الفهرس 
Histiocytic Disorders of ChildrenOnly 14 pages are availabe for public view
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Abstract
In 1987, the Writing Group of the Histiocyte Society classified histicocytic disorders into dendritic cell disorder, of which the most common is Langerhans cell histiocytosis (LCH) and the macrophage cell disorder, that includes primarily hemophagocytic lymphohistiocytosis (HLH) and Rosai-Dorfman Disease (RD), finally the malignant histiocytosis.
Our goal in this study was to evaluate the different clinical presentations of histiocytes disorders and to determine their outcome and survival, mainly LCH and HLH, in relation to predisposing factors whether genetic or infectious and the current treatment protocols.
A retropspective study included 19 LCH and 26 HLH diagnosed in the Hematology and Oncology Unit at Children’s hospital, Ain Shams University in the period from September 2003till September 2014. Data was collected from files and or care givers including full medical history for age, gender of the patient, presence of consanguinity, residency, type of histiocytic disorders (LCH or HLH), age of onset of the disease, family history of sibling death. Laboratory evaluation, diagnosic criteria, radiological evaluation (abdominal ultrasound, pelviabdominal CT, chest radiograph, CT chest (CXR), skeletal radiograph survey (bone survey), MRI brain, pathology and immunohistochemistry for both disorders were recorded. Evaluation of protocol of treatment and treatment response (remission and relapse rate) was evaluated and 1 and 3 year event free and overall survival rates were calculated.
In our study we had 19 children with LCH with median age of 2.3 years (ranged 0.1 - 9),they were 12 females (63.2%) and 7 males(36.8%). Most of them (63.2%) were residents of Greater Cairo. Only one LCH case in our study had family history of sibling death and 42.1% of them had consanguineous parents.
Most of LCH patients 16(84.2%) presented initially with pallor, 15(78.9%) with chest symptoms, 13(68.4%) with fever, 13(68.4%) of with hepatomegaly, 12(63.2%) with splenomegaly, 11(57.9%) presented with generalized lymphadenopathy, 5(26.3%) with localized lympha-denopathy, 9(47.4%) with skin lesions, 7(36.8%) with bone swelling, 2(10.5%) with bone fracture due to osteolytic lesions and 4(21.1%) of patients with LCH presented initially with jaundice.
As regards the baseline laboratory data of LCH patients, hemoglobin ranged from 3.3-13.7 (gm/dl) with mean 8.5± 2.66(gm%), platelets ranged from 38-922 (x103/uL) with median value 248 (x103/uL), initial TLC ranged from 3.4-32.7(x103/uL) with median value 11.4(x103/uL), total serum bilirubin ranged from 0.1-5.4 (mg/dL) with median value 0.9 (mg/dL), initial alanine aminotransferase ranged from14-138 (IU/L) with median value 23 (IU/L) and AST ranged from18-98 (IU/L) with median value 35(IU/L). Five patients with LCH (26.3%) were CMV IgG positive and 3patients (15.8%) were EBV IgG positive,All of them were EBV and CMV IgM negative.
Bone marrow infiltration in 7(36.8%) of patients; 9 patients (47.4%) had osteolytic lesions on skeletal survey, 13 (68.4%) patients had organomegally or masses and 14 (73.7%) had positive CT chest findings as lung infiltrations or masses.
Sixteen (84.2%) patients had multisystem affection with involvement of risk organs and 3 patients had multisystem affection with no risk organ affection. In our study 19(94.7%) of LCH patients received LCH III protocol, while only one (5.3%) patient received LCHII protocol of treatment. Six (31.6%) had received salvage line, half of them (3 patients) needed only one treatment protocol, 1patient needed one salvage, the last 2 patients needed 2 salvage lines. Six patients died, the duration from diagnosis till death duration ranged from 0.75-4.6 years with median duration of 1.9 year.
There was no difference in one and 3 year overall or event free survival in subgroups divided according to age at diagnosis, gender, consanguinity, residency and patient risk. There was difference in survival according to clinical presentation yet those who presented with pallor had associated significant higher overall survival than those who did not.
Subgroups of patients divided according to baseline laboratory and radiological results of LCH patients did not show difference in 1 and 3 years overall survivals.
Patients with LCH who presented with jaundice had a significantly lower 1and 3 years event free survival than those who did not have jaundice. Patients with LCH who presented with total serum bilirubin >2mg/dl had a significantly lower 1and 3 year event free survival compared to those who had total serum bilirubin <2mg/dl.
