Clinical variability in multifocal lymphangioendotheliomatosis with thrombocytopenia: a review of the literature.

Multifocal lymphangioendotheliomatosis with thrombocytopenia (MLT) is a recently recognized disorder characterized by vascular lesions marked by distinct endothelial proliferation. Lesions affect multiple tissues, and MLT can be associated with refractory thrombocytopenia resulting in life-threatening bleeding. Diagnosing MLT may be challenging given its rarity and phenotypic variability. There is no consensus on the optimal management or treatment duration. We report a 4-month-old male who presented with multiple vascular malformations involving the gastrointestinal tract, lung, bones, choroid plexus, and spleen, with minimal cutaneous involvement and no thrombocytopenia. Wedge resection of a pulmonary nodule was strongly positive for lymphatic vessel endothelial hyaluronan receptor 1 favoring MLT despite the lack of thrombocytopenia. The patient's clinical symptoms and vascular lesions improved on sirolimus therapy. We review the literature to highlight the clinical variability of MLT and discuss the diagnostic and therapeutic options for MLT.

Radiation therapy for the treatment of canine progressive cutaneous angiomatosis: Description of 2 cases.

Two dogs with histologically confirmed progressive cutaneous angiomatosis were presented because of extensive and progressive cutaneous lesions of 1 hind limb causing pain and lameness. Radiation therapy was offered to treat disease recurrence after amputation in the first case and as first treatment in the second case. Metronomic therapy was added in both dogs. Complete and partial regression of the cutaneous lesions was achieved, respectively, with a period of 31 months of disease-free interval (first case) and 12 months of stable disease (second case). Self-limiting grades I and II acute side effects were observed. Radiation therapy can be an alternative to surgery in the treatment of inoperable cutaneous progressive angiomatosis.

Radiothérapie pour le traitement de l'angiomatose cutanée progressive canine : description de 2 cas. Deux chiens ayant un diagnostic d'angiomatose cutanée progressive confirmé par histologie ont été présentés en raison de lésions cutanées vastes et progressives d'un membre postérieur qui causaient de la douleur et de la boiterie. La radiothérapie a été offerte pour traiter la récidive de la maladie après l'amputation dans le premier cas et comme premier traitement dans le deuxième cas. La thérapie métronomique a été ajoutée chez les deux chiens. Une régression complète et partielle des lésions cutanées a été obtenue, respectivement, avec un intervalle de 31 mois sans maladie (premier cas) et de 12 mois de maladie stable (deuxième cas). Des effets secondaires aigus spontanément résolutifs de grades I et II ont été observés. La radiothérapie peut représenter un traitement de remplacement à la chirurgie pour le traitement de l'angiomatose cutanée progressive inopérable.(Traduit par Isabelle Vallières).

CLINICOPATHOLOGIC CORRELATION OF RETINAL ANGIOMATOUS PROLIFERATION TREATED WITH RANIBIZUMAB.

PURPOSE: To describe histopathologic features of an eye with retinal angiomatous proliferation (RAP) secondary to age-related macular degeneration treated with serial ranibizumab injections and to correlate these findings with spectral domain optical coherence tomography. METHODS: Histopathologic features from serial sections through the globe of a 93-year-old man with age-related macular degeneration were studied and compared with spectral domain optical coherence tomography images obtained 7 weeks before his death. RESULTS: The pathologic correlate of ranibizumab-treated RAP was a circumscribed, branching paucicellular vascular complex extending from the inner plexiform layer to Bruch membrane. The histopathologic findings corresponded to an area of hyperreflectivity on spectral domain optical coherence tomography imaging, substantiating the reported tomographic appearance of RAP lesions. A frank anastomosis with choroidal or retinal vasculature was not seen in this treated RAP lesion. There was a lack of retinal pigment epithelium underlying the lesion in an area of retinal pigment epithelium detachment. The elastic portion of Bruch membrane appeared intact. Treatment with ranibizumab over an extended period of time may have been associated with a loss of cellularity of the RAP lesion. CONCLUSION: In a patient with ARMD extensively treated with ranibizumab, color fundus photography, fluorescein angiography and SD-OCT images of RAP correlated histopathologically with a paucicellular intraretinal vascular complex.

[The benefit of new angiogenesis (bevacizumab and aflibercept) inhibitors for multiple angiomatosis therapy: a case report]. / Prínos nových inhibitoru angiogeneze (bevacizumab a aflibercept) pro lécbu mnohocetné angiomatózy: kazuistika.

