Volume 120 Number 5
from 1986 to 1988. Of the 226 patients, 14 (6.19%) had a predated neurologic disorder: cerebral palsy, developmental delay, or Down syndrome. Recently we reported on the epidemiology of hemolytic-uremic syndrome in the northeast of Scotland from 1978 to 1989. 2 On further analysis of our data and on including nine patients admitted in 1990 and the first half of 1991, we found that six patients (16.6%) of a total of 36 had a predated neurologic disorder; two had cerebral palsy, hydrocephalus, and ventriculoperitoneal shunts, two had gross developmental delay, one had dyslexia, and one patient had Down syndrome. The combined total of our patients and those reported by Rowe et al. shows that 5 (1.9%) of 262 patients had Down syndrome, an incidence that is at least 10 times higher than the prevalence of Down syndrome in the general population (1.14/1000).3 Furthermore, 4.63% had cerebral palsy and developmental disorders, an incidence that is also at least 10 times higher than in the general population. It is not possible to draw any firm conclusions from this observation. However, eating habits and possibly poor personal hygiene in children with mental retardation and motor disabilities may have a role in the higher-than-expected incidence of infectious diseases and, possibly, the hemolytic-uremic syndrome. Studies of a larger number of patients are necessary to evaluate this observation. L A. Abu-Arafeh, M R C P L A. Auchterlonie, M R C P P. J. Small, FRCP Royal Aberdeen Children's Hospital Aberdeen AB9 2ZG, United Kingdom REFERENCES
1. Rowe PC, Orrbine E, Wells GA, McLaine PN, and members of the Canadian Pediatric Kidney Disease Reference Center. Epidemiology of hemolytic-uremic syndrome in Canadian children from 1986 to 1988. J PEDIATR 1991;119:218-24. 2. Abu-Arafeh IA, Small P J, Youngson GG, Auchterlonie IA. Haemolytic-uraemic syndrome in the defined population of north-east of Scotland. Eur J Pediatr 1991;150:279-81. 3. Kinsbourne M. Disorders of mental development. In: Menkes JF, ed. Textbook of child neurology. Philadelphia: Lea & Febiger, 1990:770.
Chemotherapy for lymphoid malignancy in immunosuppressed
patients To the Editor." Dr. Malatack and his colleagues (J PEt)IATR 1991;118:667-75) provided a useful review of "Epstein-Barr virus-driven lymphoproliferative disease (LPD) in patients receiving cyclosporine after liver transplantation." In particular, their working classification of LPD in these patients is logical and should be useful in future publications. The use of chemotherapy in these patients deserves further comment. If our reading is correct, only three patients in the Malatack
E d i t o r i a l correspondence
835
series received "cytotoxic" chemotherapy: two of these children died (one of complications of therapy and one of progressive disease), and the third patient was still receiving treatment at the time of writing. These results are not particularly encouraging, and readers might be excused for believing that chemotherapy has only a small role. Our experience, in a single patient, is different. This 6-year-old boy had cardiac transplantation in July 1988 for rapidly progressive idiopathic cardiomyopathy. Two years later, right cervical and right axillary lymphadenopathy developed; the axillary node mass infiltrated the adjacent chest wall. Biopsy, in August 1990, showed a malignant non-Hodgkin lymphoma. The tumor was positive, by in situ hybridization, with an Epstein-Barr-virus DNA probe but, at this stage, showed no immunoglobulin light-chain restriction (i.e., was polyclonal). Initially, there was a good response to reduction of the cyclosporine dose and two courses of intravenously administered acyclovir, but in September 1990 recurrent lymphadenopathy, a right subscapular mass, hepatomegaly, multiple subcutaneous masses, and signs of an upper motor neuron lesion of the legs developed. Myelography showed extradural compression from the third cervical vertebra to the tenth lumbar vertebra, with complete blockage at the fifth cervical vertebra. Ultrasonography suggested focal involvement of the liver by lymphoma. The bone marrow and cerebrospinal fluid were not involved. 