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Histiocytic diseases caused by proliferation and accumulation of phagocytosing macrophages (foamy macrophages) have many clinical forms. These are classified under "juvenile xanthogranuloma" within the WHO classification of blood disorders. Localized forms with benign course include normolipaemic xanthomatosis, xanthogranuloma and necrobiotic xanthogranuloma. Disseminated forms in children take a form of so called "disseminated juvenile xanthogranuloma" or Erdheim-Chester disease in adults. We describe a case of a patient who, at 53 years of age, first noticed yellow granulomas on her eyelids. The disease progressed gradually and, at 59, affects the eyelids as well as their closest surroundings. According to MR and PET-CT, the disease gradually infiltrated the inside of the orbit, orbital fat as well as extraocular muscles and started to cause exoftalmus of one of the eyes. Propagation of the xanthogranuloma into the orbit and infiltration of extraocular muscles might impair eye function. Over the last year, the patient complained of cough. Pulmonary function evaluation confirmed recent asthma bronchiale. These findings correspond to periocular xanthogranuloma associated with adult-onset asthma. No other abnormities have been shown in this patient. Exoftalmus was observed in 2011 after 6 years of monitoring with very slow progression of eyelid and extraocular infiltration. Therefore, prednisone was initiated in 2011, leading to cessation of exoftalmus. It is not known at present whether this is a permanent improvement with a suppression of histiocytary proliferation or whether this was a temporary improvement due to suppression of inflammatory changes in the xanthogranuloma with no effect on histiocytary proliferation. Progression during therapy with corticosteroids would warrant cytostatic treatment. The discussion section provides an overview of diseases caused by foamy histiocytes with illustrations and an overview of experiences with their treatment.

Introduction: Pulmonary Langerhans cell histiocytosis (PLCH) is a rare cause of interstitial lung disease characterized by formation of nodules in the active phase of the disease that evolve into nonactive cystic lesions later on. To evaluate PLCH activity in patients, we developed a new method for measuring diffuse metabolic activity on fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) using a lung-to-liver activity ratio., Material and Methods: We retrospectively studied a series of 4 FDG-PET and 23 FDG-PET/CT scans from 7 patients with PLCH and analyzed a sample of 100 randomly chosen FDG-PET/CT studies free from any known lung or hepatic diseases. Maximum standardized uptake value (SUVmax) in a spherical volume (6-8 cm in diameter) in the right lung was put into relation with SUVmax in a spherical volume (9-10 cm in diameter) in the reference liver parenchyma to set up the SUVmaxPULMO/SUVmaxHEPAR index. The index values were compared to the disease course in each patient., Results: In patients with PLCH, a close correlation between the index value and the disease course was found in all seven subjects, where the increasing index values indicated disease activity, while decreasing index values were observed after therapy administration. In the group of 100 healthy control subjects, we found index values lower than 0.3 in 80% and lower than 0.4 in 96% [range: 0.14-0.43; 0.24±0.07 (100)]., Conclusion: Measuring SUVmaxPULMO/SUVmaxHEPAR values and their time-trend monitoring represent simple, noninvasive screening tools allowing an early diagnosis and treatment response follow-up assessment in patients with PLCH., (Copyright © 2012 Elsevier Inc. All rights reserved.)

We describe a case of an Erdheim-Chester disease patient. First line chemotherapy treatment with 2-chlorodeoxyadenosine did not reduce fluorodeoxyglucose accumulation in pathological lesions. The patient had continuously increased CRP values of 17-20 mg/l. The disease continued to cause subfebrile temperatures and significant fatigue that made the patient to spend most of the daytime in bed. To manage the permanently increased inflammation markers, we decided to start treatment with anakinra, successfully used in some other autoinflammatory diseases (e.g. Schnitzler syndrome). We have now been able to evaluate the first 6 months of treatment. Daily subcutaneous administration of anakinra (KineretTM 100 mg daily) led to normalization of CRP values, cessation of subfebrile temperatures and, importantly, significant reduction of fatigue. Time periods the patient was able to spend out of the bed increased significantly. Consequent to the reduced fatigue, the patient was able to perform basic household tasks he was unable to undertake without treatment. After 3 months of treatment, fatigue of the same intensity returned following a short interruption of therapy. The CRP values went up again to 12 mg/l. CRP value returned back to norm and fatigue ceased after re-initiation of daily Kineret injections. Objective treatment response was assessed by measuring the degree of fluorodeoxyglucose accumulation in pathological bone lesions. PET-CT was performed before and 3 and 6 months after anakinra initiation. Intensity of accumulation did not change significantly after the first 3 months of therapy but decreased after 6 month therapy. Follow up CT of abdominal cavity was performed at the end of the 6th month of treatment. Presented CT images from before and 6 months after the treatment evidence an obvious reduction in fibroid changes in the retroperitoneum. Daily administration of anakinra to a patient with active Erdheim-Chester disease significantly reduced intensity of fatigue and improved quality of life, led to a reduction in inflammatory markers and regression in retroperitoneal fibrotization.

