Erdheim-Chester disease (ECD) is a non-Langerhans cell histiocytosis that affects multiple body organs, notably the skeletal system. We examined a 58-year-old man who presented with ataxia and T2 hyperintensity of the middle cerebellar peduncles and dentate nuclei without contrast enhancement on MRI brain. Workup for malignancy revealed “hairy kidneys” on CT scan of the abdomen, and excisional biopsy of the retroperitoneal mass for concerns of lymphoma revealed foamy histiocytes that tested positive for CD68 and negative for CD1a, confirming the diagnosis of ECD. Further genetic testing on excised tissue revealed BRAF (V600E) gene mutation that is present in 50% of ECD patients. Treatment was initiated with targeted therapy using the BRAF inhibitor Dabrafenib. X-ray of the lower extremities did not reveal sclerosis of the long bones, and bone scan with technetium 99 was negative except for a nonspecific tracer uptake in left calvarial bone with no corresponding CT changes or T1/T2 signal changes on MRI. His MRI brain revealed classic cerebellar involvement in ECD without other central nervous system (CNS) involvement. It has been postulated that bone involvement is almost universal in ECD; however, our patient with ECD had ataxia and cerebellar involvement without significant bone involvement, as evidenced by bone scan. This is a rare presentation of ECD affecting the CNS and sparing the skeletal system. It confirms the wide spectrum of presentation this multisystem disease can have.
A 58-year-old man presented complaining of balance problems, falls, and visual disturbance consistent with oscillopsia for 2 years. He had lost 80 pounds over 1 year. His past medical history was significant for chronic folliculitis of the skin that required corticosteroid injections, ulnar artery thrombosis with surgical bypass and maintenance anticoagulation, and surgically repaired bilateral rotator cuff injuries. His family history was negative for ataxia, neuropathy, tremors, and dementia. On exam, patient had horizontal gaze nystagmus and hypermetric saccades in both horizontal and vertical directions. His fundoscopic and pupillary examinations were unremarkable. His speech was ataxic. He had dysmetria on finger-nose test in both upper extremities, though more pronounced of the left upper extremity. Motor and sensory systems were unremarkable, and he had preserved deep tendon reflexes in all extremities. He had a wide-based gait. Brain MRI with contrast revealed T2 hyperintense lesions symmetrically involving the middle cerebellar peduncles and dentate nuclei. The lesions did not demonstrate contrast enhancement. Careful review of his MRI brain revealed normal retro-orbital space and pituitary gland without meningeal enhancement (Fig. 1).
Figure 1. MRI brain. (A) T2 fluid-attenuated inversion recovery image showing hyperintensity of middle cerebellar peduncles extending to the dentate nuclei symmetrically. (B) T1 axial postcontrast showing no contrast enhancement of the lesion depicted in (A).
His thyroid-stimulating hormone, thiamine, vitamin B12, vitamin E, antinuclear antibody, liver enzymes, and electrolytes were normal. His urine and serum sodium and osmolality were within normal limits. We pursued workup for neoplasia: Bone marrow biopsy revealed normocellularity; his abdominal CT scan revealed diffuse strand-like soft tissue densities surrounding the kidneys bilaterally (hairy kidneys) and involving the retroperitoneal fat with confluent nodular masses (Fig. 2). Cerebrospinal fluid (CSF) analysis results were within normal limits, and cytology and flow cytometry were negative for malignant cells. Paraneoplastic panel, including ANNA-1, ANNA-2, ANNA-3, AGNA-1, PCA-1, PCA-2, PCA-Tr, amphiphysin antibody, and CRMP-5-IgG, of both CSF and serum were negative. CSF Venereal Disease Research Laboratory, bacterial, and fungal cultures were also negative. Given the typical appearance of hairy kidneys on CT abdomen and T2 hyperintense lesions of the middle cerebellar peduncles and dentate nuclei, the possibility of non-Langerhans cell histiocytosis (i.e., ECD) was raised. He had an X-ray of his lower extremities to look for sclerosis of the diaphysis or metaphysis of long bones, and results were negative. He had a bone scan with technetium-99 that revealed a non specific tracer accumulation over the left frontal calvarium (Fig. 3). There were no corresponding CT or MRI signal changes of this specific area of increased tracer uptake in the skull. Tissue obtained from retroperitoneal excisional biopsy was tested for markers of lymphoma by flow cytometry and was negative for T- or B-cell non-Hodgkin's lymphoma. Microscopic examination showed foamy histiocytes that expressed the histiocytic marker, CD68, found in ECD and Langerhans cell histiocytosis. To further differentiate the two entities, CD1a and S100 stains were applied and were negative (Fig. 4). The retroperitoneal biopsy finding of foamy histiocytes that stained positive for CD68 and negative for CD1a and S100, in addition to the patient clinical presentation and classic radiological features, confirmed the diagnosis of ECD. Genetic testing of the excised retroperitoneal tissue done later revealed a mutant BRAF gene (V600E, GTC>GAG), further supporting the diagnosis. We elected to treat our patient with Dabrafenib, a BRAF inhibitor similar to Vemurafenib (U.S. Food and Drug Administration–approved medication for treatment of metastatic nonresectable melanoma with BRAF (V600E) mutation). By the time of this work submission, patient was on targeted therapy with Dabrafenib for few weeks only and was following up with our service monthly. Repeat MRI brain to monitor the lesion will be obtained in 3 months after therapy initiation.