9 Laminectomy was carried out and all visible tumor removed. There was no response to further reduction of cyclosporine or to intravenously administered acyclovir. In December 1990, another tumor biopsy from a right maxillary lesion again showed malignant nonHodgkin lymphoma, but there was more light-chain restriction, with a rearranged IgHJ region band, indicating elonal proliferation. Courses of interferon alfa, first alone and then in combination with interleukin-2, had only a transient effect, the minor progressed at many sites, and the child became cachectic. In March 1991 we commenced combination chemotherapy, using the so-called GRAB protocol (good risk and Burkitt [lymphoma]). l The child first received two courses of cyclophosphamide, doxorubicin, oncovin, and prednisolone, followed by rotating combinations of chemotherapy including "CNS-directed therapy" with intravenous infusion of methotrexate and six intrathecal injections of methotrexate. There was a good tumor response, and at the end of 6 months of treatment (September 1991) the child was in complete remission, although handicapped by symptoms of a right brachial plexus compression because of the previous chest wall mass. Therapy has now been discontinued for 5 months and the child is still in complete remission. Although anecdotal, this experience shows that at least some Epstein-Barr virus-driven LPD is chemoresponsive and that even very bulky disease can be successfully treated, at least in the short term. We suspect that when clinicians contemplate chemotherapy for immunosuppressed patients, such as those described by Malatack and colleagues, they are concerned about the myelosuppression and added immunosuppression that chemotherapy will cause. This may lead them to use "gentler" regimens than are usually used to treat "nonimmunosuppressed" patients with B-cell non-Hodgkin lymphoma. Our patient tolerated his treatment without any life-threatening episodes of infection. We therefore support the suggestion, made by Malatack et al., that when cyclosporine dose
836
Editorial correspondence
reduction fails to control monoclonal LPD in these patients, a suitably "aggressive" regimen, such as the GRAB protocol, should be used.
Jon Pritchard, FRCP Consultant Paediatric Oncologist Department of Haematology and Oncology Ayad Atra, MRCP Clinical Research Fellow/Senior Registrar Department of Haematology and Oncology Hospitals for Sick Children Great Ormond Street London WC1N 3JH, England
The Journal of Pediatrics May 1992
with chemotherapy in our series. However, both patients ultimately had a relapse. Finally, in the last paragraph of our article we raised the concern that the use of the new immunosuppressive agent FK506 would likely have the same complication of lymphoproliferative disease as did cyclosporine. Since the publication of that article, we have seen a number of patients who have had various presentations of lymphoproliferative disease and whose immunosuppressive therapy was with FK506 and steroids only.
J. Jeffrey Malatack, MD Associate Professor of Pediatrics Children's Hospital of Pittsburgh University of Pittsburgh Pittsburgh, PA 15213-2583
We thank Dr. Rosemary Radley-Smith for referring the patient to us. REFERENCE
1. A1-Attar A, Pritchard J, A1-Saleem T, A1-Naimi M, Alash N, Atra A. Intensive chemotherapy for non-localised Burkitt's lymphoma. Arch Dis Child 1986;61:1013-9.
