A 72‐year old female with multiple supra‐ and infratentorial dural masses

Clinical History and Imaging

A 72‐year‐old woman presented with a 4‐year clinical history of increasing confusion, memory loss, depression, and dizziness. Neuroimaging studies including CT and MRI showed bifrontal dural masses (Figure 1a) and a right‐sided tentorial mass in the cerebello‐pontine angle (Figure 1b). The supratentorial masses were considered suspicious for multiple meningiomas or CNS lymphoma, whereas schwannoma was favored for the cerebello‐pontine angle mass. Microsurgical resection was performed of the both frontal lesions and right cerebello‐pontine mass. After the pathological diagnosis was rendered, systemic lesions were detected by PET in the humerus and femur, piriform sinus, ilium, clavicles and mandible (Figure 1c). The patient underwent a course of vemurafenib treatment, a BRAF‐inhibitor, which improved the neurological status.

Figure 1.

 

Microscopic Pathology

H&E‐stained sections (Figure 1d) revealed a moderately cellular infiltrate arranged in sheets and nests partially and compartmentalized by connective tissue bands. Numerous foamy macrophages, some of which were multinucleated (Touton‐like) (Figure 1e), were admixed with lymphocytes, plasma cells and granulocytes, and often concentrated around blood vessels. Scattered histiocytes contained engulfed inflammatory cells, reminiscent of emperipolesis (Figure 1f, arrow). Immunohistochemically, the foamy macrophages stained with CD68 (Figure 1g) and CD163; variable numbers of cells were S100 positive (Figure 1h). Rare cells stained for CD207, but CD21 and CD23 were negative. IgG and IgG4 had a normal ratio; immunohistochemical stains for κ and λ light chains revealed a mixed population, consistent with polyclonal plasma cells. The cells suggestive for emperipolesis were CD68 positive. Factor VIIIa, a marker for dendritic cells and histiocytes was focally positive. The Ki‐67 index ranged between 10 and 20%. BRAF^V600E immunostaining was positive (Figure 1i). PCR analysis confirmed a BRAFV600E mutation. (Scale bars Figure 1 d, e, f ‐ 10 µm; Figure 1g, h, I ‐ 100 µm.). What is your diagnosis?

Diagnosis

Erdheim–Chester Disease.

Discussion

Erdheim‐Chester disease (ECD) is an uncommon systemic histiocytic disorder with a predilection for adult males (3:1), 30–65 years of age. The disease may affect any organ; however, skeletal lesions are present in the vast majority (>95%) of patients. Cardiovascular involvement, retroperitoneal fibrosis, xanthelasma of the eyelids and periorbital edema are less frequent manifestations. The central nervous system (CNS) is affected in 56% of cases 2. Lesions typically arise in the pituitary stalk, orbit, dura and posterior fossa. Accordingly, patients commonly present with diabetes insipidus, visual disturbances, cerebellar and pyramidal syndromes. Orbital, CNS and cardiovascular involvement seems to portend a worse prognosis 3. Interestingly, CNS disease also correlates with a higher rate of kidney involvement. Histiocytoses are traditionally classified into Langerhans cell, non‐Langerhans cell and malignant histiocytosis. In Langerhans cell histiocytosis (LCH), the histiocytes, Langerhans cells, harbor clefted, lobulated nuclei and immunolabel with CD1a or CD207 (Langerin), S100 and CD68. The microscopic features of ECD are non‐specific, comprising foamy macrophages, and scattered giant cells. Occasionally, as in this case, emperipolesis with S100‐positivity, characteristic findings in Rosai‐Dorfman disease (RDD), are seen. In general, ECD should be negative for CD207 and RDD negative for the BRAF^V600E mutation. In the current case, the clinical phenotype with skeletal involvement and the BRAF‐mutation strongly favors ECD. Of note, 20% of patients with ECD also harbor Langerhans cell populations, sometimes within the same biopsy. In addition, both diseases share clonal mutations in the MAPK pathway 3. In the histiocytosis classification recently proposed by Emile 3, LCH and ECD are grouped in the same category, with overlapping features observed in the mixed LCH/ECD subtype. Contemporary therapeutic strategies for ECD vary according to the location of lesions and the degree of involvement. In the past, corticosteroids and cytotoxic drugs were the mainstay of therapy. Currently, first line therapy is interferon α. Agents targeting TNFα (Infliximab), tyrosine kinase – inhibitor (Imatinib) and recombinant interleukin‐1 receptor (Anakinra) have been successfully used in selected cases 1. More recently, patients with BRAF^V600E mutations, present in approximately 50%, have shown dramatic responses to therapy with the BRAF inhibitor vemurafenib 4. However, long‐term survival data is still lacking.