Kusumakumary P.
Krishnan Nair M.

From the Regional Cancer Center, Thiruvanan-thapuram, Kerala.

Reprint requests: Dr. Kusumakumary P, Associate Professor of Pediatric Oncology, Regional Cancer Center, Post Box No. 2417, Medical College. P.O. Thiruvananthapuram, 695 011, Kerala.

Manuscript received: July 19, 1999;
Initial review completed: September14, 1999;
Revision accepted: January 13, 2000

Langerhans cell histiocytosis (LCH) is a comparatively rare disease and the term embrances the whole clinical spectrum of the disorder form single bone lesions to an aggressive widespread multisystem disease. Its clinical course is often unpredictable and patients can experience spontaneous remission and exacerbations.

There have been numerous efforts to define predictive factors that would allow separation of children expected to have a favorable course from those with fulminant disease. The best prognostic parameters currently available are age, extent of disease and presence of organ dysfunction (OD) as defined by Lahey in 1975(1). It was generally agreed that disease confined to bone or lymph node had a good prognosis with minimal therapy and was associated with little morbidity. Those patients with multi-system disease fared less well, had a chronic course, high rate of morbidity and possible mortality. Prognosis of young children who had extensive disease involving many organs particularly those with dysfunction of vital organs was very bad with a high mortality irrespective of the treatment given.

The aim of this study was to find the pattern and outcome of LCH patients with OD seen in our center from 1985 to 1996.

During the period from January 1985 to December 1996, 74 children with diagnosis of LCH were registered in our division. Of these 74 patients, 12 patients were found to have organ dysfunction at the time of diagnosis or later and they were the subject of the study. In all these patients diagnosis was based on clinical and histopathological data. Laboratory studies included complete blood counts, urinalysis, chest X-ray, skeletal survey, liver function test and renal function test. Bone marrow studies were done when the peripheral counts were abnormal. The diagnosis was established by biopsy of the lesions and the diagnostic level achieved was presumptive (based on light microscopic features).

Lahey’s criteria for organ dysfunction were used to identify patients with hepatic, hematopoietic and pulmonary dysfunction(1). Treatment consisted of chemotherapy in all evaluable cases. Injection Vinblastine and oral prednisolone, endoxan ± methotrexate were the drugs used in combination in most patients. Injection VP-16 was added to patients whose response was not satisfactory.

Treatment response was assessed as per Raney’s criteria(2). The duration of survival was calculated from the data of diagnosis.

Patients ranged in age from 52 days to 8 years; the median age at diagnosis was 18 months. The male female ratio was 1:1. Of these 12 children with organ dysfunction, 10 children had organ dysfunction at the time of diagnosis and two developed organ dysfunction during the course of disease.

Table I shows the clinical picture, results of treatment and current status of the 10 children who presented with organ dysfunction. Of these 10 children, all but two were below the age of 2 years. Five patients had hematopoietic dysfunction alone, one had hepatic dysfunction, 3 patients had hepatic and hematopoietic dysfunction and one had dysfunction of liver, lung and bone marrow.

Table II shows the clinical picture and treatment outcome of 2 children who developed organ dysfunction during the course of the disease. Both of them were above the age of 2 years, one had only localized disease of gum and mandible and the other had more disseminated disease. Both of them developed pulmonary dysfunction during recurrence.

Of the 10 children with OD, 2 did not receive any treatment because of parental refusal. One patient died of disease before any form of treatment was given and another died next day of starting treatment. Chemotherapy was started for other patients but 4 of them below the age of 2 years died of progressive disease within 4 weeks of starting chemo-therapy. Partial response was seen in one patient (who received Vinblastine, Endoxan, Doxorubicin and Prednisolone). She developed progressive disease and died of disease at 6 months. Complete response was seen in only one patient who had hepatic and hematopoietic dysfunction. The child was 38 months old at the time of diagnosis and she completed 1 year of chemotherapy. The child developed multiple recurrences and is alive with diabetes insipidus and partial teeth loss as late sequelae of disease (survival 126 months).

The patient with localized disease of mandible and gum was treated with local radiotherapy (600s cGY/3F) initially, but he developed local recurrence and pulmonary dysfunction after 5 months. He was given vinblastine and prednisolone at the time of recurrence, response was partial and hence Inj. Etoposide was also added. He died of progressive disease at 14 month. The other patient with disseminated disease received Inj. Vinblastine, cyclophosphamide, and steroids for 10 months and then discontinued chemo-therapy. He developed pulmonary dysfunction and multiple bone lesions after 13 months of stopping chemotherapy. He was given Inj. Etoposide and steroids for 6 months and he developed gum lesions and is alive with evidence of pulmonary fibrosis (36 months) Thus, only 2 children above the age of 2 years with organ dysfunction are alive at present. Both of them suffered multiple recurrences and are having permanent disabilities due to the disease.

