Short Communication
LEUKEMIA IN A CHILD WITH A HISTORY OF MEDULLOBLASTOMA
J.Blatt, MD Pediatr Hematol Oncol Downloaded from informahealthcare.com by Mcgill University on 11/22/14 For personal use only.
0 Division of Hematology-Oncology, Department of Pediatrics, The Children’s Hospital of Pittsburgh, Pittsburgh, PA 15213
1. Penchansky, MD
0
Department of Pathology, The Children’s Hospital of Pittsburgh,
Pittsburgh, PA 15213
C. Phebus, MD, and M. Horn, MD
Division of Hematology-Oncology, Department of Pediatrics, The Children’s Hospital of Pittsburgh, Pittsburgh, PA 15213
0 Leukemia of mixed lineage, was diagnosed in a 6.5yar-old boy with a history of medulloblastoma, 38 months after his initial cancer diagnosis. Therapy had included craniospinal radiation and nitrosourea-based chemotherapy. In addition, onset of leukemia was preceded by therapy with recombinant growth hormone for short stature. Although rare, leukemia is a treatment-related complicationfor patients with past brain tumors whose follow-up should therefre include surveillance with complete blood counts.
KEY WORDS: leukemia; medulloblastoma; second malknancy.
INTRODUCTION The occurrence of multiple sequential cancers in a single patient has been extensively reviewed. In the absence of an underlying predisposing condition such as neurofibromatosis or primary immunodeficiency, the second cancers generally have been thought to be treatment-related. Where the second cancer is leukemia, radiation, chemotherapy, and, more recently, administration of exogenous growth hormone (GH) 3-5 have been implicated. The primary cancer diagnosis may also be important since, despite similarities in treatment regimens, leukemia appears to be more likely to follow some cancers than others. Although brain tumors comprise the second largest category of pediatric cancers, occurring with an annual incidence of approximately 1,200 new cases per year in the United States, and although prolonged disease-free survival is achieved in many of these, the number of patients with secondary leukemias is small. Nonetheless, to emphasize that such patients are at risk, we describe a 6.5-year-old boy who developed a leukemia of mixed lineage 38 months after he was diagnosed as having medulloblastoma.
‘J
Pediatric he ma to log^ and Oncoloo, 8:77-82, 1991 Copyr;Sht 0 1991 by Hemisphere Publishinf Corporation
77
78
J. BLATT ET AL.
Pediatr Hematol Oncol Downloaded from informahealthcare.com by Mcgill University on 11/22/14 For personal use only.
CASE In July 1986, a medulloblastoma of the posterior fossa with extension to the suprasellar cistern was diagnosed in a 3-year-old white boy. Metastatic workup, including myelogram with cerebrospinal fluid (CSF) cytology and bone marrow aspirate and biopsy, was negative. Following resection of the posterior fossa component of the tumor, the child was treated with radiation (3600 cGy to the neuraxis with an 1800 cGy boost to the tumor bed) and chemotherapy (prednisone, vincristine, and lomustine [CCNU]) according to a previously described Childrens Cancer Study Group protocol.6 Serial computed tomography (CT) scans documented resolution of disease, and chemotherapy was completed in September 1987. Complications of therapy included prolonged pancytopenia which had resolved by May 1987, endocrinopathy for which the child had received synthroid and recombinant growth hormone (protropin 1.6 mg subcutaneously three times weekly) since January 1989, and mild learning disability. At a routine clinic visit in June 1989, the child, now almost 6.5 years old, was feeling well. However, 2 months later, following a brief diarrheal illness he developed intermittent low-grade fevers, pallor, and fatigue. Physical examination showed no hepatosplenomegaly, adenopathy, petechiae, or changes in neurological findings. Complete blood count showed hemoglobin 4 .O gm/ dL, white blood cell count 3,200/mm3, with an absolute neutrophil count of 330/mm3, 10% blasts, and a platelet count of 70,000/mm3. Periodic acidSchiff, myeloperoxidase, nonspecific esterase, and chloroacetoesterase stains were negative in the blast cells. An adequate bone marrow aspirate could not be obtained. A bone marrow biopsy showed a cellular marrow with areas of sclerosis. Multiple aggregates of cells with high nuclear-to-cytoplasmic ratio, round nuclei, prominent nucleoli, and poorly defined cellular borders were present. These