Langerhans cell histiocytosis: a multisystem disorder.

Langerhans cell histiocytosis can involve single or multiple organ/tissue systems and may go undiagnosed for years until it enters the clinician's differential diagnosis framework. We report on a young patient who initially presented with diabetes insipidus and subsequently with pyrexia of unknown origin. She progressed from single system Langerhans cell histiocytosis to multisystem involvement and remains in long-term remission following chemotherapy.

Langerhans cell histiocytosis.

Langerhans cell histiocytosis is a rare disease. Depending on which organs are involved, the disease may prove rapidly fatal, develop a chronic reactivating but therapy-responsive pattern or resolve spontaneously. Understanding of the pathology of the disease is progressing rapidly, and while clinical trials of standard chemotherapy agents continue, it is likely that novel targeted therapy will become feasible in the next decade. Permanent consequences of the disease are more commoner than generally realised.

Incidence and clinical features of Langerhans cell histiocytosis in the UK and Ireland.

OBJECTIVES: There are few published studies on the epidemiology of Langerhans cell histiocytosis (LCH). We undertook a survey to ascertain all newly diagnosed cases aged 0-16 years in the UK and Republic of Ireland. DESIGN: Three methods of ascertainment were used: the British Paediatric Surveillance Unit (BPSU) system, a survey by Newcastle University, and the Children's Cancer and Leukaemia Group (CCLG) registry. Deaths data were obtained from the UK Office for National Statistics and the Central Statistics Office in Ireland. Clinicians who reported cases were sent a questionnaire to obtain demographic and clinical details. RESULTS: Over the 2-year period, 94 cases were identified. The age-standardised incidence rate of LCH in children aged 0-14 years was 4.1 per million per year. The sex ratio (M:F) was 1.5:1 and the median age at diagnosis was 5.9 years. Single system disease (predominantly bony involvement) accounted for 73% of cases and 27% had multisystem disease of whom 7% had involvement of "risk organs" (liver, lung, spleen and bone marrow). Three children died, two of whom were diagnosed after death. CONCLUSIONS: This is the first study of LCH to use an active surveillance method with additional sources of ascertainment. Our incidence is comparable with those in other national reports, although it is likely to be an underestimate as each method may have missed some cases, either diagnosed or undiagnosed.

Outcome of a risk-related therapeutic strategy used prospectively in a population-based study of Hodgkin's lymphoma in adolescents.

The aim was to assess outcome in a population-based cohort of adolescents with Hodgkin's lymphoma (HL) diagnosed in the UK's northern region over a 10-year period. Among a population of 3.09 million, 55 of 676 patients (8%) diagnosed with HL were aged 13-19. Seven had nodular lymphocyte-predominant HL, 48 classical HL (cHL). Of the latter, 36 were >or=16 years. Application of the Scottish and Newcastle Lymphoma Group (SNLG) prognostic index meant 21 patients were considered high risk (index >or=0.5). They received PVACEBOP multi-agent chemotherapy as primary therapy. Standard risk patients (SNLG index <0.5) were treated with standard ChlVPP or ABVD chemotherapy+/-radiotherapy. Scottish and Newcastle Lymphoma Group indexing is not valid for patients under 16. Twelve patients therefore received UKCCSG protocols (n=8), ABVD plus radiotherapy (n=2), or PVACEBOP (n=2). Forty-six patients with cHL (96%) achieved complete remission. Seven patients relapsed but all entered complete remission after salvage therapy. Five patients died: three of HL, one in an accident and one of disseminated varicella complicating cystic fibrosis. Five- and 10-year overall survival was 93 and 86%, respectively; disease-specific survival was 95 and 92%. The data suggest that older adolescents with high-risk HL require intensive protocols as primary therapy to secure optimal outcome.

Follicular dendritic cell tumour in a 9-year-old child.

Follicular dendritic cell tumour (FDCT) or sarcoma is a rare tumour first described in 1986. Some 80 cases have been reported, the youngest being in teenagers. Our patient first presented at 9 years of age with a cervical mass that was removed and revealed an apparently benign, but florid reactive process. At age 14 the lump recurred and biopsy was diagnostic of FDCT. Radical block dissection showed disease to level III and 6 weeks of radiotherapy was followed by 6 months adjuvant chemotherapy. Three years after completing his final treatment he shows no signs of recurrent disease.