Table I–Summary of Patients who Presented with Organ Dysfunction

Table II__Patients who Developed Organ Dysfunction During the Course of Disease

DOD - Died of disease; RT - Radiation treatment.

LCH is a rare disease with extreme clinical heterogeneity. Patients with single system disease can generally be cured with conser-vative management and overall survival is about 100% in almost all series(3-6). Multi-system disease without organ dysfunction has been associated with, a chronic course, a high rate of morbidity and low mortality(5-7). Those patients with organ dysfunction require polychemotherapy because they have a life threatening disorder. Treatment modalities that are currently available today only benefit about one half of the patients with the disease and for children with OD mortality is 30-50% regard-less of treatment(8-11).

Risk of fatal outcome has been related to young age (<2 yr) at diagnosis and multisystem disease particularly with OD. A Southwest Oncology Group Study reported a 50% mortality in this group of children while the mortality was 66% in another series(2,12). Rivera-Luna reported an overall mortality of 77% in 39 patients with OD(13). Patients who presented with dysfunction of one organ had a mortality of 46% and those with initial dysfunction of two or three organs had a mortality of 92%. Five out of eight patients with OD are long term in the series reported by Eagler et al.(14).

The two largest co-operative clinical trials were those of the Italian group (AIEOP-CNR-HX83) and an Austrian/German group DAL-HX 83/90(10,15). In the Italian group, the patients were stratified into prognostic groups depending on presence or absence of organ dysfunction. The mortality was 54% in this series. DAL-HX 83/90 studies used combina-tion chemotherapy for 1 year and the mortality was 38%. They hypothesized that in dissemi-nated LCH relatively intense chemotherapy initiated soon after diagnosis followed by long term continuation therapy would rapidly decrease the disease activity.

Organ dysfunction alone was found to be an unfavorable prognostic factor in the above studies. Thrombocytopenia appeared as an uniformaly poor prognostic sign in Raney’s series(2) while presence of respiratory dys-function or thrombocytopenia was significantly related to mortality in the series reported by Rivera-Luna(13). Liver dysfunction adversely affected the ultimate survival more than other dysfunction in Italian series. Liver dysfunction at diagnosis and lack of response to initial treatment and mortality were highly correlated in DAL H X-83 study. Vital organ dysfunction was more in children under 2 years of age and prognostic effect of age was not independently documented in these studies. In a recent series of 22 cases of childhood histiocytosis, the treatment outcome was not detailed and hence no comparison can be made(16).

Of the 10 children who presented with organ dysfunction in our series, all but 2 were below the age of 2 years and 9 of them had hematopoietic dysfunction. Nine patients died of progressive disease within few weeks and toxicity of treatment was not a major contri-buting factor to this mortality. Two children who developed organ dysfunction during the course of disease were above the age of 2 years and both of them developed pulmonary dys-function. One of them is alive with pulmonary fibrosis.

The LCH-1 study by Histiocyte Society(17) did not show any difference in outcome to therapy with methyl prednisolone plus vinblas-tine or methyl prednisolone plus etoposide. The findings of LCH-1 and DAL HX-83/90 support the fact that a poor or null response to initial therapy is highly correlated with mortality. The reason for lack of response to therapy remains unclear. Those patients who are unresponsive to initial therapy hardly benefited by switching over to alternative therapy and they can be considered for experimental approaches.

Only preliminary data exist on the efficacy of alternate treatment approaches in poor prognostic patients. Recent studies suggest a possible role of cyclosporin A (CSA) therapy in young children with OD(18). The rationale for using CSA arises from its immuno-suppressive and immunodulatory effects, by selective inhibition of cellular immune response and cytokine mediated cellular activation. A relatively new agent 2-chlorodeoxy adenosine (2 CdA) has been utilized in paients with LCH and other forms of histiocytosis(19). The limited experience with bone marrow trans-plantation show that sustained complete remission of LCH can be achieved by hemato-poietic stem cell transplantation(20). Auto-logous marrow rescue is a less attractive option but may be considered in the absence of HLA matched donor.

In conclusion nature of disease process in LCH is still not known and hence all current treatments for LCH are empirical, not rational. The prognosis for patients with organ dys-function is not satisfactory and despite the best attempts, the mortality in these patients remains high. Advances in our knowledge of patho-genetic mechanism of LCH will be required to refine therapy in the future.