foci of blast cells appeared to be intermixed with erythroid precursors and immature myeloid elements. Mature granulocytes were rare. Megakaryocytes were increased. Immunohistochemical stains were negative for neuron-specific enolase, common leukocyte antigen, and T- and B-cell surface markers, but positive for hemoglobin F, and the cells were thought possibly to be erythroid precursors. Cytogenetics done on peripheral blood demonstrated an abnormal karyotype in unstimulated culture (45,XY, - 7, t(3;3)(q23;q29)) but a normal 46,XY karyotype in PHA-stimulated culture. A repeat magnetic resonance imaging scan of the head and CSF obtained by lumbar puncture showed no tumor. A diagnosis of leukemia or preleukemia was felt to be likely but not definitive, and the child was managed symptomatically. Growth hormone therapy was suspended. Over the next month, the patient experienced several febrile episodes in the face of persistent neutropenia and thrombopenia, a progres-
LEUKEMIA SECONDARY TO MEDULLOBLASTOMA
sively rising peripheral blast count (up to 47% with WBC 4,00O/mm"), and recurrent anemia. A follow-up bone marrow aspirate and biopsy showed 50% blasts, a decrease in myeloid and erythroid precursors, and immunophenotyping of peripheral blood and aspirate material was consistent with a biphenotypic leukemia [lymphoid markers: CD2 (32% of blasts), CD7 (50%), 1 2 + (56%); myeloid markers CD33+ (55%), and CD34+ (57%)]. Double labeling of peripheral blood blasts with CD7 and CD33 demonstrated that more than half of the blasts marked with both monoclonal antibodies. Molecular analysis of blast cell DNA showed neither T-cell receptor nor immunoglobulin gene rearrangement. The patient was sequentially treated with antinonlymphocytic leukemia therapy (cytosine arabinoside and daunomycin) and anti-lymphocytic leukemia therapy (vincristine, prednisone, L'asparaginase, daunomycin) in anticipation of an allogeneic bone marrow transplant from an HLA-compatible sibling. However, he failed to achieve a remission and died.
+
Pediatr Hematol Oncol Downloaded from informahealthcare.com by Mcgill University on 11/22/14 For personal use only.
79
+
DISCUSSION Brain tumors have been reported in approximately 2% of children following treatment for acute lymphoblastic leukemia.' In contrast, reports of leukemia occurring in patients with a history of brain tumors have been few, making it difficult to generalize about what factors other than chance might contribute to this phenomenon. As shown in Table 1, secondary leukemias, both acute lymphocytic leukemia (ALL) and acute nonlymphocytic leukemia (ANLL), have been described in patients with a range of histologic types.J,8-12The present case seems to be the first of leukemia following medulloblastoma. Central nervous system tumors and hematopoietic malignancy have occurred in family members of patients with secondary leukemias, suggesting that there may be shared oncogenic potential between the 13 two organ systems. O n the other hand, in this group of patients, a relationship to therapy seems more likely. Leukemia has occurred in patients treated with radiation therapy, chemotherapy, or both. Although chemotherapy usually has been polypharmacy, one patient was treated with C C N U alone,g and the nitrosoureas seem to be common to all the reported regimens. Certain chromosomal abnormalities, including the monosomy 7 observed in the blast cells of our patient, appear to be characteristic of chemotherapy-related secondary leukemias. The interval between initial diagnosis and documentation of leukemia has been as short as 15 months and as long as 81 months. Some but not all secondary leukemias have appeared in patients who had experienced significant bone marrow toxicity which had either resolved prior to or appeared together with the onset of leukemia. That our patient is the only example of a mixed-lineage leukemia (simultaneous expression of myeloid
0
W
-
CCNU/ VM26 CCNU
Malignant ependymoma
Germ cell tumor ( C N S ) ~
“Malignant tumor” occiput
Astrocytoma, grade IV
Anaplastic astrocytoma
Meningioma, angioblastic
Oligodendroglioma
M
M
F
M
F
F
F
12
18
30
39
42
56
60
7
8
9
10
ANLL
+
AMML AMML
-
AMML (RAEB)
+
-
APL
ALL
APL
Mixed lineage
+
+ + +
AMML
ALL
Leukemia (L)
+ +
Radio-
51 mo
81 mo
43 mo
51 mo
38 mo
6 Y’
1.5 yr
83 mo
15 mo
36 mo
Interval between diagnosis of BT and L
12
11
3, 5
8
Present case
10
4
Reference
~
-.