A comparison of self-reported satisfaction between adolescents treated in a "teenage" unit with those treated in adult or paediatric units.

BACKGROUND: Despite recommendations that adolescents should have in-patient management amongst their peers, there is little literature to support this. The study aim was to evaluate and contrast patient satisfaction for teenage cancer patients treated in two settings. The first is a split site unit (a paediatric ward and adult cancer centre in different locations within one city) and the second, a dedicated adolescent unit for patients aged 13-20. PROCEDURE: Eligible patients aged 13-20 years received treatment from September 1997 to June 2000 and totalled sixty-five adolescents. The patients were identified at both centres from departmental databases. Postal questionnaires (the Youth Satisfaction Questionnaire) were sent to those eligible. RESULTS: Patients receiving treatment in the teenage cancer unit (TCU) were not significantly more satisfied overall than those receiving treatment in adult or paediatric units. However, significant differences were noted in: recreational and relaxation facilities (P < 0.005, P < 0.0002), studying space (P < 0.004), ward noise (P < 0.02), and company of the same age (P < 0.0001). The Grade Point Average (a score of all specific items) was higher in favour of the TCU (P < 0.03). Patients at both centres were dissatisfied with hospital food and menus offered. CONCLUSIONS: Adolescents with cancer are satisfied with the overall care they receive independent of whether it is a TCU or a split site unit. Teenagers are significantly more satisfied with environmental aspects of care in the TCU. More research is required to establish the correct provision for teenagers with cancer. This is the first study that contrasts satisfaction between different centres and thus adding to an understanding of the needs of teenagers with cancer.

Demographic study of leukaemia presenting within the first 3 months of life in the Northern Health Region of England.

AIMS: To determine the incidence and outcome of congenital leukaemia. METHODS: Retrospective population based study of putative leukaemia arising during the first 3 months of life over an 18 year period within the Northern Health Region of England. RESULTS: Nine infants with putative leukaemia were identified. Five had acute leukaemia and four had transient myeloproliferative disorder (TMD). Trisomy 21, either as Down's syndrome or perhaps restricted to proliferating marrow cells, was present in all four infants with TMD. The incidence of congenital acute leukaemia was 8.6/10(6) live births/year, but would be less than half this value if only patients presenting within 4 weeks of birth were counted. Remission was induced in three of the five patients with acute leukaemia. One patient, who presented at birth, remains well five years after diagnosis. All four patients with TMD survive. CONCLUSIONS: Congenital leukaemia is very rare but is not inevitably fatal. Finding trisomy 21 in spontaneously dividing blood or bone marrow cells of an infant with putative acute leukaemia, particularly within 3 months of birth, should encourage a cautious clinical approach and suggests that the diagnosis might be TMD.

Strategic approach to the management of Hodgkin's disease incorporating salvage therapy with high-dose ifosfamide, etoposide and epirubicin: a Northern Region Lymphoma Group study (UK).

The Northern Region Lymphoma Group is a population-based group covering 3.1 million people in Northern England. From 1991 total data collection for all Hodgkin's disease patients for this population has been in place and it has been possible to demonstrate that the overall survival for Hodgkin's disease for younger patients within this population has moved from 80% pre- 1988 to 87% post- 1988. This improvement has been brought about by the introduction of clinical trials for advanced stage disease and effective salvage regimens. This report describes the outcome of 51 patients treated with the ifosfamide, etoposide and epirubicin (IVE)schedule and includes 28 males and 23 females with a median age of 34 years. Overall 43 of 51 patients responded to treatment (84%) with 31 achieving a complete response, four a good partial response and eight a partial response. Thirty-one proceeded to autologous stem-cell transplantation. In total, with a median follow-up of 24 months (range 6-51), 26 patients remain alive and in continuous remission. Haematological toxicity,in particular neutropenia WHO grade 4, was observed in all cases but improved over the three courses of treatment. Non-haematological toxicity was not a major problem, with no significant cardiac, hepatic, renal or neurotoxicity. We conclude that the high-dose ifosfamide-containing regimens should be prospectively evaluated in the various types of non-responsive and relapsing Hodgkin's disease.

