstrated SMIg using a fluorescein-conjugated polyvalent antiserum. Experiments using monospecific antisera for IgG, IgA, IgM, and
Supported in part by USPH CA-O3161from the National Cancer Institute.
Volume 94 Number 3
F(ab')~ confirmed that the SMIg was an IgM which failed to elute following ten washings and overnight incubation at 37~ Doseresponse experiments measuring tritiated thymidine incorporation in response to mitogens showed normal responses to phytohemagglutinin (4,901 to 136,636 counts per minute [CPM]), but subnormal responses to concanavalin A (4,645 to 17,128 CPM), and pokeweed mitogen (10,402-20,628 CPM). A diagnosis of B cell ALL was established and chemotherapy was begun with vincristine, cyclophosphamide, and prednisone. Complete remission was obtained after a month of this therapy but was followed quickly by relapse in the bone marrow and central nervous system. Although a subsequent transitory response was obtained with high-dose cyclophosphamide, he failed to respond tO combinations of vincristine, cyclophosphamide, prednisone, high-dose methotrexate, doxorubicin, and cytosine arabinoside. The central nervous system leukemia also responded briefly to cranial radiotherapy and intrathecal chemotherapy. However, by the time of death the child had progressive bone marrow, central nervous system, and testicular leukemia as well as evidence of an encephalopathy. Postmortem examination confirmed the clinical diagnosis and revealed the continued presence of hand mirror cells. DISCUSSION The weak positivity for acid phosphatase, normally present in T lymphoblasts, the negative staining for pyronin methyl green, commonly present in B lymphoid neoplasms, and the patterns of mitogen responsiveness (response to phytohemagglutinin normally being associated with T lymphoid cells) are bothersome. However, the presence of SMIg on this child's blasts was unequivocal and indicates that these cells were of B lymphoid origin. In addition, the rapid progression and extra-medullary involvement of this boy's leukemia are characteristic of B lymphoid neoplasms in children2 Other authors 4 ~ have suggested that the presence of hand mirror cells connote a favorable prognosis and attributed this morphologic finding to amoeboid movement of hematopoietic cells. Our patient's hand mirror cells were B cells and his disease course was much more rapidly progressive than in the usual child with ALL. Hand mirror cell leukemia, like ALL in general, is a heterogeneous entity and lymphoid cell surface marker analysis may provide more useful prognostic information than the mere notation of the presence of a morphologic variant. William L. Nix, M.D. Nalini Mukhopadhyay, M.S. C Philip Steuber, M.D. Donald J. Fernbach, M.D. Hematology-Oncology Section Department of Pediatrics Baylor College of Medicine Texas Children's Hospital 6621 Fannin St. Houston, TX 77030
Editorial correspondence
499
detailed cytological and ultrastructural study with an analysis of the immunologic surface markers, Am J Hematol 4:67, 1978. 3. Flandrin G, Brouet JC, Daniel MT, and Preud'homme JL: Acute leukemia with Burkitt's tumor cells: A study of six cases with special reference to lymphocyte surface markers, Blood 45:183, 1975. 4. Sjogren U: Amoeboid movement configuration and mitotic indices of lymphoid cells from children with acute lymphoblastic leukemia, Lymphology 9:69, 1976. 5. Sjogren U, Norberg H, and Rydgren L: Amoeboid movement configuration in tumor cells of bone marrow smears from patients with leukemia, Acta Med Scand 201:381, 1977.
