Langerhans Cell Histiocytosis

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93.1 Clinical and Laboratory Findings

Histiocytosis-X was the name initially given to a group of disorders with seemingly unrelated clinical features, but characterized by the same pathological finding: infiltration of the involved tissue by large numbers of histiocytes, often organized as granulomas. The disease was later renamed Langerhans cell histiocytosis (LCH), after the cell (X) was identified as the Langerhans cell. LCH includes eosinophilic granuloma, Letterer–Siwe disease and Hand–Schüller–

Christian disease. The eosinophilic granuloma in- volves the bone. Letterer–Siwe disease is a multiorgan disease in children under the age of 2 years. Hand–

Schüller–Christian disease includes the triad of ex- ophthalmos, diabetes insipidus, and bone lesions.

The second type of histiocytic disorders comprises non-Langerhans histiocytosis, which includes Erd- heim–Chester disease, isohemophagocytic lympho- histiocytosis, and histiocytosis with massive lymph- adenopathy. Erdheim–Chester disease is mentioned explicitly here, because it can mimic many of the features of brain involvement in LCH.

The third type of histiocytic disorders comprises malignant histiocytosis.

LCH can now be defined as abnormal proliferation of clonal, dendritic Langerhans cells, which can be found in lungs, bone, skin, liver, spleen, lymph nodes, thymus, bone marrow, brain, pituitary, and other en- docrine organs. In adults usually only two organs are involved, whereas in younger children LCH is most commonly a multiorgan disease.

Primary involvement of the brain is rare in LCH.

Patients who develop CNS disease are likely to have multiorgan disease, with lesions in the calvaria and the temporal and orbital bones. Involvement of the brain and related structures can be subdivided into four different forms: (1) involvement of the pituitary–hypothalamic structures; (2) intra- or extra-axial granulomatous lesions; (3) abnormalities in the posterior fossa, in particular the cerebellopontine pathways; and (4) combinations of these three manifestations, with overlapping symptoms.

Involvement of the pituitary–hypothalamic structures leads to the most common symptom of cerebral involvement, diabetes insipidus. Diabetes insipidus can precede other CNS lesions by more than 3 years.

When diabetes insipidus occurs as isolated symptom, it is often referred to as Ayala disease or Gagel granu-

loma. The symptoms and signs of pituitary–hypothalamic involvement vary widely and may include changes in social behavior, appetite, changes of sleep pattern, polyuria and polydipsia, indicating posterior pituitary dysfunction, and growth failure, precocious or delayed puberty, amenorrhea, hypothyroidism, or hypocortisolism, indicating anterior pituitary dysfunction.

Intra- and extra-axial granulomas cause symptoms dependent on their location. The intra-axial lesions can occur in many places, supra- and infraten- torial, and behave as space-occupying lesions. Extra- axial lesions may exist as a continuous extension from bone lesions, or they may develop as lesions from the leptomeninges. They may exert pressure on the brain.

LCH may also occur in the choroid plexus.

Involvement of structures in the posterior fossa, in particular the cerebellum, are, after diabetes insipidus, the second most common manifestation of CNS involvement in LCH, and may occur many years after the initial diagnosis of LCH. Lesions in the posterior fossa may consist of local granulomas, or of symmetrical abnormalities in the white matter of the hilus of the dentate nucleus and corpus medullare of the cerebellum. Related clinical features are ataxia, re- flex abnormalities, tremor, dysarthria, and dysphagia.

Combinations of the symptoms and progression of the disease are not rare and may lead to severe CNS deterioration.

Combinations of diabetes insipidus and cerebellar symptoms also occur in Erdheim–Chester disease.

Other manifestations of this disease can also be similar to LCH.

Diagnosis of LCH in nearly all cases demands a biopsy and histological confirmation of the pathological Langerhans cell.

93.2 Pathology

Histologically, the granulomatous lesions consist of a proliferation of clonal Langerhans cells, combined with an inflammatory reaction. Four stages are usually distinguished: a hyperplastic–proliferative stage, a granulomatous stage, a xanthomatous stage, and a stage of fibrosis. Lesions in the first stage are most likely to show the characteristics of LCH. Electron mi- croscopy reveals Birbeck granules, characteristic of LCH. Immunostaining can be performed for the

Langerhans Cell Histiocytosis

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S-100 protein and for CD1a (OKT6) antigenic reactiv- ity, but these tests have a lower level of confidence.