Attentional ability among survivors of leukaemia treated without cranial irradiation.

BACKGROUND: Previous research has indicated that children who have received treatment for leukaemia which includes cranial irradiation exhibit deficits in their ability to focus attention. It has been suggested that the use of cranial irradiation may have a role to play in long term sequelae. AIMS: To investigate neuropsychological functioning among children treated for leukaemia without cranial irradiation. METHODS: In a cross sectional study, 17 leukaemic patients and their sibling controls were assessed using a neuropsychological model of attention. All were treated on the UKALL XI protocol and none had received cranial irradiation. Participants completed the Arithmetic subtest and Digit Span subtest of the Weschler Intelligence Scale for Children-Revised to assess focus-encode elements of attention; the Coding subtest and the Speed of Information subtest of the BAS to assess focus-execute aspects of attention; the VIGIL computerised battery to assess sustain elements of attention; and the Wisconsin Card Sorting test to assess the ability to shift attention. RESULTS: These children did not exhibit the deficits witnessed in previous cohorts, and were performing at comparable levels to their controls on all measures of attention CONCLUSIONS: These findings suggest that children who have received treatment for leukaemia without the use of cranial irradiation do not show the neuropsychological insult found in earlier treatment groups.

Chemotherapy and marrow transplantation for congenital leukaemia.

The optimum approach to congenital leukaemia is unclear. Results of treatment are generally discouraging and palliation is offered to many. The successful treatment of an infant with congenital leukaemia is reported.

High dose ifosfamide in combination with etoposide and epirubicin followed by autologous stem cell transplantation in the treatment of relapsed/refractory Hodgkin's disease: a report on toxicity and efficacy.

Patients with Hodgkin's disease (HD) refractory to first line chemotherapy and those who have rapid or multiple relapses have a very poor prognosis. With the increasing use of hybrid chemotherapy these patients will have been exposed to many of the drugs active in HD so it is important to develop salvage regimens that are novel and demonstrate activity in this group of patients. We report the use of a continuous high dose infusion of ïfosfamide at a dose of 9g/m(2) over 3 days in combination with etoposide and epirubicin followed by autologous stem cell transplant with either BEAM or Melphalan/VP16 conditioning in this difficult group. Forty six patients (28M:18F) with a median age of 28 years (range 13-45) were treated. Overall 39 out of 46 (85%) patients responded to treatment, with 17 achieving complete remission and 11 a good partial remission; 28 proceeded to autologous bone marrow/stem cell transplantation. In total, 23 patients are alive and in continuous remission with a follow up of between 12 and 61 months. Median overall survival for the whole group is 36 months. Haematological toxicity, particularly neutropenia (WHO grade IV), was observed in all cases but improved over the 3 courses of treatment in all patients. Non-haematological toxicity was not a major problem; no significant cardiac, hepatic, renal, pulmonary or neuro toxicity was observed and there were no deaths on treatment. This regime shows promise in patients with difficult Hodgkin's disease and warrants further study.

Posttransplantation B lymphoblastic leukemia with Burkitt-like features.

BACKGROUND: Posttransplantation Epstein-Barr virus-associated lymphoproliferative disease (PTLPD) occurs as a spectrum of disease ranging from benign, polyclonal, localized lymphoid hyperplasia to malignant, monoclonal, disseminated lymphoma, sometimes involving the bone marrow. To our knowledge, PTLPD has not been previously reported to present as acute lymphoblastic leukemia. METHODS: We report the case of a boy who developed PTLPD in the form of acute lymphoblastic leukemia 6 years after cardiac transplantation. He had greater than 90% bone marrow invasion by Epstein-Barr virus-positive B lymphoblasts with Burkitt-like features and a t(8;14) translocation. RESULTS: He was successfully treated with combination chemotherapy but unfortunately died, 6 months after completing treatment, from ischemic heart disease. CONCLUSIONS: B lymphoblastic leukemia may occur as a manifestation of PTLPD and should be included in the classification of these diseases. Bone marrow examination should be an essential part of the investigation of patients suspected of having PTLPD.

Childhood lymphoma.