Rep& To the Editor: We have previously seen a case of Burkitt lymphoma which became leukemic and demonstrated 43% hand mirror cells (Burkitt ceUs) in the bone marrow.' This patient, like the one of Nix et al, had a rapid fulminating course and died in four months. Extensive surface marker studies revealed the cells to be B cells with an IgG surface marker. The hand mirror forms declined to 2% in the bone marrow prior to death in our patient, but these forms were abundant in the marrow at postmortem in the patient of Nix et al. Recent studies in our laboratories have indicated that the hand mirror configuration can be diminished by temperature and drugs. 2 However, the chemotherapy utilized in the above patient and ours was comparable. This suggests that therapy did not affect the hand mirror cells in their patient but we would be interested in the number of hand mirror cells at death. Age probably also plays an important role since we have now seen two young female adults and one middle-aged male with acute lymphoblastic leukemia, hand mirror variant, who have done extremely well. We entirely agree with Nix et al that acute lymphoblastic leukemia is a heterogeneous entity. Surface markers do indeed play an important role and may override any effect hand mirror cells may have on the disease. At this juncture many questions remain to be answered concerning hand mirror cells; more investigation and observations are indicated to bring the full significance of this unique cell into proper prospective. H. R. Schumacher S. A. Stass National Naval Medical Center and Uniformed Services University of the Health Sciences Bethesda, MD 20014 REFERENCES
REFERENCES
1. Schumacher HR, and Stass SA: Commentary: Significance of hand mirror cells, J PEDIATrt 93:335, 1978. 2. Stass SA, Perlin E, Jaffe ES, Simon DR, Creegan W J, Robinson JJ, Holloway ML, and Schumacher HR: Acute lymphoblastic leukemia-hand mirror cell variant: A
1. Schumacher HR, Rainey T, Simon D, Strong M, Creegan WJ, Holloway ML, and Stass SA: American Burkitt's lymphoma-hand mirror variant. A detailed cytological, ultrastructural, and immunologic marker investigation, Am J Clin Pathol 70:937, 1978. 2. Personal observation.
Editorial correspondence
The Journal ~ Pediatrics March 1979
Table I. Comparison of serum levels in pregnant and nonpregnant women* Serum Nonpregnant women (16) Pregnant women (32)
Ig G (mg/dl) 1,506 _+ 252 1,229.8_+ 313.4 P < 0.01
I
[ t
lg A (mg/dl)
lgM emg/dl)
Ceruloplasmin r
Transferrin (mg/dl)
267 _+ 63.1
328 _+ 70.2
30.9 _+ 12.3
136.9 ___53.3
221.8 • 86.8 P < 0.20
269.3 • 76.9 P < 0.025
94.4 • 28.5 P < 0.001
358.2 • 107.6 P < 0.001
*Results given as mean +_ standard deviation. Table II. C o m p a r i s o n of colostrum a n d transitional milk levels*
ig 6
Ig A
Ig M
Serum
(mg/dl)
(mg/ dl)
(mg/ dl)
Ceruloplasmin (mg/dl)
Transferrin (mg/dl)
Colostrum (24) Milk (19)
47.3 _ 23.8 23.4 _+ 12.9 P < 0.001
354.2 • 99.2 216.3 • 79.7 P < 0.001
404.7 _+ 117 124.4 _+ 52.9 P < 0.001
6.4 _+ 1 5.0 • 0.4 P < 0.20
23.5 ___ 19.3 8.2 • 6.4 P < 0.005
*Results given as mean + standard deviation.
concentrations of antibodies, the milk antibody content reflecting the intestinal antibody response of the mother against microorganisms to which the infant in exposed after birth. The colostrum provides also ceruloplasmin and transferrin (lactoferrin) which are important protein fractions in phagocytosis. ~
S. (Hker Ones, M.D. Associate Professor of Pediatrics Section of Infectious Diseases and Clinical Immunology Facultv of Medicine of Istanbul University of Istanbul-~apa Turkey REFERENCES
1. Ogra SS, and Ogra PL: Immunologic aspects of human colostrum and milk. I. Distribution characteristics and concentrations of immunoglobulins at different times after the onset of lactation, J PEDIATR 92:546, 1978. 2. Frankel S, Reitman S, and Sonnenwirth AC: Gradwohl's clinical laboratory Methods and Diagnosis, ed 6, Saint Louis, 1963, The CV Mosby Co. 3. Mancini G, Carbonara AO, and Heremans JF. Immunochemical quantitation of antigens by single radial immunodiffuslons, Immunochemistry 2:235, 1965. 4. Ouchterlony O: Diffusion in gel methods for immunological analysis, Prog Allergy 5:1, 1958. 5. Hanson LA, and Winberg J: Breast milk and defense against infection in the newborn, Arch Dis Child 47:845, 1972 6. Ogra PL, and Karzon DT: The role of immunoglobulins in the mechanism of mucosal immunity to virus infection, Pediatr Clin North Am 17"385, 1970. 7. Tomasi TB, and Bienenstock JM: Secretory immunoglobulins, Adv Immunol 9:1, 1968. 8. Beisel WR, Pekarek RS, and Wannemacher RW Jr: In Hoekstra WG, Suttie JW, Ganther HE, and Mertz W, editors: Trace element metabolism in animals, Baltimore, 1974, University Park Press, p 217.
