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Commentary: “Histiocytosis X”
  1. Dinah V Parums
  1. Department of Histopathology, Freeman Hospital, Newcastle upon Tyne NE7 7DN, UK
  1. Dr D V Parums.

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Pulmonary Langerhans’ cell granulomatosis (LCG) is a diffuse, smoking-related lung disease characterised pathologically by bronchiolocentric inflammation, cyst formation, and widespread vascular abnormalities, and physiologically by exercise limitation. Pulmonary fibrosis is a long term sequel. Diagnosis may be made by lung biopsy and by bronchoalveolar lavage (BAL).

The papers by Gabbay et al 1 and Habibet al 2 present two cases of LCG which recurred after double lung transplantation at two years and four years, respectively. These are the first reports of recurrent LCG in the transplanted lung. As lung transplantation is now recognised as a treatment for this disease, these two reports serve to draw our attention to what may prove to be the beginning of a series of such cases.

The titles of these two papers1 2 also draw our attention to the remaining confusion about the terminology of this disease. This confusion has been based upon historical morphological reports. The “histiocytoses” are reactive or proliferative diseases of cells of the mononuclear phagocyte system classically seen in childhood, and they include Langerhans’ cell histiocytosis (LCH) or granulomatosis (LCG), haemophagocytic syndrome (familial and reactive), sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease), juvenile xanthogranuloma, and malignant histiocytosis. These disorders show wide variation in their clinical presentation, prognosis, and genetic implications.3 All are characterised by localised or generalised proliferation of histiocytes, but they differ in their morphology, histochemical and immunochemical staining patterns, and electron microscopical features. Histiocytic diseases may be generalised or involve single organs with involvement of the bone, skin, spleen, brain and lung, in order of frequency.4 5

The term “histiocytosis X” was meant to cover a spectrum of three diseases: eosinophilic granuloma, Hand-Schüller-Christian disease, and Letterer-Siwe disease. However, these terms are rather meaningless pathologically. Hand-Schüller-Christian disease has become a synonym for multifocal LCG. The term Langerhans’ cell histiocytosis (LCH)2 reflects the belief that this disease is a true “histiocytosis”. Some prefer the term Langerhans’ cell granulomatosis (LCG)1 to avoid confusion with the term histiocytosis X because there is some evidence to support the view that the Langerhans’ cell is not a member of the mononuclear phagocyte system and hence not a tissue macrophage (or histiocyte).3 5

Langerhans’ cells are part of the widespread system of “dendritic cells” which arise from CD34+ progenitors in the bone marrow. Langerhans’ cells are specialised and efficient antigen presenting cells for T cell mediated immunity. In LCG, however, the major associated cells are not T cells but mature eosinophils, hence the original name “eosinophilic granuloma”.

These two case reports have elegantly demonstrated the role of immunohistochemistry in confirming the diagnosis and have relied upon the use of S100 as a marker for the Langerhans’ cell. The immunophenotype and proliferation fraction have been investigated recently in 26 cases of LCG.3 In all cases LCG cells were positive for S100 protein, CD1a, or both. In most cases LCG cells expressed the macrophage associated marker CD68 and, in two cases, they contained lysozyme. Expression of both cytoplasmic CD2 and CD3 was observed in cryostat sections. An unexpected finding was the presence of placental alkaline phosphatase in LCG cells. Langerhans’ cells in normal skin were negative for both CD2 and CD3, but a proportion contained placental alkaline phosphatase.

Langerhans’ cell granulomatosis has been regarded as a non-malignant, reactive condition, implying that the DNA content of the Langerhans’ cells is normal. However, Isaacson et al 3have recently shown that LCG cells have an aberrant phenotype and are proliferating locally. Mitoses are seen in the Langerhans’ cells in LCG which might suggest that LCG is a neoplastic rather than a reactive process. The implications of these studies may be of relevance in determining future treatment regimes.

Subjects with pulmonary LCG present with either normal or predominantly restrictive pulmonary physiology; exercise impairment is common and appears to reflect pulmonary vascular dysfunction.6 The course of pulmonary LCG is variable, difficult to predict, and ranges from spontaneous remission to progressive respiratory insufficiency and death. To identify the determinants of survival Delobbe et al 4 recently performed a survival analysis on 45 patients with pulmonary LCG. The patients were aged from 12 to 62 years, 32 were men, and they were almost exclusively current smokers (96%). These 45 patients were followed for a median period of six years (range 1–29) after the diagnosis. During the period of observation 33 patients (73%) survived (median follow up period 5.8 years; range 1–29) and 12 (27%) died or underwent lung transplantation (median follow up 8.4 years; range 1.4–16.1). The median survival was approximately 13 years. A univariate analysis showed that diminished survival was significantly associated with an older age at diagnosis, a lower forced expiratory volume in one second/forced vital capacity (FEV1/FVC) ratio at diagnosis, a higher residual volume/total lung volume (RV/TLV) ratio at diagnosis, and steroid therapy during follow up.

Recurrent LCG may mimic obliterative bronchiolitis (OB) in the transplanted lung. The bronchiolocentricity of the disease and the association with smoking suggest that there is an immunological basis to the genesis or the progression of the disease, so the first line of treatment is for the patient to stop smoking. The involvement of Langerhans’ cells in T lymphocyte mediated immune reactions raises the possibility of a role for transplant immunosuppressive therapy including cyclosporin and prednisolone in the treatment of recurrent LCG.7 As the case report by Gabbay et al 1 has shown, cyclophosphamide may prove to be effective in the treatment of recurrent pulmonary LCG.

In conclusion, these two reports have shown that it is important to think of the possibility of the diagnosis of recurrent pulmonary LCG in lung transplant patients and that this disease can mimic bronchiolitis obliterans syndrome clinically. Adequate tissue for histopathological examination and the use of immunophenotypic markers will confirm the diagnosis. Clinical trials are now awaited to determine appropriate treatment regimes for recurrent LCG in the context of the transplanted lung.

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