Lymphoma accounts for some 10% of childhood malignancy. Hodgkins disease is slightly less common than Non Hodgkins lymphoma, of which lymphoblastic, Burkitts and large cell anaplastic are the common subtypes. Accurate subtyping and staging are critical to ensure correct therapy is initiated. With current therapeutic strategies, almost all cases of Hodgkins and in excess of 70% of Non Hodgkins lymphomas can be cured.

Recurrent pneumomediastinum and pneumothorax in Langerhans cell histiocytosis.

Pneumothorax is an unusual complication of pulmonary Langerhans cell histiocytosis. We report three children who developed recurrent intrathoracic air leaks. In one case, bilateral pneumothoraces may have been precipated by intermittent positive pressure ventilation during general anaesthesia. Chemical pleurodesis was unsuccessful in preventing recurrence of pneumothoraces in two children. The use of extracorporeal membrane oxygenation as an alternative to intermittent positive pressure ventilation in children with respiratory failure from Langerhans cell histiocytosis is discussed.

Central venous catheter use in UKCCSG oncology centres. United Kingdom Children's Cancer Study Group and the Paediatric Oncology Nursing Forum.

A cross sectional audit of central venous catheter (CVC) use was performed in United Kingdom Children's Cancer Study Group oncology centres. There were wide variations in choice of line, insertion technique, aftercare practice, and diagnosis of CVC related sepsis. These variations highlight the difficulty in interpretation of published data on CVC efficacy.

Successful treatment of non-familial haemophagocytic lymphohistiocytosis with interferon and gammaglobulin.

Two cases of non-familial haemophagocytic lymphohistiocytosis (HLH) are presented in which treatment with interferon alfa and gammaglobulin was associated with complete clinical remission. In one case, serological evidence of recent Epstein-Barr virus infection was found. Natural killer cell activity was within normal limits in both children, compatible with a secondary form of HLH. The combination of interferon alfa and intravenous gammaglobulin requires further evaluation in the treatment of non-familial HLH.

Spontaneous regression in angiocentric T-cell lymphoma.

An 8-year-old boy presented with a 10-week history of ulcerating lesions which were histologically and immunocytochemically consistent with the diagnosis of angiocentric T-cell lymphoma. The disease was limited to the skin and resolved with no chemotherapy. Angiocentric T-cell lymphoma is commonly a disease with considerable morbidity and is often fatal. Epstein-Barr virus (EBV) could not be identified in involved tissue by immunostaining or by in situ hybridization. We consider whether the uncharacteristic absence of EBV in this case has prognostic significance.

Flow cytometric determination of intracellular calcium changes in human peripheral blood mononuclear cells during conjugation to tumour cell lines.

Using a flow cytometric assay, conjugate formation between human peripheral blood mononuclear cells (PBMC) and three different human tumour cell lines has been analysed. Changes in the intracellular calcium levels of PBMC were monitored using the calcium sensitive dye Fluo-3. Target cell populations were distinguished by forward scatter or following loading with the fluorescent dye, SNARF-1. Intracellular calcium was expressed as a ratio of fluorescence of conjugated to unconjugated PBMC and followed for ten minutes after initiation of conjugation. The results demonstrate an apparent increase in intracellular calcium in PBMC conjugated to the NK-sensitive cell line K562, and that the kinetics and magnitude of this response varied considerably between individuals. Tumour cells which were resistant to lysis (as determined in a 4 h chromium release assay) were also capable of eliciting a calcium response from PBMC. Although the induction of a rise in intracellular calcium was therefore not correlated with cytotoxicity, it was greater in IL-2-activated PBMC upon exposure to the same target cell lines as PBMC.

Nail features in Langerhans cell histiocytosis.

We report the case of an infant who presented with isolated cutaneous manifestations of Langerhans cell histiocytosis before the evolution of systemic features. In the transition period, at 9 months of age, nail unit changes became prominent, and persisted throughout the duration of systemic treatment. A change in clinical features coincided with a course of systemic gamma-interferon, which was given because immune paresis was suspected. Nail unit changes are rare in Langerhans cell histiocytosis, and this case illustrates the range of findings, including paronychia, nail fold destruction, onycholysis with subungual expansion, and nail plate loss. The significance of these changes as a prognostic indicator is controversial.