Depending on the extent of organism affected, there is a systemic (amyloid is deposited in the interstitial space of multiple tissues and organs) and localized (amyloid is deposited in one or a few solitary lesions) form of amyloidosis. Localized forms of amyloidosis have a significantly better prognosis than the systemic ones. The respiratory tract might be affected by diffuse interstitial involvement, associated with systemic AL-amyloidosis, as well as localised involvement of respiratory tract (localised laryngotracheobronchial amyloidosis) or pulmonary parenchyma called nodular form of localized pulmonary amyloidosis. Tracheobronchial form may affect larynx and bronchial tree, and forms plaques or nodules in the epithelium of the respiratory tract. Nodular form causes spherical or irregular lesions in the pulmonary parenchyma, indistinguishable from pulmonary parenchyma metastases. We describe a two-year follow up of a patient with nodular form of pulmonary amyloidosis. The patient had multiple lesions in both lungs, clearly visible on HRCT (High Resolution Computer Tomography) that intensively accumulated fluorodeoxyglucose (FDG) during the first PET-CT. At the time of diagnosis, the largest lesion SUV for FDG accumulation was 8.2. Histochemical analysis showed that amyloid consisted of the light λ chains, i.e. AL-amyloid. Investigations to detect a systemic form of amyloidosis, if present, were negative. The patient had no monoclonal immunoglobulin either in the urine or serum (negative immunofixation) and had normal levels of free light chains in the serum. Her symptoms were previously suggestive of the Sjögrens syndrome. However, the rheumatologist consulted at the time of diagnosis of the nodular form of pulmonary amyloidosis did not find any signs of an active systemic connective tissue disorder. CRP was repeatedly normal. When systemic AL-amyloidosis was excluded, we decided to only monitor lesion development with no treatment intervention. The patient had 3 PET-CTs. CT showed that no lesions enlarged, some lesions decreased in size slightly. It should be emphasized that follow-up PET-CTs did not show increased FDG accumulation. We assume that the increased FDG accumulation in pulmonary lesions seen during the first PET-CT was due to the activity of the cells that formed this amyloid and that this activity spontaneously ceased, leading to normalization of FDG accumulation in pulmonary nodules. PET-CT is useful for monitoring of the development of pulmonary nodular amyloidosis. Normalization of originally increased FDG accumulation in amyloid lesions suggests cessation of the process of amyloid formation and is a positive prognostic sign.

Background: Multiple angiomatosis is a rare disease with angiomatous formations in multiple organs and tissues and associated with a risk of fatal bleeding., Case Description: In this patient, the bones, pleural and peritoneal cavities and digestive tract were involved. The patient had long-term been administered zoledronate that provided relief from bone pain as early as after the second dose. The effect of antiangiogenics was evaluated on CT and MRI. Since angiomatous proliferation is associated with chronic disseminated intravascular coagulation (DIC) and anaemisation, blood count and fibrinogen as well as D-dimer and soluble fibrin monomer concentrations are also used to assess treatment response., Results: Before treatment, D-dimer levels were in excess of 20 μg/mL, fibrinogen 1.4 g/L and soluble fibrin monomers were at measurable levels. During treatment with interferon α at a dose of 6 million units 3 times a week with the dose reduction after 10 month, the median fibrinogen concentration increased to 1.5 (1.2-2.0) g/L, the median D-dimer levels declined to 17.2 (13.4-20.0) μg/mL and fibrin monomers were still detectable. Thalidomide therapy (100 mg/day) provided reduction in the median D-dimer levels to 6.07 (4.71-10.21) μg/ml and increase in median fibrinogen concentration to 1.9 g/L; soluble fibrin monomers were unidentifiable. CT imaging suggested significant reduction of angiomatous mass. Progressing neuropathy required dose reduction of thalidomide to 50 mg/day, leading to D-dimer increase. Lenalidomide 10 mg/day provided an increase in median D-dimer concentration to 10.8 (10.8-17.35) and decline in the level of haemoglobin to a median of 124 (135-117) g/L. Soluble fibrin monomers became detectable again. Therefore, a low dose of lenalidomide 10 mg/day was combined with thalidomide 100 mg and, subsequently, 50 mg/day. Treatment with lenalidomide 10 mg and thalidomide 50 mg provided median D-dimer levels of 9.32 and the disease has remained stable for 9 months., Conclusion: Thalidomide 100 mg/day stabilized multiple angiomatosis better than interferon alfa. Thalidomide 50 mg/day was insufficient to maintain disease stability. Lenalidomide at a dose of 10 mg was tolerated really well but this dose was insufficient to maintain low D-dimer levels and normal haemoglobin concentrations. The combination of lenalidomide 10 mg and thalidomide 50 mg daily stabilized the disease for 9 months.

