Erdheim-Chester disease – A case report Oboljenje Erdhajm-Č ester

Introduction. Erdheim-Chester disease (ECD) is a rare non-Langerhans-cell histiocytosis. About 500 cases are published so far. It is multisystemic disease characterised by bilateral symmetric long bones sclerosis. Main histopathological finding is accumulation of big foamy histiocytes, immunohistochemically positive to CD68, and negative to S-100 and CD1a. There are no guidelines that reliably identify population that requires therapy, but symptomatic ECD, organ failure and central nervous system involvement require treatment. Case report. We described a patient with a multisystemic form of ECD affecting long bones, the hypophysis, abdomen, and the peripheral nerves. Five years after initial symptoms ECD was suspected. Prednison was initiated, 60 mg once a day. After obtaining the diagnosis of ECD, interferon alpha 2A was introduced, but soon after stopped due to severe side effects. Considering that histiocytes were positive to platelet derived growth factor receptor alpha (PDGFR alpha) imatinib mesylate was started, but after two months stopped due to no clinical and radiological improvement. The disease was worsening and the patient died. Conclusion. We described the patient with intraperitoneal form of ECD, without cardiac and pulmonary involvement. There are several important issues: the diagnosis of ECD could be difficult to make, three treatment regimens were included and the patient died nine years after the initial symptoms due to indolent course of the disease and unsuccessful treatment.


Introduction
Erdheim-Chester disease (ECD) is a rare non-Langerhanscell histiocytosis of unknown etiology.Around 500 cases have been published so far, especially in the last 10 years due to increased awereness of this disease.The disease was named after William Chester and Jakob Erdheim who first described two cases with "lipoid granulomatosis", in 1930 1 .It affects adults, Correspondence to: Stanko Petrović, Military Medical Academy, Clinic of Gastroenterology and Hepatology, Crnotravska 17, 11 000 Belgrade, Serbia.E-mail: stanko53@gmail.comboth sexes equally, rarely affects children.The pathogenesis of ECD is not known.Th1 immune response is dominant, thus suggesting it as inflammatory disease, but a recent finding of BRAF V600E mutation suggests it as a clonal disease, dependent on impaired RAS/RAF/MEK/ERK signalling 2 .Activating mutation of NRAS gene is found in 3.7% of patients 3 .Pathogenic BRAF V600E mutation is found in 54% of patients 4 .The disease is characterized by extensive proliferation and accumulation of histiocytes in tissue, particularly connective and fat ones.It primarily affects long bones leading to bilateral, symmetric cortical sclerosis, sparing epiphysis.Bone lesions could be confirmed on magnetic resonance imaging (MRI), technetium-99m bone scintigraphy, 18 fluoro-2-deoxy-d-glucose ( 18 FDG) positron emission tomography/computed tomography (PET)/CT scanning, but they are often missed on plain radiographs.FDG PET/CT is also usefull for extraskeletal disease and in surveillance 5 .The diagnosis of ECD relies on two criteria, proposed by Veyssier-Belot et al. 6 and they are typical histological and skeletal findings.Almost 50% of the patients have extraskeletal manifestations, including hypophysis, orbit, heart, lungs, kidneys, retroperitoneum, central nervous system (CNS) and skin.The histology is characterized by the accumulation of big foamy histiocytes with lipid-rich eosinophilic cytoplasm.Histocytes are immunohistochemically positive to CD68, negative to S-100 and CD1a, lacking Birbeck granules on electronic microscopy.The prognosis depends upon visceral manifestations.Approximately 50-60% of the patients die after 3 years of disease, most often due to cardiac and pulmonary involvment.Treatment regimens include: glucocorticoids, cyclophosphamide, vincristine, cladribine, methotrexate, lenalidomide, imatinib mesylate, anakinra, interferon alpha, sirolimus, infliximab, vemurafenib, canakinumab, autologous hematopoietic-stem cell transplantation, radiotherapy, and surgery  .

Case report
A male patient, 58 years old, was diagnosed with central diabetes insipidus of unknown etiology.He was treated with substitution therapy -desmopressin (Minirin ® spray).Two years after, surgical ablation of the tumor, affecting soft tissue of the right lower extremity, was done.There was neither bone infiltration, nor distant metastasis.The final histopathological finding showed dedifferentiated liposarcoma or dedifferentiated schwannoma.Following the surgery, the patient was treated with radiotherapy and chemotherapy and scheduled for follow-up.Two years later, due to nausea, abdominal pain and distension, multislice computed tomography (MSCT) of the abdomen was performed.It showed ascites and the thickened peritoneum and mesenteric structures.After that, explorative laparoscopy and biopsy of the omentum, lymph nodes and small bowel mesentery were done.The final histopathological finding confirmed inflamatio chronica xantogranulomatosa textus adiposus.A year later, ECD was suspected based on anamnesis, clinical features and examinations performed (increased serum markers of inflammation, plain radiography survey showing bilateral simmetric cortical sclerosis of the lower extremities sparing epiphysis), wihout cardiac and pulmonary involvement.Prednisone was started, 60 mg once a day, tapered to 15 mg once a day which he was taking for the next three years.
Due to paresthesia and weakness of the lower extremities we performed electromyoneurography (EMNG), showing sensory polyneuropathy.Alpha-lipoic acid was introduced, resulting in partial improvement.Few months later, he developed gangrene of the right lower extremity, thus above knee amputation was performed.Eight months later, we performed revision of the histopathological finding of biopsies of the peritoneum, omentum and lymph nodes, done 4 years ago, with immunihystochemical staining that confirmed the ECD (CD68+, CD1a-, S100-, CD14+, CD163+).After evaluation [upper and lower endoscopy, CT of the abdomen, bone scintigraphy, magnetic resonance imaginig of the lumbosacral spine (MRLS), bone marrow biopsy, peripheral blood and bone marrow samples testing for clonal rearrangments Ig (immunoglobulin)/TCR (T cell receptor) genes, dual-energy x-ray absorptiometry], progressive disease (PD) was confirmed, along with osteoporosis as sequelae of prednison therapy (Figures 1  and 2).Interferon alpha 2A was introduced, 3,000,000 IJ 3 times weekly subcutaneously.Osteoporosis was treated with bisphosphonates.Three months later interferon alpha 2A was discontinued due to severe side effects (nausea, loss of appetite, fever, abdominal pain, diarrhea, depression), and prednisone was restarted, 20 mg once a day.
Additional immunihystochemical staining confirmed that histiocytes were positive to PDGFR alpha, so imatinib mesylate was introduced, 400 mg once a day, with tapering off prednison till discontinuation.After two months of the treatment with imatinib mesylate there was no clinical improvement.Laboratory analysis showed increased serum markers of inflammation, low albumin (21 g/L), so imatinib mesylate was discontinued and prednisone restarted, 20 mg once a day.The introduction of prednisone led to a shortterm clinical improvement.The patient's general condition got worse, swelling of the legs was pronounced, he had syncope.The patient was not motivated for hospitalization, and died.