H a n d mirror cell acute lymphoblastic leukemia with B lymphoid surface markers To the Editor: Schumacher and Stass L' ~ have reported recently in this and other journals on the significance of"hand mirror" cells in acute lymphoblastic leukemia (ALL). The hand mirror cells in Schumacher's patient were unmarked or "null" cells. Recently we cared for a patient with the hand mirror variant of ALL whose blasts bore B lymphoid cell surface markers and who had a fulminating disease course. CASE REPORT
A 13-year-old white boy presented to Texas Children's Hospital with bone pain, anorexia, and fever. The spleen was palpable 2 cm below the left costal margin. The hemoglobin was 10.9 gm/dl, hematocrit 31.8%, platelet count 231,000/mm 3, and WBC count 6,700/mm:' with a differential leukocyte count of 48% neutrophils, 37% lymphocytes, 4% monocytes, and 11% eosinophils. Radial immuno-diffusion showed a decrease in IgA to 52 mg/dl (normal for age 81 to 232 mg/dl) but normal amounts of IgM and IgG. Bone marrow smears showed 84% blast forms, of which 71% were hand mirror cells. Cytochemical staining for pyronin methyl green, periodic acid-Schiff, chloroacetate and combined esterases, and peroxidase was negative, but 45% of the blasts exhibited small amounts of acid phosphatase. Surface marker determinations performed on Ficoll-triosil-separated marrow lymphoid cells (93% blasts) revealed the following: (1) 1.5% active E-R at 37~ and 4% total E-R at 4~ after overnight incubation; (2) 1.5% EAC-R; and (3) 74% of blasts demonstrated SMIg using a fluorescein-conjugated polyvalent antiserum. Experiments using monospecific antisera for IgG, IgA, IgM, and
Supported in part by USPH CA-O3161from the National Cancer Institute.
Volume 94 Number 3
F(ab')~ confirmed that the SMIg was an IgM which failed to elute following ten washings and overnight incubation at 37~ Doseresponse experiments measuring tritiated thymidine incorporation in response to mitogens showed normal responses to phytohemagglutinin (4,901 to 136,636 counts per minute [CPM]), but subnormal responses to concanavalin A (4,645 to 17,128 CPM), and pokeweed mitogen (10,402-20,628 CPM). A diagnosis of B cell ALL was established and chemotherapy was begun with vincristine, cyclophosphamide, and prednisone. Complete remission was obtained after a month of this therapy but was followed quickly by relapse in the bone marrow and central nervous system. Although a subsequent transitory response was obtained with high-dose cyclophosphamide, he failed to respond tO combinations of vincristine, cyclophosphamide, prednisone, high-dose methotrexate, doxorubicin, and cytosine arabinoside. The central nervous system leukemia also responded briefly to cranial radiotherapy and intrathecal chemotherapy. However, by the time of death the child had progressive bone marrow, central nervous system, and testicular leukemia as well as evidence of an encephalopathy. Postmortem examination confirmed the clinical diagnosis and revealed the continued presence of hand mirror cells. DISCUSSION The weak positivity for acid phosphatase, normally present in T lymphoblasts, the negative staining for pyronin methyl green, commonly present in B lymphoid neoplasms, and the patterns of mitogen responsiveness (response to phytohemagglutinin normally being associated with T lymphoid cells) are bothersome. However, the presence of SMIg on this child's blasts was unequivocal and indicates that these cells were of B lymphoid origin. In addition, the rapid progression and extra-medullary involvement of this boy's leukemia are characteristic of B lymphoid neoplasms in children2 Other authors 