‘Age given in years, months, at time of development of leukemia. k H administered following diagnosis of brain tumor. Note: mo, months; yr, years; CCNU, lomustine; BCNU, carmustine; V, vincristine: Mtx, methotrexate; Dec, decadron; VP16, etoposide; P, prednisone; not given; ALL. acute lymphocytic leukemia; ANLL, acute VM26, teniposide; DDMP, 2,4-diamin0-5-4~-dichlorophenyl-6-methylpyrimidine; nonlymphocytic leukemia; APL, acute promyelocytic leukemia; AMML, acute myelomonocytic leukemia; RAEB. refractory anemia with excess blasts; Adr, Adriamycin.
CCNU Procarbazine VM26 Adr
CCNU VP16 DDMP Dec
CCNU VM26
CCNU V P
Medulloblastoma
M
6.6
3
BCNU V Mtx Dec VP16
Glioblastoma multiforme
M
-
Chemo-
5
2
Brain NmOr (BT)
Astrocytoma, pilocyticb
Sex
M
4.2
Age“
1
Patient
Therapy
TABLE 1 Review of Literature on Patients with Leukemia Following Treatment of Brain Tumors
Pediatr Hematol Oncol Downloaded from informahealthcare.com by Mcgill University on 11/22/14 For personal use only.
Pediatr Hematol Oncol Downloaded from informahealthcare.com by Mcgill University on 11/22/14 For personal use only.
LEUKEMIA SECONDARY TO MEDULLOBLASTOMA
81
and lymphoid surface markers)14 may reflect the exhaustive immunophenotyping done in this case. None of the features of the secondary leukemias in these patients is specific for patients with a history of brain tumors. The more frequently described leukemias secondary to Hodgkin’s disease, multiple myeloma, or ovarian carcinoma have similar characteristics, including abnormal leukemia cell karyotypes. Although nitrosoureas are not extensively used for treatment of those diseases, other alkylating agents do seem to play a causative role. It is of interest that M O P P (Mechlorethamine, vincristine, prednisone, procarbazine), which has been strongly associated with the development of secondary leukemias following Hodgkin’s disease, has been used to treat patients with medulloblastoma. Presumably the lack of reports of secondary leukemias in brain tumor patients treated with that regimen reflects the small number of patients involved. One confounding feature in the present case is the use of exogenous growth hormone for short stature associated with his brain tumor. I n addition to several cases of acute leukemia developing after GH therapy in children with brain tumors (some of whom also received chemotherapy or radiothera ~ y ) , there ~ - ~ have been reports of acute leukemia in children who had not been treated for brain tumors but who had received G H for short stature of other e t i o l ~ g y . ’ * ~However, ’ ’ ~ ’ ’ ~ in contrast to the recombinant G H with which our patient was treated, these other patients had received pituitary G H . Those leukemias most often have been lymphoid although myeloid leukemia has been reported. Causality, either as an “initiating” or “promoting” agent, has not been proven. In the present case, the past exposure to known chemical leukemogens and the chromosomal abnormality in the blast cells make G H an unlikely contributing factor, in our opinion. It seems reasonable that follow-up of patients with malignant brain tumors should include serial, perhaps yearly, blood counts. It is unlikely that our patient already had leukemia at the time of initiation of growth hormone, 6 months before diagnosis of a second malignancy. However, because it is possible that in future cases the interval between the initiation of growth hormone and the development of leukemia will be shorter, and in order to avoid unfairly implicating growth hormone as the cause of the leukemia, it may be useful to obtain a baseline bone marrow aspirate. Although a leukemia-free bone marrow would not be definitive, a positive bone marrow aspirate might be useful in this regard. Outcome following development of secondary leukemias, regardless of the primary tumor, has been poor. However, recent reports of prolonged survival after bone marrow transplantation” make aggressive surveillance appropriate.
