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Service d’Hémato-Oncologie Pédiatrique (J.D.), Hopital Trousseau, 75012 Paris, France; Service d’endocrinologie pédiatrique Hopital Necker (M.-A.R., M.P.), 75015 Paris, France; Laboratoire Pharmacia (I.P.), Guyancourt 78200, France; Service d’Hémato-oncologie Pédiatrique (C.T.), CHU de Nantes, Nantes 44000, France; Service de Pédiatrie (F.D.), Institut Curie, 75005, Paris, France; Délégation à la recherche clinique (M.B.), Hopital St. Louis, 75010 Paris, France; Service d’hémato-Oncologie Pédiatrique (A.R.), Hopital Purpan, Toulouse, France; Service d’hémato-Oncologie Pédiatrique (A.D.), Fondation Lenval, Nice, France; Service d’hémato-Oncologie Pédiatrique (F.M.), Hopital Jeanne De Flandres, Lilles, France; Service d’endocrinologie pédiatrique (M.D.), Hopital Lyon-sud, Lyon, France; Service d’endocrinologie pédiatrique (R.B.), Hopital St. Joseph, 75014 Paris, France; Service d’endocrinologie pédiatrique (S.C.), Hopital Trousseau, 75012 Paris, France; and Service de Radiologie (C.G.), Hopital Robert Debré, 75019 Paris, France
Address all correspondence and requests for reprints to: Michel Polak, Service d’endocrinologie Pédiatrique, Hopital Necker, 149 rue de Sèvres, 75015 Paris, France. E-mail: michel.polak{at}nck.ap-hop-paris.fr.
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Patients and Methods |
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The diagnosis of LCH was based on the Histiocyte Society criteria (8).
The database was initially created for a retrospective study of LCH from 1983 to 1993 (9). Enrollment has been prospective since 1994. Since April 1, 1996, all patients have been included in Histiocyte Society trials. All French pediatric hematology-oncology and endocrinology units were invited to participate in this survey. Patients for whom baseline or follow-up data were lacking (n = 68), patients with erroneous diagnoses (n = 2) and patients older than 18 yr at diagnosis (n = 27) were excluded. At the end of 2001, 589 patients had been included in the database. The proportions of patients with liver, lung, and hematologic involvement were 17%, 16%, and 13.4%, respectively; 37.8% of patients had involvement of at least one of these organ systems. Overall, median follow-up is 3.7 yr (range 0.6–31 yr).
Pituitary involvement, with a deficiency in at least one pituitary hormone, was diagnosed in 145 of the 589 patients in whom LCH was diagnosed before age 18 yr.
Data monitoring and follow-up
Data monitoring, based on medical charts, was performed at each site. Clinical information, including growth curves, radiological findings, magnetic resonance imaging (MRI), and LCH disease extension as well as new episodes and therapies received were recorded. In keeping with French bioethics legislation, written informed consent was obtained if the patients participated in clinical trials, and the database was approved by the French computer watchdog commission (Commission Nationale de L’Informatique et des Libertés certificate 99.087). Standard medical practice during the period of the survey was to perform full-body radiography at LCH diagnosis and cerebral and pituitary MRI after diagnosis of DI.
Definition of organ involvement
Involvement of at least one organ was considered to represent a new disease episode. Bone involvement was defined as compatible radiologic and/or scintigraphic images (i.e. solitary or multiple lytic lesions, with or without periosteal new bone formation). The number and sites of distinct bone locations were taken into account. Ear, nose, and throat involvement was defined by chronic otorrhea or mastoid or sinus infiltration. Skin involvement was defined by histological criteria or skin rash associated with another confirmed disease location. The site and extension of skin rash were also considered.
Gum and mouth involvement was defined by histological criteria, a rash, or a hypertrophic formation associated with another confirmed disease location.
Liver involvement was defined by hepatic cytolysis (liver enzymes > 5 N), signs of hepatocellular insufficiency, and/or hepatomegaly. Cholangitis sclerosis was defined on the basis of pathologic criteria or by means of retrograde cholangiography. Spleen involvement was defined by a clinical increase in spleen size. Lymph node involvement was defined by histologic features and/or an increase in lymph node size (>1 cm diameter). Hematological dysfunction was defined by red blood cell or platelet requirements. Lung involvement was defined by signs of respiratory distress (dyspnea, polypnea, and/or oxygen desaturation without acute infection) and/or pulmonary computed tomography abnormalities. Gastrointestinal involvement was defined according to histologic criteria.