Backgrounds: Multiple angiomatosis is a rare disease causing angiomatous lesions in multiple organs and tissues with a risk of life-threatening haemorrhage., Observation: A young man was diagnosed with multiple angiomatosis at the age of 28 after two years of back and abdominal pain. Laparotomy revealed multiple spongy lesions mostly within the retroperitoneal space. Also, an involvement of the gut wall, bones and mediastinum was evident. After 6 years of treatment, the disease has been stabilized. Bone pain ceased with a significant contribution of zoledronate. Using CT and MR imaging, the effectiveness of antiangiogenic drugs was evaluated. Furthermore, treatment response was evaluated using laboratory values for coagulation and blood count, as angiomatous proliferation is known to be associated with disseminated intravascular coagulation and anaemia., Results: Baseline laboratory examination revealed elevated D-dimer (more than 20 µg/mL), low fibrinogen (1.4 g/L), and the presence of fibrin monomers. After treatment with 6 mil. IU of interferon-alpha thrice weekly, there was only partial improvement in D-dimer (17.2 µg/mL) and fibrinogen (1.5 g/L) concentrations but fibrin monomers remained positive. After thalidomide (100 mg daily), D-dimer decreased to 6.1 µg/mL and fibrinogen levels increased to 1.9 g/L with the disappearance of fibrin monomers. CT scanning showed significant regression of angiomatous lesions. Progressive neuropathy was the reason to lower the dose of thalidomide by half and this caused D-dimer to rise again. Switching to lenalidomide 10 mg daily led to an increase in D-dimer to 10.8 µg/mL and decrease in haemoglobin concentration to 124 g/L. Fibrin monomers became positive again. Combined therapy with thalidomide (50 mg/day) and lenalidomide (10 mg days 1-21 in 28-day cycles) has led to stabilisation of the disease. Median concentration of haemoglobin increased to 131 (84-141) g/l. The median of D-dimer decreased to 9.3 (8.0-17) µg/mL., Conclusion: Thalidomide in the dose of 100 mg daily led to better stabilisation of the disease than interferon-alpha. However, lowering the dose because of adverse effects failed to be effective sufficiently. Lenalidomide 10 mg daily was well-tolerated but insufficient to improve D-dimer and haemoglobin concentrations. Therefore, for further treatment we have decided to use the combination of lenalidomide and thalidomide in doses of 10 mg and 50 mg, respectively because both drugs have desirable antiangiogenic activities with different adverse effect profiles. On this therapy, the patients disease has been stable for 9 months.