82
I. BLATT ET AL.
Pediatr Hematol Oncol Downloaded from informahealthcare.com by Mcgill University on 11/22/14 For personal use only.
REFERENCES I . Meadows AT. Second malignant neoplasms. Clin Oncol. 1985;4:247-261. 2. Li FP. Second malignant tumors after cancer in childhood. Cancer 1977;40:1899-1902. 3. Sasaki U , Hara M , Watanabe S. Occurrence of acute lymphoblastic leukemia in a boy treated with growth hormone for growth retardation after irradiation to the brain tumor. Jpn J Clin Oncol. 1988;18:8 1-84. 4. Redman GP, Shu S, Norris D. Leukaemia and growth hormone. Lancet. 1988;1:1335. 5. Watanabe S, Tsunematsu Y, Fujimoto J , et al. Leukemia in patients treated with growth hormone. Lancet. 1988; 1:1 159. 6. Allen JC. Childhood brain tumors: current status of clinical trials in newly diagnosed and recurrent disease. Pediatr Clin North Am. 1985;32:633-651, 7. Albo V, Miller D, Leiken S, et al. Nine brain tumors as a late effect in children “cured” of acute lymphoblastic leukemia from a single protocol study. Proc Am Sac CIin Oncol. 1985;4:172. 8. Pai M R , Advani S H , Gopal R, et al. Acute leukemia following malignant ependymoma: a case report. ,J Surg Oncol. 1985;29:1-4. 9. Cohen RJ, Wiernik PH, Walker MD. Acute non-lymphocytic leukemia associated with nitrosourea therapy: report of two cases. Cancer Treat Rep. 1976;1257-1261. 10. Vogel SE. Acute leukemia complicating treatment of glioblastoma multiforme. Cancer 1978;333-336. 11. Genot JY, Krulik M , Poisson M, et al. Two cases of acute leukemia following treatment of malignant glioma. Cancn: 1983;52:222-226. 12. Hildebrand J , Malarme M, Flament-Durand J , et al. Acute non-lymphoblastic leukemia in a patient treated for brain tumor. Arch Neuro. 1982;39:664-665. 13. Li FP, Tucker MA, Fraumeni J F J . Childhood cancer in sibs. J Pediatr. 1976;88:419-423, 14. Mirro J , Zipf TF, Pui C H , et al. Acute mixed lineage leukemia. Clinicopathological correlations and prognostic significance. Blood. 1985;60:1115-1123. 15. Ogawa M , Mori 0, Kamigo T, et al. The occurrence of acute lymphoblastic leukemia shortly alter the cessation of human growth hormone therapy. ,/pn f Clin Oncol. 1988;18:255-260. 16. Endo M , Kaneko Y, Shikano T, et al. Possible association of human growth hormone treatment with an occurrence of acute myeloblastic leukemia with an inversion of chromosome 3 in a child with pituitary dwarfism. Med Pediatr Oncol. 1988;16:45-47. 17. Geller RB, Vogelsang GB, Wingard J R , et al. Successful marrow transplantation for acute myelocytic leukemia following therapy for Hodgkin’s disease. J Clin Oncol. 1988;6:1558-1561,
Received May 16, 1990 Accepted August 23, 19.90 Requesf reprints from J . Blaft.