Neurologic involvement was defined as any neurologic sign and/or compatible computed tomography or MRI findings. Neurologic abnormalities were classified as tumoral or pseudodegenerative lesions (10). Pseudodegenerative MRI findings correspond to type Ia, Ib, IIA, and IIb of Grois’ classification (11). Distinct forms of neurological involvement occurring sequentially each defined a new event.
Isolated pituitary involvement (posterior or anterior) was not included in the definition of central nervous system involvement, but constituted, even when isolated, a new disease event.
MRI findings
MRI was recommended for all patients with pituitary involvement, but only 91 MRI scans corresponding to 46 of the 145 patients concerned were available for central review. MRI scans were reviewed by the same neuroradiologist (C.G.), who was unaware of the patients’ endocrine status, using a method described elsewhere (5, 12, 13). MRI with gadolinium contrast injection was performed in 29 patients. The diameter and shape of the pituitary stalk and the height of the anterior pituitary were estimated as previously described and were compared with published reference data (14, 15).
Growth assessment
Height SD scores (SDSs) were calculated at diagnosis of LCH; 1, 2, and 3 yr after LCH diagnosis (if patients were not diagnosed as GH deficient during this period); at diagnosis of GHD; at the outset of GH treatment; after 1, 2, and 3 yr of GH treatment; and when final height was reached (if relevant). This analysis focused on 121 patients for whom sufficient growth data were available, and used KGS software with French reference data (KGS Pfizer Pharmacia SAS, Paris, France) (16). Target height was calculated from parental heights (17). Growth analyses focused on the entire group of 121 patients and on the following three subgroups: GH nondeficient patients and GH-deficient patients with and without GH treatment.
Definition of endocrine dysfunction
Anterior and posterior pituitary dysfunction was diagnosed as described elsewhere (18).
Various GH secretion tests were used during the study period (18). GHD was diagnosed if two GH stimulation tests failed to yield a peak response above 10 ng/ml. The date of GHD diagnosis was recorded as the date of the first abnormal GH secretion test.
Age at puberty onset corresponded to Tanner stage 2 breast development (females) or a testicular volume of more than 3 cc (males).
GH treatment
Forty-seven patients were treated with GH for GHD, at a median dose of 0.18 mg/kg·wk (range 0.03–0.26 mg/kg·wk), representing 0.54 U/kg·wk. Among these 47 patients, the five patients treated before 1985 received low-dose extractive GH. All the other patients received biosynthetic human GH. Fourteen GH-deficient patients were not treated with GH for the following reasons: in two patients the physician feared that GH treatment would aggravate LCH; in one patient the physician considered that the patient’s general condition, with lung and liver dysfunction related to LCH, was too severe to expect a benefit from GH therapy; four patients had completed puberty before the diagnosis of GHD; and seven patients were being considered for GH treatment at the time of this analysis.
Statistical methods
Stata version 7 software (Stata Corp., College Station, TX) was used for all statistical analyses. Categorical data were compared using Fisher’s exact test and quantitative data using the Mann-Whitney U test. All tests were two tailed. P < 0.05 was considered to indicate statistical significance unless otherwise stated. Because multiple tests had been performed on the same sample, P < 0.001 was considered significant when assessing the relation between GHD and organ involvement, following the Bonferroni method. Logistic regression was used to investigate the relative weight of organ involvement and treatments in the onset of GHD. The end point for survival analysis was the onset of GHD. The period taken into account was the interval between diagnosis and an event or the last examination when no event occurred. The Kaplan-Meier method was used to estimate survival rates. Survival was compared between subgroups of subjects by using the log-rank test (19). The cut-off date for this analysis was March 30, 2002.
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Results |
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Individual endocrinopathies and their combinations are shown in Table 1
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). The median interval between DI and GHD onset was 2.9 yr (range 0–11.3 yr). Only four patients developed isolated anterior pituitary dysfunction.
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Risk factors for GHD
To identify risk factors for GHD, clinical features and the main therapeutic parameters of the 61 patients with GHD were compared with those of the 528 patients without GHD. Only ear, nose, and throat involvement (sinus, mastoid, external auditory tract, and gums) and neurological involvement were significantly associated with the risk of GHD, in both univariate and multivariate analysis.