Reply To the Editor." The comments of Drs. Pritchard and Atra in response to our article are not at odds with our conclusions. However, a few comments require a response. Three children received chemotherapy in our series; a Table II footnote points out that of the three patients who received chemotherapy, one received it so late in the course that efficacy could not be evaluated. Of the two remaining patients, both went into clinical remission. The second patient had a relatively prolonged remission before his relapse. The patient described in the letter by Pritchard and Atra would have met our criteria for initiating chemotherapy. As noted in the second to the final paragraph of our article, "intervention in the patients with a lymphomatous presentation, if disease progresses without immunosuppressive therapy, should conform to current approaches to the management of disseminated Burkitt lymphoma, including immunomodulation, chemotherapy, or bone marrow transplantation." Drs. Pritchard and Atra properly selected their patients for chemotherapy. However, their comments, meant to avoid what they view as a misleading implication of our article, should not mislead the reader in the opposite direction. We are, in fact, concerned that the further immunosuppression occurring with chemotherapy could lead to an adverse outcome for those patients with lymphoproliferative disease who are still immune responsive (i.e., those whose disease potentially could regress when normal cytotoxic T-ceU function is allowed to occur). We believe that it is important that the patient to be given chemotherapy be appropriately selected, as was Pritchard and Atra's patient, from the group of patients with lymphoproliferative disease. These are patients with monoclonal monomorphic disease whose tumor progresses in the absence of immunosuppression. Monoclonal monomorphic disease that progresses despite elimination of immune suppression should be viewed as a lymphoma and treated as such. We remain interested in the outcome of Pritchard and Atra's patient because, as noted, a brief remission in one patient and a prolonged remission in another was obtainable
Thyroid dysfunction after cranial irradiation To the Editor: One mechanism of thyroid dysfunction caused by cranial irradiation not considered by Ogilvy-Stuart et al. 1 is secretion of immunoreactive but biologically hypoactive thyroid-stimulating hormone. 2 This might be mistaken for mild primary hypothyroidism or "compensated hypothyroidism" and attributed to direct thyroid damage. A simple way of attempting to detect this condition is to look for the absence of a rise in the triiodothyronine level at the end of a thyrotropin releasing hormone test, but definitive evidence could be obtained by testing thyrotropin for bioactivity or receptor binding. 2
Lyman A. Page, MD Director, Waterbury Regional Department of Pediatrics Professor of Pediatrics University of Connecticut School of Medicine Waterbury, CT 06721
REFERENCES
1. Ogilvy-Stuart AL, Shalet SM, Gattamaneni HR. Thyroid function after treatment of brain tumors in children. J PEonATe 1991;119:733-7. 2. Beck-Peccoz P, Amr S, Menzezes-Ferreira MM, et al. Decreased receptor binding of biologically inactive thyrotropin in central hypothyroidism. N Engl J Med 1985;312:1085-7.
Reply To the Editor." We completely agree with the suggestion that one explanation for thyroid dysfunction after cranial irradiation might be secretion of immunoreactive but biologically inactive thyroid-stimulating hormone. As far back as 1977 we made the very same suggestion I but did not actively pursue this line of research. We note, however, that Lee et al. 2 recently described central hypothalamic hypothyroidism with thyroid-stimulating hormone of decreased bioactivity
from 1986 to 1988. Of the 226 patients, 14 (6.19%) had a predated neurologic disorder: cerebral palsy, developmental delay, or Down syndrome. Recently we reported on the epidemiology of hemolytic-uremic syndrome in the northeast of Scotland from 1978 to 1989. 2 On further analysis of our data and on including nine patients admitted in 1990 and the first half of 1991, we found that six patients (16.6%) of a total of 36 had a predated neurologic disorder; two had cerebral palsy, hydrocephalus, and ventriculoperitoneal shunts, two had gross developmental delay, one had dyslexia, and one patient had Down syndrome. The combined total of our patients and those reported by Rowe et al. shows that 5 (1.9%) of 262 patients had Down syndrome, an incidence that is at least 10 times higher than the prevalence of Down syndrome in the general population (1.14/1000).3 Furthermore, 4.63% had cerebral palsy and developmental disorders, an incidence that is also at least 10 times higher than in the general population. It is not possible to draw any firm conclusions from this observation. However, eating habits and possibly poor personal hygiene in children with mental retardation and motor disabilities may have a role in the higher-than-expected incidence of infectious diseases and, possibly, the hemolytic-uremic syndrome. Studies of a larger number of patients are necessary to evaluate this observation. L A. Abu-Arafeh, M R C P L A. Auchterlonie, M R C P P. J. Small, FRCP Royal Aberdeen Children's Hospital Aberdeen AB9 2ZG, United Kingdom REFERENCES
1. Rowe PC, Orrbine E, Wells GA, McLaine PN, and members of the Canadian Pediatric Kidney Disease Reference Center. Epidemiology of hemolytic-uremic syndrome in Canadian children from 1986 to 1988. J PEDIATR 1991;119:218-24. 2. Abu-Arafeh IA, Small P J, Youngson GG, Auchterlonie IA. Haemolytic-uraemic syndrome in the defined population of north-east of Scotland. Eur J Pediatr 1991;150:279-81. 3. Kinsbourne M. Disorders of mental development. In: Menkes JF, ed. Textbook of child neurology. Philadelphia: Lea & Febiger, 1990:770.