Figure 2. CT abdomen revealing strand-like soft tissue densities in the retroperitoneum and surrounding the kidneys, the classic appearance of hairy kidneys
Figure 3. Bone scan using technetium-99 showed no significant tracer uptake in long bones of lower extremities, but revealed increased tracer uptake in left calvarium bone (blue arrow). MRI and CT scan of the same area did not reveal corresponding changes to the area of increased tracer uptake.
Figure 4. Photomicrographs of the retroperitoneal mass biopsy show histological findings compatible with ECD. (A) The soft tissue is involved by a reactive inflammatory infiltrate, with clusters of foamy histiocytes in a background of fibrosis and small lymphocytes (hematoxylin and eosin [H&E] stain: 100×). (B) On high-power examination, the foamy histiocytes contain small, round nuclei without atypia (blue arrows; H&E stain: 400×). (C) The foamy histiocytes express the histiocytic marker, CD68 (blue arrow; immunostain for CD68, clone KP-1: 200×) as well as (D) the senescence marker, p16Ink4a (immunostain for p16Ink4a: 200×). (E) CD1a immunostain is negative. (F) S100 immunostain is negative for the foamy histiocytes. Scattered reactive dendritic cells are positive.
ECD is a non-Langerhans cell histiocytosis disorder characterized by involvement of multiple organ systems, notably the skeletal system and the nervous system in addition to skin, retroperitoneum, lungs, and heart. Individuals affected are often in their fifth to seventh decades of life with a mean age at diagnosis of 53 years and a slight male predominance. The heterogeneity and rarity of the disease and its variable clinical presentation make it one of the most difficult entities to diagnose. The diagnosis is made based on a distinctive histopathological finding in the appropriate clinical and radiological context. Histopathologically, the disease is characterized by tissue infiltration of foamy histiocytes that are CD68(+) and CD1a(−). Whether the histiocytes represent monoclonal neoplastic populations or a polyclonal reactive process is still controversial, with lack of studies involving an appropriate sample size for this determination. A point mutation in the BRAF gene, which is a member of a serine-threonine kinase family and plays a part in the RAS/RAF/MEK/MAPK signaling pathway, is identified in 50% of ECD cases. The high frequency of this specific mutation in both ECD and Langerhans cell histiocytosis suggests a possible common origin of the two diseases, but further studies are needed for determining exact pathogenesis. Histiocytes stain positive for CD68 in both Langerhans cell histiocytosis and ECD; however, CD1a stains only the Langerhans histiocytes (Table 1). At the electron microscopy level, Birbeck granules characterize Langerhans cell histiocytes and are absent in ECD. Clinically, the disease has a wide variety of presentations: In one retrospective cohort, bone pain, mainly in the lower extremities, was the most common symptom and constitutional symptoms, such as fever and weight loss, if not present early in the disease, seem to occur seldom later. Exophthalmos, diabetes insipidus, and retroperitoneal involvement were found in less than one-third of ECD patients. A wide array of neurological symptoms can be encountered in ECD (i.e., headaches, seizures, cranial nerve paralysis, mental status change, ataxia, and loss of libido). Cerebellar involvement was the most common CNS presentation of ECD after diabetes insipidus and orbital involvement and hence should alert the neurologist to consider the diagnosis in the appropriate clinical context. In a retrospective review of 33 patients with biopsy-proven ECD, MRI brain revealed hypothalamic-pituitary involvement in 53% of the cases, orbital involvement in 30%, meningeal involvement in 23%, multiple intra-axial enhancing masses in 17%, and bilateral symmetric T2 hyperintensity in dentate nuclei in 10%. Multiple therapies with corticosteroids, cladribine, interferon-alpha, and infliximab have been tried in the past with various outcomes, but no randomized controlled trials were conducted. Currently, no medication is approved for treatment of ECD, but clinical trials are ongoing, especially with the advent of targeted therapies, such as the BRAF inhibitors, that are showing promise in treating ECD cases with BRAF mutation. In fact, Vemurafenib, a BRAF inhibitor, induced rapid and substantial clinical improvement in three patients with multisystemic severe and refractory ECD with the mutation. Prognosis is dismal in ECD, with one cohort showing a mortality rate of 26% over a course of 55 months, and CNS involvement appears to be an independent indicator of death. Our patient had a rare presentation of ECD with ataxia. His MRI brain revealed T2 hyperintense nonenhacing lesions symmetrically involving the middle cerebellar peduncles and dentate nuclei. ECD should be on the differential diagnosis list of a similar lesion in addition to malignancy (such as lymphoma), paraneoplastic syndromes, fragile X tremor ataxia syndrome, and MSA. Screening for malignancy in our patient revealed classic hairy kidneys on CT abdomen, which was suggestive of ECD in the setting of his cerebellar MRI findings. The diagnosis was biopsy confirmed on a retroperitoneal tissue that revealed the foamy CD68(+), CD1a(−) histiocytes. His lack of skeletal system involvement (Fig. 3) was not typical for patients with ECD, who usually present with long bone involvement at the level of diaphysis and metaphysis with relative sparing or partial involvement of the epiphysis. Bone involvement was reported to be universal in ECD.[13, 14] His CNS involvement was limited to the cerebellum with absence of diabetes insipidus and no evidence of pituitary, orbits, or meninges involvement on MRI. Cerebellar involvement may occur years after diagnosis of diabetes insipidus in ECD or may occur in isolation without other CNS involvement. His brain MRI revealed classic findings of cerebellar ECD,[8, 17] though contrast uptake of the lesion has been described in few cases.[15, 18]