Patients with LCH with initial osteolytic lesion and those without as well as those with positive lung lesions in CT and those without had comparable 1and 3 years event free survival rate.
Twenty six patients with HLH were registered with age ranged between (0.16 - 15) and median age 3.4 years among those patients 8 were females (30.8%) and 18 were males (69.2%). History of consanguineous parents was positive among (53.8%) of them. Most of HLH patients (69.2%) were living in greater Cairo and 3(11.5%) had positive family history of sibling death from the same condition.
HLH patients were classified into primary HLH including 16(61.5%) patients and 10 patients had HLH as secondary to another disease (2 patients (7.7%) had ALL, 2 patients (7.7%) had Chediak Hegashi, 3 patients (11.5%) had LCH, one had Wolman, one with myelodyplasia and one with ALPS). Genotyping for common HLH loci was done to 8 HLH patients, 2 patients had no abnormality and 6 had positive mutations 4(15.4%) patients had mutation in MUNC13-4 gene, 1(3.8%) patient had mutation in RAB27A gene and 1(3.8%)) patient had positive LYST gene mutation).
As regard initial clinical presentation of HLH patients, (92.3%) had hepatosplenomegaly, 69.2% fever, 26.9% lymphadenopathy, 23.1% chest symptoms, 53.8% jaundice, 88.5% pallor, (7.7%) thrombosis and (19.3%) of HLH patients presented initially with skin lesions. Five (19.3%) patients had CNS manifestations and only 2 of them had positive findings in their MRI and CT brain.
As regards the baseline laboratory results of HLH patients, intial serum ferritin ranged from 559.9-17951 (mg/L) with median value 1805.5 (mg/L), intial triglycerides ranged from 109-683(mmol/L) with a median of 256(mmol/L), initial fibrinogen ranged from 0.06-219(g/L) with a median value of 0.75(g/L), hemoglobin ranged from 2.5-11.5 (gm%) with mean 7.43 ± 2.1(gm%), platelets ranged from 12-534 (x103/uL) with a median of 76.5 (x103/uL), initial TLC ranged from 1.1 - 80(x103/uL) with median 4.8(x103/uL), total serum bilirubin ranged from 0.3-8.8 (mg/dL) with median 2.25(mg/dL), initial liver function test as ALT ranged from 16-226 (IU/L) with median 52.5 (IU/L) and AST ranged from19-483 (IU/L). Five patients (19.2%) had CMV IgG positive and 5 had EBV IgG positive, all of them had EBV and CMV IgM negative.
88.5% of patients were treated according to HLH 2004 protocol, while only 7.7% received HLH 94 protocol of treatment. Many HLH patients had reactivation which needed reinduction therapy, those patients were 12(46.2%), 6 of them needed only one reinduction, 4 patients needed 2 reinductions and 2 patients needed 3 reinductions. Duration from diagnosis till last follow up ranged from 0.01 -5.3 years with median duration 0.3 year. 18 patient died, they lived from diagnosis till death a median duration of 0.28 year, range from 0.01-1.08 year.
Patients with HLH secondary to another disease had a significantly lower 1 and 3 year overall survival compared to with primary HLH, while there was no difference in overall survival according to age at diagnosis, gender, consanguinity and family history of sibling death.
HLH patients who presented with initial lymphadenopathy localized or generalized had significantly lower 1 and 3 year overall survival compared to those who did not. No EFS difference were found in subgroups divided according to baseline fever, HSM, chest symptoms, jaundice, pallor, bleeding and CNS manifestations. HLH patients with positive CMV IgG had significantly lower 1and 3 years overall survival than those with negative CMV IgG.
The presence of lung infiltration in CT chest, as well as skull or brain infiltration in MRI brain did not show 1 and 3 years overall survival difference in HLH patients.
Patients with primary HLH had significantly lower 1 and 3 years event free survival than patients with HLH secondary to another primary disease. Presence of baseline lymphadenopathy, fever, hepatosplenomegaly, chest symptoms, jaundice, pallor, bleeding and CNS manifestations did not affect the event free survival rate of HLH patients. HLH patients with WBC >4 x109/L had significantly lower 1and 3 years event free survival compared to those less than 4 x103/L.
In conclusion patients with LCH presents commonly with multisystem disease and risk organ involvement, they had a one year OS of 77.3% and 3 year survival of 38.6%; while patients with HLH either primary or secondary had one year OS of 78.9 and 3 year OS of 48.3%.Genotyping for common HLH loci was performed in 31% of patients with presumed primary HLH and proved positive in 6/8 (75%) of tested patients.