Discussion
ECD is a rare disease.Considering different clinical features and disease activity, varying from asymptomatic to fulminant organ failure, the diagnosis is usually delayed.Patients without cardiac and pulmonary involvement have longer life expectancy.Intraperitoneal localization of ECD is very rare.That is exactly what we want to emphasize with this case report -the diagnosis is delayed, almost every organ can be affected, intraperitoneal localisation is very rare, there are no established guidelines for treatment.Regarding the abdominal form, the most affected is the retroperitoneum 33 .There are only few cases of ECD with intraperitoneal involvement published [16][17][18][19] , one case describes histiocytes in ascites fluid 15 .The gastrointestinal tract is rarely affected 20,21 .Only one case published in the literature describes mucosal findings with histiocyte infiltration found on histology -nodular gastritis of the entire stomach and small hyperpigmented lesions on colonic mucosa 22 .
Treatment regimen depends on the localization of the disease.Cytotoxic therapy is commonly used, but interferon alpha 2A, 3-9 million units 3 times per week, is considered as the first-line therapy 23 .The mechanism of action of interferon alpha 2A in ECD is not fully understood: it influences maturing and activation of dendritic cells, activates the natural killer cells which leads to the destruction of histiocyte and acts cytotoxicly directly to histiocyte 23 .
As salvage therapy in six patients with severe multisystemic ECD, refractory to other therapies, and histiocytes positive to PDGFR beta, Haroche et al. 24 used imatinib mesylate, 100-800 mg once a day.Autologous hematopoietic-stem cell transplantation in a young patient, after disease progression following a few lines of therapy, has also been described 25 .In case of bone involvement, zoledronic acid showed promising results 26 .Mammalian target of rapamycin (mTOR) could be a new target in ECD.Gianfreda et al. 29 treated 10 patients with prednison and sirolimus, and achieved stable disease in 8 patients.Tumor necrosis factor alpha (TNF α) is a key regulator of inflammation in ECD.Infliximab was safely used in treating two patients, with clinical improvement 30 .BRAF inhibitor vemurafenib could be used to treat patients with BRAF mutation 31 .Recent data suggest that canakinumab is a potential new drug for ECD 32 .Systematic review of 448 patients, published recently, provides detailed clinical features, prognostic and predictive factors.INF α based therapy is a reliable option, but a new therapy is emerging: infliximab, BRAF inhibitors, and mTOR inhibitors 33 .
We described a case with the multisystemic form of ECD, affecting long bones, the hypophysis, abdominal cavity, and peripheral nerves.The disease presented with diabetes insipidus, then manifested as soft-tissue tumor of the right lower extremity.It was probably histiocytoma, unrecognized histopathologically.Xanthogranulomatous inflammation of fat tissue of the omentum was confirmed with laparoscopic biopsy, while the diagnosis of ECD was made based on clinical features, pathological/ immunohistochemical findings and radiological criteria.The differential diagnosis included: Langerhans cell histiocytosis, Rosai-Dorfman disease, multiple myeloma, Whipple's disease, hemophagocytic syndromes.Taking into consideration that the patient was not motivated for chemotherapy, treatment included: prednisone, interferon alpha 2A, imatinib mesylate.Due to dise-ase progression the patient died, nine years after the initial symptoms (five years after the diagnosis was made).

Conclusion
ECD is a rare form of a non-Langerhans-cell histiocytosis of unknown etiology.It affects elderly, usually is unrecognized in the beginning.It is mainly multisystemic, thus it is necessary to start therapy as soon as possible.The prognosis depends on the extraskeletal manifestations of the disease, especially cardiac and pulmonary involvement.There are no guidelines for treatment of ECD.Interferon alpha is thought to be the first-line therapy.New therapy appears on horizon: infliximab, BRAF inhibitors, mTOR inhibitors.

Fig. 1 -Fig. 2 -
Fig. 1 -Bone scyntigraphy -increased accumulation of radiopharmaceutical along the diaphysis of radius, ulna and humerus bilaterally, in the lower part of the left femur and along the left tibia.