4 ~ have suggested that the presence of hand mirror cells connote a favorable prognosis and attributed this morphologic finding to amoeboid movement of hematopoietic cells. Our patient's hand mirror cells were B cells and his disease course was much more rapidly progressive than in the usual child with ALL. Hand mirror cell leukemia, like ALL in general, is a heterogeneous entity and lymphoid cell surface marker analysis may provide more useful prognostic information than the mere notation of the presence of a morphologic variant. William L. Nix, M.D. Nalini Mukhopadhyay, M.S. C Philip Steuber, M.D. Donald J. Fernbach, M.D. Hematology-Oncology Section Department of Pediatrics Baylor College of Medicine Texas Children's Hospital 6621 Fannin St. Houston, TX 77030
Editorial correspondence
499
detailed cytological and ultrastructural study with an analysis of the immunologic surface markers, Am J Hematol 4:67, 1978. 3. Flandrin G, Brouet JC, Daniel MT, and Preud'homme JL: Acute leukemia with Burkitt's tumor cells: A study of six cases with special reference to lymphocyte surface markers, Blood 45:183, 1975. 4. Sjogren U: Amoeboid movement configuration and mitotic indices of lymphoid cells from children with acute lymphoblastic leukemia, Lymphology 9:69, 1976. 5. Sjogren U, Norberg H, and Rydgren L: Amoeboid movement configuration in tumor cells of bone marrow smears from patients with leukemia, Acta Med Scand 201:381, 1977.
Rep& To the Editor: We have previously seen a case of Burkitt lymphoma which became leukemic and demonstrated 43% hand mirror cells (Burkitt ceUs) in the bone marrow.' This patient, like the one of Nix et al, had a rapid fulminating course and died in four months. Extensive surface marker studies revealed the cells to be B cells with an IgG surface marker. The hand mirror forms declined to 2% in the bone marrow prior to death in our patient, but these forms were abundant in the marrow at postmortem in the patient of Nix et al. Recent studies in our laboratories have indicated that the hand mirror configuration can be diminished by temperature and drugs. 2 However, the chemotherapy utilized in the above patient and ours was comparable. This suggests that therapy did not affect the hand mirror cells in their patient but we would be interested in the number of hand mirror cells at death. Age probably also plays an important role since we have now seen two young female adults and one middle-aged male with acute lymphoblastic leukemia, hand mirror variant, who have done extremely well. We entirely agree with Nix et al that acute lymphoblastic leukemia is a heterogeneous entity. Surface markers do indeed play an important role and may override any effect hand mirror cells may have on the disease. At this juncture many questions remain to be answered concerning hand mirror cells; more investigation and observations are indicated to bring the full significance of this unique cell into proper prospective. H. R. Schumacher S. A. Stass National Naval Medical Center and Uniformed Services University of the Health Sciences Bethesda, MD 20014 REFERENCES
REFERENCES
1. Schumacher HR, and Stass SA: Commentary: Significance of hand mirror cells, J PEDIATrt 93:335, 1978. 2. Stass SA, Perlin E, Jaffe ES, Simon DR, Creegan W J, Robinson JJ, Holloway ML, and Schumacher HR: Acute lymphoblastic leukemia-hand mirror cell variant: A
1. Schumacher HR, Rainey T, Simon D, Strong M, Creegan WJ, Holloway ML, and Stass SA: American Burkitt's lymphoma-hand mirror variant. A detailed cytological, ultrastructural, and immunologic marker investigation, Am J Clin Pathol 70:937, 1978. 2. Personal observation.