Radiotherapy (with a target field including the pituitary and hypothalamus), mainly indicated for mastoid involvement or for other skull lesions (not for tumoral processes in the pituitary or hypothalamic region), was associated with an increased frequency of GHD, contrary to chemotherapy. The radiotherapy dose was less than 15 Gy in all but one case (70 Gy). Among the 363 patients with skull lesions including mastoid involvement, 33 cases of GHD were observed among the 340 patients who had not received radiotherapy (9.7%), whereas 13 cases of GHD were observed among the 23 subjects who had received radiotherapy (56%) (P < 0.001).
Growth patterns according to GHD
Growth could be analyzed in 121 subjects (55 males and 66 females). Four patients had already reached their final height or near-final height at LCH diagnosis and were therefore excluded from the analysis of final height. Fifty-three subjects could be assessed for final height, genetic target height, and the impact of LCH on growth.
No difference in height (expressed in SDS) was found at LCH diagnosis between patients who did and did not develop GHD, and height did not differ from that of the general population. One year after LCH diagnosis, a significant difference was found between the subjects who did not subsequently develop GHD and those who did (-0.2 vs. -1.2 SD; P = 0.03). This difference increased 2 yr after diagnosis (-0.47 vs. -1.5 SD; P = 0.006). The two groups did not differ in terms of the treatments received, including the dose and duration of steroid therapy. A growth defect during the first 2 yr after LCH diagnosis was more frequent in patients who subsequently became GH deficient (Fig. 2).
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Ninety-one MRI scans for 46 patients were centrally reviewed. A single MRI scan was available for 27 patients. A tumoral process was observed in five patients, in the hypothalamic region in three cases and the supratentorial region in two cases. Neurodegenerative lesions were observed in four patients. GHD occurred in 27 of the 46 patients studied by MRI.
Among 26 assessable patients without GHD, the size of the anterior pituitary differed according to subsequent GH secretory status. Future GH-deficient patients were more likely to have a smaller anterior pituitary (7 of 11 vs. 2 of 15, P = 0.01) with a smaller median height (2.5 vs. 4.5 mm, P = 0.0035), whereas the dimensions of the posterior pituitary and stalk were not significantly different.
Growth response to GH therapy
Median growth velocity increased from -1.7 SDS to 1.8 SDS after 1 yr of GH treatment. Mean height increased gradually with the year of treatment (Fig. 3).
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The difference in final height minus target height between the non-GH-deficient group and the GH-deficient GH-treated group (0.32 SD) was not significant (Fig. 3
). Final height SD among GH-deficient GH-untreated patients was -2.8 SD (n = 6), a value far below target height (final stature - midparental height = -3 SD).
The moderate fall in growth velocity at LCH diagnosis may have been due to the disease itself or to steroid therapy.
Safety of GH therapy
No adverse effects clearly related to GH therapy were observed in the 47 treated patients.
A total of 19 new LCH events occurred among 12 of the 47 patients treated with GH. The first relapses in these 12 patients occurred after a median of 1.4 yr on GH therapy (range 0.3–6.9 yr). Three patients receiving recombinant GH developed a neurodegenerative syndrome. In two patients osseous involvement was the first nonpituitary site of LCH. Lung involvement was diagnosed 6 yr after LCH onset (and after 1.4 yr on GH) in a teenager who had started to smoke. In the six remaining patients, the events consisted solely of bone lesions. Before GH treatment, relapses were significantly more frequent in patients with pituitary involvement than in patients without pituitary involvement. Interestingly, among patients with pituitary involvement, the relapse rate was not significantly influenced by GHD or GH therapy, arguing against a deleterious effect of GH therapy on LCH disease activity. Finally, 36 of the events observed in GHD patients occurred during periods without GH therapy, compared with 19 during GH therapy (Fig. 4).
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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The 10-yr cumulative incidence of GHD in the French nationwide LCH survey was 53.7% among patients with DI. GHD was the second most common endocrine deficiency, confirming the results of a single-center survey (5).
Two early findings were associated with subsequent GHD in patients who apparently had isolated posterior pituitary involvement, namely early loss of growth velocity, and an MRI-documented decrease in anterior pituitary height. In the year after DI onset, a growth deficiency of 0.5 SD appeared among patients without GHD (probably resulting from the disease itself and/or from its treatment), compared with 1.5 SD among patients who subsequently developed GHD. A further loss was noted between GHD diagnosis and the outset of GH treatment, which was implemented at a median height SDS of -2. This delay in treatment may have been due to reluctance to use GH in this immunological disorder and to a focus on controlling disease activity. The value of MRI for early detection of patients at high risk of GHD must be confirmed in a prospective study because it has not previously been reported (5).