Background: The effectiveness of cladribine depends on the ratio of activating (deoxycytidine kinase) and inactivating (5-nucleotidase) enzymes. Not only is this ratio high in resting lymphocytes but also in Langerhans cells as well in some other histiocytic cells. Therefore, cladribine shows high effectiveness in patients with Langerhans cell histiocytosis (LCH). In 2003, the first report on excellent results with cladribine in first line treatment of patients with multisystem or multifocal LCH was published. That is why we use cladribine for adult patients with relapsing form of LCH and also for first line treatment of multifocal and multisystem LCH at our department., Patients and Methods: Since 2001, we have treated altogether 10 adults (9 male and 1 female) with cladribine. The median age at diagnosis was 31.5 years (range: 5-45). The multiorgan form of the disease was present in 8 patients, and 2 patients had the multifocal skeletal form with aggressive disease course. Cladribine at a dose of 5 mg/m2 SC per day was given as a 5-day course at 28-day intervals. In cases of insufficient effectiveness, in two patients after the 3rd cycle with cladribine monotherapy, we proceeded to combination therapy with cladribine of 5 mg/m2 per day, cyclophosphamide 150 mg/m2 per day and dexamethasone 20 mg per day, all on days 1-5. We planned 6 cycles at the most., Results: The median of cladribine cycles was 5 (range: 4-6). Altogether, 10 patients finished therapy; out of them 9 are in complete remission with the follow-up median of 26 months (range: 16-94). Treatment failure was noted only in 1 patient - in 60 days after therapy cessation the disease progressed and required further treatment (CHOEP, high-dose BEAM chemotherapy with autologous transplantation followed by Revlimid treatment and allogeneic transplantation). Treatment response - disappearance of infiltrate in the pituitary infundibulum - was observed in 2 patients with LCH affecting the pituitary infundibulum., Conclusion: Cladribine is a suitable medication for multiorgan and multifocal forms of LCH. In our group of ten evaluated patients, cladribine therapy resulted in 90% of long-term complete remissions. Three patients had CNS involvement and in all three patients, treatment responses have been achieved.

Adult Langerhans cell histiocytosis (LCH) usually follows a favorable course. Very rarely, however, multi-system (multi-organ) LCH difficult to manage either with traditional first line treatment (vinblastine, mercaptopurine, prednisone or etoposide) or 2-chlorodeoxyadenosine occurs. In these patients, other treatment modalities have to be used. We describe a patient with LCH manifesting with generalized lymphadenopathy and infiltrating the pulmonary parenchyma and skin. The disease activity was always associated with B-symptoms (weight loss, subfebrile states, night sweats). Histological investigations repeatedly showed higher proliferation activity than that usual in adult patients with LCH. Expression of Ki-67 proliferation marker was up to 30% and there were 8-10 cells in mitosis in the microscope viewing field. Therefore, therapy started with the application of stimulation regimen (cyclophosphamide 2 g/m2 on day 1 and etoposide 200 mg/m2 on days 1-3) followed by collection of peripheral blood stem cells. Then, treatment with 2-chlorodeoxyadenosine, the first 3 cycles as monotherapy of 5 mg/m2 SC on days 1-5 in 28-day cycles, the next 3 cycles in combination with cyclophosphamide 150 mg/m2 on days 1-5 and methylprednisolone 250 mg on days 1-5, was used. However, the disease relapsed 2 months after completion of the therapy. This early relapse was treated with 4 cycles of CHOEP chemotherapy (cyclophosphamide, doxorubicin, vincristine, etoposide, prednisone). Following the 4th cycle of CHOEP, high-dose BEAM chemotherapy (carmustine, etoposide, cytarabine, melphalan) with autologous stem cell transplantation were administered. According to the follow-up PET-CT examination, this treatment resulted in complete disease remission. However, the disease relapsed again in the lymph nodes, lungs, skin and bones 5 months after the high-dose chemotherapy. The progression was documented on PET-CT scanning. Lenalidomide 25 mg daily for 21 days in 28-day cycles with dexamethasone 20 mg once a week were administered as the 4th line treatment. After the 4th cycle of lenalidomide, PET-CT was performed, where the CT component suggested a significant reduction (more than 50%) in the size of the lymph nodes and the PET component showed substantial reduction in fluorodeoxyglucose accumulation in the affected lymph nodes as well as in the bone lesions. HRCT showed disappearance of pulmonary nodules. During the treatment, CRP levels declined and hemoglobin rose from 110 to 141 g/l, i.e. partial remission was achieved after 4 cycles. Etoposide (100 mg IV) was added to lenalidomide and dexamethasone on days 22, 23 and 24 of the above mentioned 28-day cycle. The added etoposide further intensified treatment response. In all, 11 cycles of this chemotherapy were given, resulting in complete remission confirmed by follow-up PET-CT. The achieved remission was consolidated using allogeneic bone marrow transplantation after FLAMSA reduced intensity conditioning without amsacrine. Four months after allogeneic transplantation, the patient has been relapse free. Herein we presented treatment response of highly aggressive LCH to lenalidomide. The used four cycles led to partial remission only and with the combination of lenalidomide, dexamethasone and etoposide the treatment response was further intensified to complete remission.