LEUKEMIA IN A CHILD WITH A HISTORY OF MEDULLOBLASTOMA
J.Blatt, MD Pediatr Hematol Oncol Downloaded from informahealthcare.com by Mcgill University on 11/22/14 For personal use only.
0 Division of Hematology-Oncology, Department of Pediatrics, The Children’s Hospital of Pittsburgh, Pittsburgh, PA 15213
1. Penchansky, MD
0
Department of Pathology, The Children’s Hospital of Pittsburgh,
Pittsburgh, PA 15213
C. Phebus, MD, and M. Horn, MD
Division of Hematology-Oncology, Department of Pediatrics, The Children’s Hospital of Pittsburgh, Pittsburgh, PA 15213
0 Leukemia of mixed lineage, was diagnosed in a 6.5yar-old boy with a history of medulloblastoma, 38 months after his initial cancer diagnosis. Therapy had included craniospinal radiation and nitrosourea-based chemotherapy. In addition, onset of leukemia was preceded by therapy with recombinant growth hormone for short stature. Although rare, leukemia is a treatment-related complicationfor patients with past brain tumors whose follow-up should therefre include surveillance with complete blood counts.
KEY WORDS: leukemia; medulloblastoma; second malknancy.
INTRODUCTION The occurrence of multiple sequential cancers in a single patient has been extensively reviewed. In the absence of an underlying predisposing condition such as neurofibromatosis or primary immunodeficiency, the second cancers generally have been thought to be treatment-related. Where the second cancer is leukemia, radiation, chemotherapy, and, more recently, administration of exogenous growth hormone (GH) 3-5 have been implicated. The primary cancer diagnosis may also be important since, despite similarities in treatment regimens, leukemia appears to be more likely to follow some cancers than others. Although brain tumors comprise the second largest category of pediatric cancers, occurring with an annual incidence of approximately 1,200 new cases per year in the United States, and although prolonged disease-free survival is achieved in many of these, the number of patients with secondary leukemias is small. Nonetheless, to emphasize that such patients are at risk, we describe a 6.5-year-old boy who developed a leukemia of mixed lineage 38 months after he was diagnosed as having medulloblastoma.
‘J
Pediatric he ma to log^ and Oncoloo, 8:77-82, 1991 Copyr;Sht 0 1991 by Hemisphere Publishinf Corporation
77
78
J. BLATT ET AL.
Pediatr Hematol Oncol Downloaded from informahealthcare.com by Mcgill University on 11/22/14 For personal use only.
CASE In July 1986, a medulloblastoma of the posterior fossa with extension to the suprasellar cistern was diagnosed in a 3-year-old white boy. Metastatic workup, including myelogram with cerebrospinal fluid (CSF) cytology and bone marrow aspirate and biopsy, was negative. Following resection of the posterior fossa component of the tumor, the child was treated with radiation (3600 cGy to the neuraxis with an 1800 cGy boost to the tumor bed) and chemotherapy (prednisone, vincristine, and lomustine [CCNU]) according to a previously described Childrens Cancer Study Group protocol.6 Serial computed tomography (CT) scans documented resolution of disease, and chemotherapy was completed in September 1987. Complications of therapy included prolonged pancytopenia which had resolved by May 1987, endocrinopathy for which the child had received synthroid and recombinant growth hormone (protropin 1.6 mg subcutaneously three times weekly) since January 1989, and mild learning disability. At a routine clinic visit in June 1989, the child, now almost 6.5 years old, was feeling well. However, 2 months later, following a brief diarrheal illness he developed intermittent low-grade fevers, pallor, and fatigue. Physical examination showed no hepatosplenomegaly, adenopathy, petechiae, or changes in neurological findings. Complete blood count showed hemoglobin 4 .O gm/ dL, white blood cell count 3,200/mm3, with an absolute neutrophil count of 330/mm3, 10% blasts, and a platelet count of 70,000/mm3. Periodic acidSchiff, myeloperoxidase, nonspecific esterase, and chloroacetoesterase stains were negative in the blast cells. An adequate bone marrow aspirate could not be obtained. A bone marrow biopsy showed a cellular marrow with areas of sclerosis. Multiple aggregates of cells with high nuclear-to-cytoplasmic ratio, round nuclei, prominent nucleoli, and poorly defined cellular borders were present. These foci of