Histochemistry demonstrates that LCH and adjuvant T cell lymphocytes in lymph nodes produce high levels of several cytokines, including tumor necrosis factor-a (TNF-a), granulocyte–macrophage colony- stimulating factor (GM-CSF), interferon-g, and inter- leukins (IL)-1, -2, -3, -4, -7, and -10. In pulmonary lesions LCH expresses the costimulatory molecules B7-1 and B7-2.

In the lesions in the cerebellar hemispheres no Langerhans cells can be demonstrated. The lesions are characterized by demyelination, gliosis, and loss of Purkinje and granular cells.

93.3 Pathogenetic Considerations

LCH is a proliferative disorder of mesenchymal cells, and can therefore only develop where mesenchymal tissue is present: within the CNS in the meninges, the adventitia of blood vessels, and among free microglial cells. It is unknown what triggers the transformation of normal antigen-presenting dendritic Langerhans cells into the clonal Langerhans cells that are defec- tive in this ability. Clonal proliferation leads to func- tional deficiency. One theory assumes that LCH cells arise from the adventitia of blood vessels, causing perivascular histiocytic aggregates that develop into larger granulomatous masses with variable portions of foamy histiocytes, eosinophils, microglia, lymphocytes, and plasma cells. In later stages fibrosis and as- trocytic gliosis become dominant. Why granulomas have a special affinity to the pituitary and hypothalamic structures remains so far an unanswered ques- tion.

The symmetrical lesions located in the cerebellar white matter, also involving Purkinje and granular cells, but without Langerhans cells on histological ex- amination, require a separate explanation. One of the theories compares the cerebellar and pontine lesions in LCH to the cerebellar degeneration seen in paraneoplastic syndromes. In this paraneoplastic syndrome antineuronal (anti-Yu) antibodies can be demonstrated. The search for antibodies against cerebellar tissue has, however, been negative in LCH patients.

Another theory proposes a toxic role for the high con- centrations of cytokines produced by LCH cells, but again definitive proof is lacking.

93.4 Therapy

Therapy in LCH with CNS involvement is dependent on the nature and extent of the lesion and the sec- ondary implications. It is important to realize that in some patients the lesions tend to regress sponta-

neously with transformation to a fibroxanthomatous state. Such lesions lose the characteristics of LCH. The involvement of other organs, which is usually present, also needs consideration in the treatment planning.

Surgical removal may be an option for intracerebral granulomas. When the resection is incomplete radiotherapy is usually added. Extra-axial locations at the convexity, subdural or arachnoidal, are resected when possible. Lesions of the skull base are less suit- ed to radical surgical removal. Radiotherapy and chemotherapy are then the remaining options. In patients with multiple lesions radiotherapy combined with chemotherapy may control the disease for many years. In patients with diabetes insipidus primary treatment depends on the neuroimaging findings. In patients with a nearly empty sella and lack of high signal on T1-weighted MRI of the posterior part of the pituitary, substitution therapy is indicated. In patients with granulomatous involvement of the pituitary–hypothalamic system, surgery, irradiation and chemotherapy in addition to hormonal substitution therapy have to be considered. Substances with favor- able effects on LCH are steroids, vinblastine, and etoposide (VP16). Etoposide is a semisynthetic epi- podophyllotoxin used in the treatment of malignan- cies of the macrophage and monocyte lineage, but also effective in LCH. It is noteworthy that etoposide may cause a high signal intensity of the basal ganglia on T1-weighted MR images.

Lesions in the cerebellar white matter not contain- ing Langerhans cells cause a treatment dilemma. If an autoimmune cause is supposed, one could expect benefits from corticosteroids or immunosuppressive therapy. If another explanation is supposed, for in- stance cytokine toxicity, therapy is unclear. So far no definite guidelines have been suggested for the treatment of the cerebellar white matter abnormalities.

93.5 Magnetic Resonance Imaging

MR is aimed at depicting the different possible manifestations and the different stages of LCH of both the skull and the intracranial contents. To visualize lesions of the skull, the cranial vault as well as the skull base, one can effectively use T1-weighted images, with and without fat suppression, with and without contrast. This can be combined with using the same T1- weighted sequences for visualizing the intracranial contents, both the extra- and intra-axial structures, as these sequences are also effective in depicting subdural and leptomeningeal disease manifestations.