Radiotherapy, despite the use of low doses (10–15 Gy) in all but one of the patients thus treated, was associated with an increased risk of GHD, as previously reported with higher doses (4, 20). As the benefit of radiotherapy is probably limited in LCH, this increased risk of GHD is a further reason to avoid it (21).
Our growth data and results of GH treatment are in keeping with those reported in smaller series (5).
The long-term response to GH therapy in children with GHD due to causes other than LCH is dependent on early treatment, before the onset of significant growth failure (22, 23, 24, 25). In our study, GH therapy was started when most patients already had severe growth failure. It is noteworthy that the final height of the six children with GHD who were not treated with GH was almost -3 SD, compared with only-0.8 SD in treated children.
Median final height among non-GH-deficient LCH patients was normal, suggesting that the disease and its treatment are not growth-limiting factors in the long run. The final height of treated GHD patients remained moderately below midparental (target) height. The less satisfactory final heights obtained in this study than in other settings may have been due to the use of relatively low doses in a subgroup of five patients treated extractive hormone because the dose of GH is known to influence final stature (22).
Safety of GH treatment
Our results appear reassuring with regard to the potential adverse effects of GH treatment in LCH. In particular, the frequency of new LCH events was low during GH therapy relative to periods without GH therapy, but this observation was based on a limited number of patients (n = 47) and have to be comforted by report of distinct teams. The risk of neurodegenerative LCH appeared to be related more to pituitary involvement itself than to GH therapy, as in a previous study. Like other authors (5, 6), we did not observe other well-known adverse effects of GH treatment.
Conclusion
In pediatric-onset LCH, GHD is the most frequent anterior pituitary hormone deficiency and is commonly associated with DI. Its frequency increases with time, underlining the need for long-term follow-up. GHD can be detected by monitoring growth velocity and measuring anterior pituitary size by MRI. Radiotherapy to fields including the pituitary appeared to favor the onset of GHD and should therefore be avoided. GH therapy did not appear to increase the frequency of LCH disease events. These findings remain to be confirmed in a prospective study.
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Acknowledgments |
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Endocrinologists. Dr. Casanova, St. Denis, 93; R. Brauner, Hopital St. Joseph, Paris; Dr. Billaud-Ritz, Paris; S. Hieronimus, Hopital Cimiez, Nice; B. Le Heup, Centre Hospitalier Universitaire, Nancy; C. Metz, Centre Hospitalier Universitaire, Brest; F. Despert, Centre Hospitalier Universitaire, Tours; M. De Kerdanet, Centre Hospitalier Universitaire Rennes; L. Weil, Centre Hospitalier Universitaire Lilles; I. Netchine, S. Cabrol, Hopital Trousseau, Paris; H. Crosnier, Centre Hospitalier, Dourdan; G. Pinto, M. Polak, Hopital Necker, Paris; D. Simon, P. Czernichow, J. Leger Hopital R. Debré, Paris; M. Nicolino, Hopital Debrousse, Lyon; J. C. Carel, Hopital St. Vincent de Paul, Paris; P. Rochiccioli, M. T. Tauber, CHU Purpan, Toulouse.
The authors thank David Young for editing the manuscript.
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Footnotes |
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These data have already been presented in part at the European Society for Pediatric Endocrinology, Lawson Wilkins Pediatric Endocrine Society, VIth Joint Meeting; Montreal, Canada, 2001.
This work was supported by Grant PHRC 96/AP HP/AOM 96301-96302; Grant PHRC 2001/CHU de Nantes, Grant INSERM/AFM GIS Maladies Rares, a grant from Histiocytose France; and an educational grant from Pharmacia SAS, a branch of Pfizer. We thank Dr. O. de Beco, Dr. C. Pasik, and Mrs. C. Barbara (Pharmacia SAS, a branch of Pfizer) for their support.
Abbreviations: DI, Diabetes insipidus; GHD, GH deficiency; LCH, Langerhans cell histiocytosis; MRI, magnetic resonance imaging; SDS, SD score.
Received May 23, 2003.
Accepted October 29, 2003.
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