blast cells appeared to be intermixed with erythroid precursors and immature myeloid elements. Mature granulocytes were rare. Megakaryocytes were increased. Immunohistochemical stains were negative for neuron-specific enolase, common leukocyte antigen, and T- and B-cell surface markers, but positive for hemoglobin F, and the cells were thought possibly to be erythroid precursors. Cytogenetics done on peripheral blood demonstrated an abnormal karyotype in unstimulated culture (45,XY, - 7, t(3;3)(q23;q29)) but a normal 46,XY karyotype in PHA-stimulated culture. A repeat magnetic resonance imaging scan of the head and CSF obtained by lumbar puncture showed no tumor. A diagnosis of leukemia or preleukemia was felt to be likely but not definitive, and the child was managed symptomatically. Growth hormone therapy was suspended. Over the next month, the patient experienced several febrile episodes in the face of persistent neutropenia and thrombopenia, a progres-
LEUKEMIA SECONDARY TO MEDULLOBLASTOMA
sively rising peripheral blast count (up to 47% with WBC 4,00O/mm"), and recurrent anemia. A follow-up bone marrow aspirate and biopsy showed 50% blasts, a decrease in myeloid and erythroid precursors, and immunophenotyping of peripheral blood and aspirate material was consistent with a biphenotypic leukemia [lymphoid markers: CD2 (32% of blasts), CD7 (50%), 1 2 + (56%); myeloid markers CD33+ (55%), and CD34+ (57%)]. Double labeling of peripheral blood blasts with CD7 and CD33 demonstrated that more than half of the blasts marked with both monoclonal antibodies. Molecular analysis of blast cell DNA showed neither T-cell receptor nor immunoglobulin gene rearrangement. The patient was sequentially treated with antinonlymphocytic leukemia therapy (cytosine arabinoside and daunomycin) and anti-lymphocytic leukemia therapy (vincristine, prednisone, L'asparaginase, daunomycin) in anticipation of an allogeneic bone marrow transplant from an HLA-compatible sibling. However, he failed to achieve a remission and died.
+
Pediatr Hematol Oncol Downloaded from informahealthcare.com by Mcgill University on 11/22/14 For personal use only.
79
+
DISCUSSION Brain tumors have been reported in approximately 2% of children following treatment for acute lymphoblastic leukemia.' In contrast, reports of leukemia occurring in patients with a history of brain tumors have been few, making it difficult to generalize about what factors other than chance might contribute to this phenomenon. As shown in Table 1, secondary leukemias, both acute lymphocytic leukemia (ALL) and acute nonlymphocytic leukemia (ANLL), have been described in patients with a range of histologic types.J,8-12The present case seems to be the first of leukemia following medulloblastoma. Central nervous system tumors and hematopoietic malignancy have occurred in family members of patients with secondary leukemias, suggesting that there may be shared oncogenic potential between the 13 two organ systems. O n the other hand, in this group of patients, a relationship to therapy seems more likely. Leukemia has occurred in patients treated with radiation therapy, chemotherapy, or both. Although chemotherapy usually has been polypharmacy, one patient was treated with C C N U alone,g and the nitrosoureas seem to be common to all the reported regimens. Certain chromosomal abnormalities, including the monosomy 7 observed in the blast cells of our patient, appear to be characteristic of chemotherapy-related secondary leukemias. The interval between initial diagnosis and documentation of leukemia has been as short as 15 months and as long as 81 months. Some but not all secondary leukemias have appeared in patients who had experienced significant bone marrow toxicity which had either resolved prior to or appeared together with the onset of leukemia. That our patient is the only example of a mixed-lineage leukemia (simultaneous expression of myeloid
0
W
-
CCNU/ VM26 CCNU
Malignant ependymoma
Germ cell tumor ( C N S ) ~
“Malignant tumor” occiput
Astrocytoma, grade IV
Anaplastic astrocytoma
Meningioma, angioblastic
Oligodendroglioma
M
M
F
M
F
F
F
12
18
30
39
42
56
60
7
8
9
10
ANLL
+
AMML AMML
-
AMML (RAEB)
+
-
APL
ALL
APL
Mixed lineage
+
+ + +
AMML
ALL
Leukemia (L)
+ +
Radio-
51 mo
81 mo
43 mo
51 mo
38 mo
6 Y’
1.5 yr
83 mo
15 mo
36 mo
Interval between diagnosis of BT and L
12
11
3, 5
8
Present case
10
4
Reference
~
-.
