Waxing and Waning Neuroimaging Abnormalities in Langerhans Cell Histiocytosis

PRACTICAL IMPLICATIONS

In adult Langerhans cell histiocytosis, progressive and accumulating imaging lesions in the CNS can regress.

Langerhans cell histiocytosis (LCH) is a rare disease in adults characterized by proliferation of CD1a+/CD207+ and S100 myeloid dendritic cells, forming granulomas.¹ An inflammatory exudate is often found with “bean-shaped” nucleated histiocytes. We report a patient with multisystem (liver, lung, and brain) LCH in whom neuroimaging abnormalities accumulated and partially regressed before definitive treatment.

Case

A 47-year-old female smoker with a history of functional neurologic disorder (left hemiparesis with irregular movements and slow speech) presented with chronic vomiting. An MRI of the brain showed a 2-mm enhancing nodule in the left frontal opercular region (Figure 1A and C) and a thickened (5.1mm) enhancing pituitary stalk (Figure 1B). Hypoadrenalism and cranial diabetes insipidus developed. She was treated with hydrocortisone and desmopressin.

Figure 1. Progression and Regression of LCH Brain Lesions.

Serial axial MRI brain scans (A–H) in LCH. (A) T1 with contrast showing enhancing left frontal opercular nodule (arrow) and (B) thickened and enhancing pituitary stalk (asterisk). One month later (C), the left hemisphere nodular enhancement had decreased (arrow), and (D) the pituitary stalk had improved (asterisk). At 6 months (E), the pituitary and hypothalamic enlargement recurred and (F) progressed further at 10 months. (G) Fluid attenuated inversion recovery imaging shows extensive hypothalamic high signal at 14 months. (H) Marked improvement in hypothalamic fluid attenuated inversion recovery high signal 1 year after the start of treatment. LCH = Langerhans cell histiocytosis.

Serial MRI of the brain showed new areas of T2-fluid attenuated inversion recovery hyperintensity, including a 6-mm focal mass within the cortical/juxtacortical inferior parietal lobe. The pituitary stalk thickening partially resolved (Figure 1D). Six months later, the enhancing pituitary stalk nodule had almost completely resolved, but a new enlarging and enhancing hypothalamic nodule developed (Figure 1E). A previously observed enhancing nodular lesion in the suprasellar region had increased in size (Figure 1F). Extensive hypothalamic involvement was identified at 14 months (Figure 1G). A right middle cerebellar peduncular nodule came and went, as did a right superior collicular lesion (not shown). In summary, MRI of the brain showed a mixture of progression and partial regression of multiple lesions. CSF analyses were normal with no evidence of restricted oligoclonal bands and normal flow cytometry. A paraneoplastic screening and PET scan results were negative for malignancy. There was no increase in serum immunoglobulin G/immunoglobulin G4 ratio.

Dissociative attacks were captured on EEG without any sleep or epileptiform changes. A high-resolution CT scan of chest showed cysts and nodules, consistent with pulmonary LCH. Bone marrow had normal hematopoiesis. A pituitary biopsy revealed CD1a and Langerin-staining macrophages but no Langerhans cells. After being relatively stable, the patient then deteriorated, displaying problems with memory, sleep, delirium, and hypernatremia. Further deterioration in liver function prompted a liver biopsy, which showed severe steatosis complicated by mild steatohepatitis and LCH (Figure 2A–D). Attempts to determine v-raf murine sarcoma viral oncogene homolog B1 or BRAF (V600E) status were hampered by poor-quality DNA.

Figure 2. Liver Pathology Demonstrating LCH.

Hepatic evidence of LCH. (A) Liver core showing severe steatosis (fatty liver disease) and a nodular, cellular lesion (*) that was subsequently proven to comprise abnormal Langerhans cells. Hematoxylin and eosin stain, magnification ×2.5. (B) View of nodular lesion noted in (A) showing abnormal Langerhans cell infiltrate, fibrous tissue, lymphocytes, and eosinophils. Hematoxylin and eosin stain, magnification ×20. (C) High power (×40 magnification) view showing Langerhans cells, which have coffee bean–shaped nuclei. Eosinophils (arrow) are interspersed among the Langerhans cells, a common finding in LCH. (D) Immunohistochemistry staining shows that the abnormal cells show positive results for CD1a, aiding confirmation of LCH (magnification ×40). LCH = Langerhans cell histiocytosis.

Treatment of LCH involved 6 cycles of monthly cladribine, followed by 6-mercaptopurine for 1 year. The brain (Figure 1H) and chest lesions improved. Worsening liver function tests prompted a second liver biopsy, which showed severe steatosis and fibrosis but no evidence of LCH. Radiologically, she has remained in remission 24 months after completing treatment.

Discussion

LCH is an inflammatory myeloid neoplasm. Histopathologically, LCH is characterized by CD1a+/Langerin + Langerhans-like cells, which originate from myeloid dendritic cells. In 2010, a gain-of-function mutation in the signaling protein BRAF (V600E) was identified in more than half of samples of LCH.² All cases with LCH show extracellular signal-regulated kinase phosphorylation driving clonal expansion of a myeloid neoplasm. The BRAF (V600E) mutation is associated with a poor response to therapy.

Clinical manifestations vary from isolated bone lesions to multisystem disease. The pituitary biopsy in our patient stained for CD1a and Langerin, but the absence of Langerhans-like cells prevented a histopathologic diagnosis from the pituitary biopsy. The CT chest findings per se fulfilled the presumptive diagnostic criteria for LCH.¹ However, a liver biopsy secured the definitive diagnostic criteria for LCH.

Adult LCH has a particular predilection for pituitary gland involvement. Diabetes insipidus is the most common initial sign of CNS involvement (30% of adults with LCH).³ Anterior pituitary dysfunction is recognized in 20% of adult patients with LCH.¹

Our patient demonstrated neuroradiologic progression-regression with accumulation of new brain lesions. Craniofacial bone (absent in our patient), hypothalamic-pituitary region, and intracranial and intra-axial gray and white matter lesions are all found in LCH.⁴ Although cerebral lesions have been shown to progress,⁵ the waxing and waning of cerebral, cerebellar, and hypothalamic-pituitary lesions without any therapy have not been previously reported in the same patient with LCH. In LCH, cerebral lesions have been classified into tumorous or granulomatous, nongranulomatous or neurodegenerative, and atrophy, but considerable overlap is recognized even within the same patient. Neurodegenerative lesions that are mainly in the cerebellum and brainstem may be clinically silent but retain MR signal abnormalities⁵ and lack infiltration of CD1a + histiocytes. Hypothalamic involvement in LCH is associated with neuropsychiatric behavioral change. Our patient had gained weight and developed diabetes mellitus type 2 during the course of the illness. She also demonstrated an important clinical observation that functional neurologic disorder can coexist with other neurologic comorbidities.⁶

Our understanding and management of LCH has improved.⁷ Neuroradiologic temporal progression and regression may be a feature of LCH.

Appendix. Authors

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