Chemotherapy for lymphoid malignancy in immunosuppressed
patients To the Editor." Dr. Malatack and his colleagues (J PEt)IATR 1991;118:667-75) provided a useful review of "Epstein-Barr virus-driven lymphoproliferative disease (LPD) in patients receiving cyclosporine after liver transplantation." In particular, their working classification of LPD in these patients is logical and should be useful in future publications. The use of chemotherapy in these patients deserves further comment. If our reading is correct, only three patients in the Malatack
E d i t o r i a l correspondence
835
series received "cytotoxic" chemotherapy: two of these children died (one of complications of therapy and one of progressive disease), and the third patient was still receiving treatment at the time of writing. These results are not particularly encouraging, and readers might be excused for believing that chemotherapy has only a small role. Our experience, in a single patient, is different. This 6-year-old boy had cardiac transplantation in July 1988 for rapidly progressive idiopathic cardiomyopathy. Two years later, right cervical and right axillary lymphadenopathy developed; the axillary node mass infiltrated the adjacent chest wall. Biopsy, in August 1990, showed a malignant non-Hodgkin lymphoma. The tumor was positive, by in situ hybridization, with an Epstein-Barr-virus DNA probe but, at this stage, showed no immunoglobulin light-chain restriction (i.e., was polyclonal). Initially, there was a good response to reduction of the cyclosporine dose and two courses of intravenously administered acyclovir, but in September 1990 recurrent lymphadenopathy, a right subscapular mass, hepatomegaly, multiple subcutaneous masses, and signs of an upper motor neuron lesion of the legs developed. Myelography showed extradural compression from the third cervical vertebra to the tenth lumbar vertebra, with complete blockage at the fifth cervical vertebra. Ultrasonography suggested focal involvement of the liver by lymphoma. The bone marrow and cerebrospinal fluid were not involved. 9 Laminectomy was carried out and all visible tumor removed. There was no response to further reduction of cyclosporine or to intravenously administered acyclovir. In December 1990, another tumor biopsy from a right maxillary lesion again showed malignant nonHodgkin lymphoma, but there was more light-chain restriction, with a rearranged IgHJ region band, indicating elonal proliferation. Courses of interferon alfa, first alone and then in combination with interleukin-2, had only a transient effect, the minor progressed at many sites, and the child became cachectic. In March 1991 we commenced combination chemotherapy, using the so-called GRAB protocol (good risk and Burkitt [lymphoma]). l The child first received two courses of cyclophosphamide, doxorubicin, oncovin, and prednisolone, followed by rotating combinations of chemotherapy including "CNS-directed therapy" with intravenous infusion of methotrexate and six intrathecal injections of methotrexate. There was a good tumor response, and at the end of 6 months of treatment (September 1991) the child was in complete remission, although handicapped by symptoms of a right brachial plexus compression because of the previous chest wall mass. Therapy has now been discontinued for 5 months and the child is still in complete remission. Although anecdotal, this experience shows that at least some Epstein-Barr virus-driven LPD is chemoresponsive and that even very bulky disease can be successfully treated, at least in the short term. We suspect that when clinicians contemplate chemotherapy for immunosuppressed patients, such as those described by Malatack and colleagues, they are concerned about the myelosuppression and added immunosuppression that chemotherapy will cause. This may lead them to use "gentler" regimens than are usually used to treat "nonimmunosuppressed" patients with B-cell non-Hodgkin lymphoma. Our patient tolerated his treatment without any life-threatening episodes of infection. We therefore support the suggestion, made by Malatack et al., that when cyclosporine dose
836
Editorial correspondence
reduction fails to control monoclonal LPD in these patients, a suitably "aggressive" regimen, such as the GRAB protocol, should be used.