‘Age given in years, months, at time of development of leukemia. k H administered following diagnosis of brain tumor. Note: mo, months; yr, years; CCNU, lomustine; BCNU, carmustine; V, vincristine: Mtx, methotrexate; Dec, decadron; VP16, etoposide; P, prednisone; not given; ALL. acute lymphocytic leukemia; ANLL, acute VM26, teniposide; DDMP, 2,4-diamin0-5-4~-dichlorophenyl-6-methylpyrimidine; nonlymphocytic leukemia; APL, acute promyelocytic leukemia; AMML, acute myelomonocytic leukemia; RAEB. refractory anemia with excess blasts; Adr, Adriamycin.
CCNU Procarbazine VM26 Adr
CCNU VP16 DDMP Dec
CCNU VM26
CCNU V P
Medulloblastoma
M
6.6
3
BCNU V Mtx Dec VP16
Glioblastoma multiforme
M
-
Chemo-
5
2
Brain NmOr (BT)
Astrocytoma, pilocyticb
Sex
M
4.2
Age“
1
Patient
Therapy
TABLE 1 Review of Literature on Patients with Leukemia Following Treatment of Brain Tumors
Pediatr Hematol Oncol Downloaded from informahealthcare.com by Mcgill University on 11/22/14 For personal use only.
Pediatr Hematol Oncol Downloaded from informahealthcare.com by Mcgill University on 11/22/14 For personal use only.
LEUKEMIA SECONDARY TO MEDULLOBLASTOMA
81
and lymphoid surface markers)14 may reflect the exhaustive immunophenotyping done in this case. None of the features of the secondary leukemias in these patients is specific for patients with a history of brain tumors. The more frequently described leukemias secondary to Hodgkin’s disease, multiple myeloma, or ovarian carcinoma have similar characteristics, including abnormal leukemia cell karyotypes. Although nitrosoureas are not extensively used for treatment of those diseases, other alkylating agents do seem to play a causative role. It is of interest that M O P P (Mechlorethamine, vincristine, prednisone, procarbazine), which has been strongly associated with the development of secondary leukemias following Hodgkin’s disease, has been used to treat patients with medulloblastoma. Presumably the lack of reports of secondary leukemias in brain tumor patients treated with that regimen reflects the small number of patients involved. One confounding feature in the present case is the use of exogenous growth hormone for short stature associated with his brain tumor. I n addition to several cases of acute leukemia developing after GH therapy in children with brain tumors (some of whom also received chemotherapy or radiothera ~ y ) , there ~ - ~ have been reports of acute leukemia in children who had not been treated for brain tumors but who had received G H for short stature of other e t i o l ~ g y . ’ * ~However, ’ ’ ~ ’ ’ ~ in contrast to the recombinant G H with which our patient was treated, these other patients had received pituitary G H . Those leukemias most often have been lymphoid although myeloid leukemia has been reported. Causality, either as an “initiating” or “promoting” agent, has not been proven. In the present case, the past exposure to known chemical leukemogens and the chromosomal abnormality in the blast cells make G H an unlikely contributing factor, in our opinion. It seems reasonable that follow-up of patients with malignant brain tumors should include serial, perhaps yearly, blood counts. It is unlikely that our patient already had leukemia at the time of initiation of growth hormone, 6 months before diagnosis of a second malignancy. However, because it is possible that in future cases the interval between the initiation of growth hormone and the development of leukemia will be shorter, and in order to avoid unfairly implicating growth hormone as the cause of the leukemia, it may be useful to obtain a baseline bone marrow aspirate. Although a leukemia-free bone marrow would not be definitive, a positive bone marrow aspirate might be useful in this regard. Outcome following development of secondary leukemias, regardless of the primary tumor, has been poor. However, recent reports of prolonged survival after bone marrow transplantation” make aggressive surveillance appropriate.