Granulomatous LCH lesions in the skull base and brain will enhance after contrast injection. In addition T2-weighted and FLAIR images are indicated to survey the intracranial contents for other manifestations.

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In patients with involvement of the pituitary–hypothalamus axis, sagittal and coronal T1-weighted images with fat suppression, without and with contrast injection, will show in some patients a partially empty sella and lack of the bright signal of the posterior pituitary, and in other patients a granulomatous lesion in the suprasellar region, around the pituitary stalk, with or without extension into the skull base and meninges (Fig. 93.1). Infundibular thickening and infundibular atrophy are frequent findings. Oth- er isolated or multifocal intracerebral lesions, for ex- ample LCH of the choroid plexus, or space-occupying lesions in the frontal, temporal, parietal, or occipital

lobes, show up on the sequences indicated above. In all cases one can expect enhancement of the granulomatous lesions.

There are also two possible types of lesions in the posterior fossa. First of all, granulomatous manifestations of LCH can be observed, space-occupying, en- hancing after contrast, and usually asymmetrical.

Secondly, bilateral, symmetrical, confluent signal abnormalities can be seen in the white matter of the hilus of the dentate nucleus, the corpus medullare of the cerebellum, and the pons (Figs. 93.3 and 93.4). The bilateral cerebellar lesions do not represent LCH lesions, do not show mass effect, and do not enhance (Figs. 93.3 and 93.4). In these patients, the dentate nucleus often has a high signal on T1-weighted images.

The globus pallidus and, less often, the caudate nucleus may also have a high signal intensity on T1-weighted images (Figs. 93.3 and 93.4). Within the supraten- torial white matter, enlarged perivascular spaces are frequently present. Contrast enhancement following a vascular pattern may be present. More prominent, patchy white matter abnormalities not following a vascular pattern may also be present.

In Erdheim–Chester disease, a non-Langerhans histiocytosis, similar lesions as described for LCH may be seen (Figs. 93.2 and 93.5). Granulomatous lesions may be found in the sellar and suprasellar region as well as in other areas (Fig. 93.2). Progressive intra-axial lesions have been reported involving the pons, superior part of the medulla oblongata, the cerebellar peduncles, and areas around the fourth ventricles, as well as an extra-axial mass with encase- ment of the vertebral artery. Autopsy in one of these cases revealed histiocytic infiltration of the cerebellar pathways, in particular the base of the pons and the middle cerebellar peduncles. The nonenhancing symmetrical bilateral lesions in the cerebellar hemispheres with clinically a progressive spastic–ataxic syndrome may also occur in Erdheim–Chester disease (Fig. 93.5).

Fig. 93.1. A 65-year-old female patient with histologically confirmed LCH. The midsagittal, T1-weighted, contrast-en- hanced, fat-saturated image depicts a lesion mainly involving the hypothalamus

Fig. 93.2. A 55-year-old woman with Erdheim–Chester disease, as confirmed at autopsy. The sagittal T1-weighted image with contrast shows an intra- and suprasellar process, enlarging the sella turcica and reaching upward unto the optic chiasm. A second, extra-axial lesion is located anteriorly in the cranioverte- bral junction. Both lesions enhance homogeneously. The axial FLAIR image reveals the lesion with high signal intensity. From Thorns et al.

(2003), with permission

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Fig. 93.3. A 16-year-old male patient with LCH. The T1-weighted images (upper row) reveal high signal intensity in the globus pallidus. The coronal T2-weighted images (second row) of the posterior fossa show hyperinten- sity of the cerebellar white matter and the brain stem

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Fig. 93.4. A 17-year-old boy with LCH. The upper row shows T2-weighted (left), proton density (middle), and T1-weighted (right) images at the level of the basal ganglia. The globus pal- lidus has an increased signal on all these images. The second

row shows the T2-weighted images at the level of the brain stem and cerebellum. The tracts in the midbrain and base of the pons as well as the cerebellar white matter display a high signal. From Saatci et al. (1999), with permission

Fig. 93.5. A 44-year-old man with Erdheim–Chester disease. The T2-weighted images show hyperin- tensity of the cerebellar white matter.

From Weidauer et al. (2003), with permission