Cytogenetic abnormalities in PHA-stimulated lymphocytes from patients with Langerhans cell histiocytosis

Abstract

The aetiopathogenesis of Langerhans cell histiocytosis (LCH) is still undefined. Constitutional abnormalities in LCH have rarely been reported. One study showed chromosomal instability in lesional cells from three patients. No chromosomal studies are available on peripheral blood lymphocytes. Peripheral blood lymphocytes were analysed for the presence of chromatid and/or chromosomal breaks and structural rearrangements. A fluorescence in situ hybridization (FISH) painting technique was also applied in two cases. Sixteen patients with multisystem (MS, n = 11) or single system (SS, n = 5) LCH were studied. either at the diagnosis (n = 8), during treatment (n = 2) or during follow-up, when asymptomatic (n = 6). Thirteen patients had chromosomal abnormalities. Eleven patients (69%) had chromatid and chromosomal breaks in 7-45% of cells. Overall, chromosome and chromatid breaks were significantly more frequent in the 11 patients with MS disease than in the five patients with SS disease: the mean percentage of cells showing chromosome and chromatid breaks was 13.4% in MS patients vs. 6.2% in SS patients (P = 0.003). Chromosomal abnormalities may be found in phytohaemagglutinin (PHA)-stimulated peripheral blood lymphocytes of LCH patients at diagnosis, during the disease course and even during long-term follow-up, more frequently in MS disease. Chromosome instability may be considered as either a basic genetic instability or as a landmark of reaction to an environmental agent (viral?) that, through genome alteration, may play a role in histiocyte proliferation and, in some cases, also in the increased risk of malignancy.

Blood spotlight on Langerhans cell histiocytosis

“…Yet with lower viral loads, an elevated number of Merkel cell polyomavirus DNA sequences was detected in 12 LCH tissues compared with controls other than patients with dermatopathic lymphadenopathy. Previous studies of peripheral blood chromosomes showed that patients with LCH display an excess of spontaneous chromosomal breaks that are more evident during the acute phase of the disease 30 ; these findings resemble the genomic instability induced by respiratory syncytial virus (RSV), hepatitis C virus (HCV), or Epstein-Barr virus (EBV). 30,31 2.…”

“…Previous studies of peripheral blood chromosomes showed that patients with LCH display an excess of spontaneous chromosomal breaks that are more evident during the acute phase of the disease 30 ; these findings resemble the genomic instability induced by respiratory syncytial virus (RSV), hepatitis C virus (HCV), or Epstein-Barr virus (EBV). 30,31 2. What are the key signals that drive monocyte-derived DCs to form a granuloma?…”

Langerhans cell histiocytosis patients have HLA Cw7 and DR4 types associated with specific clinical presentations and no increased frequency in polymorphisms of the tumor necrosis factor alpha promoter

“…Most cases of LCH are sporadic, but some familial cases have been reported thus suggesting a possible genetic link [2][3][4]. There are few reports of chromosomal abnormalities in this disease [5,6]. Only one clonal abnormality was identified in tissue from a LCH lesion [5].…”

“…Only one clonal abnormality was identified in tissue from a LCH lesion [5]. Peripheral blood lymphocytes have also been found to have an excess number of chromosome breaks in mitogen-stimulated cultures [6]. Another hint regarding a possible underlying genetic abnormality is the association of LCH with major congenital malformations [7].…”

The role of BMT in childhood histiocytoses

“…This might be in keeping with recent evidence of association between LCH and cytokine gene polymorphism, chromosomal instability and 1% of familial clustering. 7,8,43,44 The finding of persistent control of the disease in a few patents who underwent auto-HSCT or experienced autologous reconstitution remains to be clarified.…”