82
I. BLATT ET AL.
Pediatr Hematol Oncol Downloaded from informahealthcare.com by Mcgill University on 11/22/14 For personal use only.
REFERENCES I . Meadows AT. Second malignant neoplasms. Clin Oncol. 1985;4:247-261. 2. Li FP. Second malignant tumors after cancer in childhood. Cancer 1977;40:1899-1902. 3. Sasaki U , Hara M , Watanabe S. Occurrence of acute lymphoblastic leukemia in a boy treated with growth hormone for growth retardation after irradiation to the brain tumor. Jpn J Clin Oncol. 1988;18:8 1-84. 4. Redman GP, Shu S, Norris D. Leukaemia and growth hormone. Lancet. 1988;1:1335. 5. Watanabe S, Tsunematsu Y, Fujimoto J , et al. Leukemia in patients treated with growth hormone. Lancet. 1988; 1:1 159. 6. Allen JC. Childhood brain tumors: current status of clinical trials in newly diagnosed and recurrent disease. Pediatr Clin North Am. 1985;32:633-651, 7. Albo V, Miller D, Leiken S, et al. Nine brain tumors as a late effect in children “cured” of acute lymphoblastic leukemia from a single protocol study. Proc Am Sac CIin Oncol. 1985;4:172. 8. Pai M R , Advani S H , Gopal R, et al. Acute leukemia following malignant ependymoma: a case report. ,J Surg Oncol. 1985;29:1-4. 9. Cohen RJ, Wiernik PH, Walker MD. Acute non-lymphocytic leukemia associated with nitrosourea therapy: report of two cases. Cancer Treat Rep. 1976;1257-1261. 10. Vogel SE. Acute leukemia complicating treatment of glioblastoma multiforme. Cancer 1978;333-336. 11. Genot JY, Krulik M , Poisson M, et al. Two cases of acute leukemia following treatment of malignant glioma. Cancn: 1983;52:222-226. 12. Hildebrand J , Malarme M, Flament-Durand J , et al. Acute non-lymphoblastic leukemia in a patient treated for brain tumor. Arch Neuro. 1982;39:664-665. 13. Li FP, Tucker MA, Fraumeni J F J . Childhood cancer in sibs. J Pediatr. 1976;88:419-423, 14. Mirro J , Zipf TF, Pui C H , et al. Acute mixed lineage leukemia. Clinicopathological correlations and prognostic significance. Blood. 1985;60:1115-1123. 15. Ogawa M , Mori 0, Kamigo T, et al. The occurrence of acute lymphoblastic leukemia shortly alter the cessation of human growth hormone therapy. ,/pn f Clin Oncol. 1988;18:255-260. 16. Endo M , Kaneko Y, Shikano T, et al. Possible association of human growth hormone treatment with an occurrence of acute myeloblastic leukemia with an inversion of chromosome 3 in a child with pituitary dwarfism. Med Pediatr Oncol. 1988;16:45-47. 17. Geller RB, Vogelsang GB, Wingard J R , et al. Successful marrow transplantation for acute myelocytic leukemia following therapy for Hodgkin’s disease. J Clin Oncol. 1988;6:1558-1561,
Received May 16, 1990 Accepted August 23, 19.90 Requesf reprints from J . Blaft.