Jon Pritchard, FRCP Consultant Paediatric Oncologist Department of Haematology and Oncology Ayad Atra, MRCP Clinical Research Fellow/Senior Registrar Department of Haematology and Oncology Hospitals for Sick Children Great Ormond Street London WC1N 3JH, England
The Journal of Pediatrics May 1992
with chemotherapy in our series. However, both patients ultimately had a relapse. Finally, in the last paragraph of our article we raised the concern that the use of the new immunosuppressive agent FK506 would likely have the same complication of lymphoproliferative disease as did cyclosporine. Since the publication of that article, we have seen a number of patients who have had various presentations of lymphoproliferative disease and whose immunosuppressive therapy was with FK506 and steroids only.
J. Jeffrey Malatack, MD Associate Professor of Pediatrics Children's Hospital of Pittsburgh University of Pittsburgh Pittsburgh, PA 15213-2583
We thank Dr. Rosemary Radley-Smith for referring the patient to us. REFERENCE
1. A1-Attar A, Pritchard J, A1-Saleem T, A1-Naimi M, Alash N, Atra A. Intensive chemotherapy for non-localised Burkitt's lymphoma. Arch Dis Child 1986;61:1013-9.
Reply To the Editor." The comments of Drs. Pritchard and Atra in response to our article are not at odds with our conclusions. However, a few comments require a response. Three children received chemotherapy in our series; a Table II footnote points out that of the three patients who received chemotherapy, one received it so late in the course that efficacy could not be evaluated. Of the two remaining patients, both went into clinical remission. The second patient had a relatively prolonged remission before his relapse. The patient described in the letter by Pritchard and Atra would have met our criteria for initiating chemotherapy. As noted in the second to the final paragraph of our article, "intervention in the patients with a lymphomatous presentation, if disease progresses without immunosuppressive therapy, should conform to current approaches to the management of disseminated Burkitt lymphoma, including immunomodulation, chemotherapy, or bone marrow transplantation." Drs. Pritchard and Atra properly selected their patients for chemotherapy. However, their comments, meant to avoid what they view as a misleading implication of our article, should not mislead the reader in the opposite direction. We are, in fact, concerned that the further immunosuppression occurring with chemotherapy could lead to an adverse outcome for those patients with lymphoproliferative disease who are still immune responsive (i.e., those whose disease potentially could regress when normal cytotoxic T-ceU function is allowed to occur). We believe that it is important that the patient to be given chemotherapy be appropriately selected, as was Pritchard and Atra's patient, from the group of patients with lymphoproliferative disease. These are patients with monoclonal monomorphic disease whose tumor progresses in the absence of immunosuppression. Monoclonal monomorphic disease that progresses despite elimination of immune suppression should be viewed as a lymphoma and treated as such. We remain interested in the outcome of Pritchard and Atra's patient because, as noted, a brief remission in one patient and a prolonged remission in another was obtainable
Thyroid dysfunction after cranial irradiation To the Editor: One mechanism of thyroid dysfunction caused by cranial irradiation not considered by Ogilvy-Stuart et al. 1 is secretion of immunoreactive but biologically hypoactive thyroid-stimulating hormone. 2 This might be mistaken for mild primary hypothyroidism or "compensated hypothyroidism" and attributed to direct thyroid damage. A simple way of attempting to detect this condition is to look for the absence of a rise in the triiodothyronine level at the end of a thyrotropin releasing hormone test, but definitive evidence could be obtained by testing thyrotropin for bioactivity or receptor binding. 2
Lyman A. Page, MD Director, Waterbury Regional Department of Pediatrics Professor of Pediatrics University of Connecticut School of Medicine Waterbury, CT 06721
REFERENCES
1. Ogilvy-Stuart AL, Shalet SM, Gattamaneni HR. Thyroid function after treatment of brain tumors in children. J PEonATe 1991;119:733-7. 2. Beck-Peccoz P, Amr S, Menzezes-Ferreira MM, et al. Decreased receptor binding of biologically inactive thyrotropin in central hypothyroidism. N Engl J Med 1985;312:1085-7.
Reply To the Editor." We completely agree with the suggestion that one explanation for thyroid dysfunction after cranial irradiation might be secretion of immunoreactive but biologically inactive thyroid-stimulating hormone. As far back as 1977 we made the very same suggestion I but did not actively pursue this line of research. We note, however, that Lee et al. 2 recently described central hypothalamic hypothyroidism with thyroid-stimulating hormone of decreased bioactivity