Angiomatosis is a term for multiple, gradually proliferating hemangiomas (angiodysplasia), affecting multiple organs or tissues at the same time. We describe a 12-year course of treatment of a patient with multiple hemangiomas located in the abdomen, retroperitoneum, oesophagus, mediastinum and also in vertebrae. The diagnosis was made in 2005 within probatory laparotomy, at the age of 28 years. The treatment was commenced right after making the diagnosis with interferon α. Due to its adverse effects (fatigue, anorexia), the use of interferon α was limited to the first year, after which the interferon dose was gradually being reduced until it was discontinued completely. From 2006 to 2011 the treatment was based on thalidomide and temporarily also on lenalidomide. By the end of the year 2011 the patient was stabilized through the effect of these drugs, without a need of repeated blood transfusions. In 2012 his condition got worse again, which required several transfusions in one month. We tested metronomic administration of cyclophosphamide and further administration of propranolol, however neither of them improved the patients situation. Injections of octreotide (Sandostatin 0.1 mg twice a day) helped reduce losses during bleeding into the alimentary tract. Still the patient continued to depend on blood transfusions. Therefore, in 2013, bevacizumab was added to the therapy (7.5 mg/kg in 3-week intervals). This treatment stabilized the patient, it reduced the use of transfusions for a period of 2 years, however after 2 years of a successful therapy with bevacizumab there was disease progression shown on CT imaging and hemorrhagic pleural effusion was also detected. After the treatment of hemorrhagic effusion, early in 2015 we transferred to the administration of aflibercept, at first at the dose of 4 mg/kg in 14-day intervals. Arising of massive proteinuria led to the dose reduction to 2 mg/kg while maintaining 14-day intervals. While receiving this dose, the patient tolerates aflibercept thera-py without significant adverse effects. At the time of publication, the patient has been treated with aflibercept for 24 months already, of that for the last ten months he has been fully independent of transfusions. Just before commencement of treatment with aflibercept his conditions required several transfusions in a week. This description demonstrates that the efficiency of individual medications for multiple angiomatosis is always time-limited and newly developed and more efficient drugs are needed to manage the disease. Bevacizumab and aflibercept are beneficial for patients with serious forms of multiple angiomatosis.Key words: aflibercept - angiomatosis - angiodysplasia - bevacizumab - hemangiomas.

TREAT-AND-EXTEND REGIMEN WITH AFLIBERCEPT FOR RETINAL ANGIOMATOUS PROLIFERATION.

PURPOSE: To evaluate the effects of aflibercept therapy using a treat-and-extend regimen on treatment-naïve retinal angiomatous proliferation (RAP) and development of retinal pigment epithelium (RPE) atrophy. METHODS: We retrospectively studied 17 treated eyes with RAP and 13 untreated fellow eyes. We assessed best-corrected visual acuity (BCVA) in logarithm of the minimal angle of resolution (logMAR) units and recorded the total number of injections for 12 months. Central macular thickness (CMT) and central choroidal thickness (CCT) were assessed by optical coherence tomography (OCT), and RPE atrophy extent in the macular area was assessed by fundus autofluorescence. RESULTS: Average BCVA in eyes with RAP was 0.57 logMAR units (Snellen 20/74 or approximately 56.5 ETDRS letters) before treatment and significantly improved to 0.38 (Snellen 20/48 or approximately 66 ETDRS letters, P < 0.01) after 3 months and 0.32 (Snellen 20/42 or approximately 69 ETDRS letters, P < 0.01) after 12 months. Average CMT was 340 µm before treatment and significantly reduced to 133 µm (P < 0.001) after 3 months and 130 µm (P < 0.001) after 12 months. Average CCT was 147 µm before treatment, 123 µm (P < 0.01) after 3 months, and 131 µm (P < 0.01) after 12 months. Average total number of injections was 7.2. Average area of RPE atrophy enlarged by 1.00 mm in treated eyes compared with 0.34 mm in fellow eyes (P < 0.01). The enlarged area of RPE atrophy was inversely correlated with central choroidal thickness after 12 months (rs = -0.49, P < 0.01) and positively correlated with the number of injections (rs = 0.58, P < 0.01). CONCLUSION: Treat-and-extend intravitreal therapy with aflibercept may be effective for improvement and stabilization of visual acuity and exudative change in eyes with RAP. However, choroidal thinning during the treatment regimen may accelerate enlargement of RPE atrophy.

Breast nodularity and ulceration: diffuse dermal angiomatosis a corticosteroid responsive disease.

Diffuse dermal angiomatosis of the breast (DDAB) is an uncommon ulcerative angiomatosis, which occurs in middle aged women with large pendulous breasts, a history of cigarette smoking, and risk factors for atherosclerosis. Based on its rarity, no well-defined therapeutic regimen has been elucidated. We report a case of DDAB in a woman with no history of smoking or radiographic evidence of occluded vasculature who presented with ulceration and pain-associated breast nodularity. She had a complete reproducible response to oral corticosteroids.

Successful treatment of bilateral symmetrical skeletal haemangiomata: a case report.

We describe a case of giant bilateral skull vault haemangiomas in a patient with diffuse skeletal haemangiomatosis. The clinical details, histological and radiographic findings and surgical management are reviewed. This is the first described case of radical surgical management of bilateral giant haemangiomas with relief of intractable headache.

Cystic bone angiomatosis: a case report treated with aminobisphosphonates and review of the literature.

Cystic angiomatosis (CA) is a rare disease characterized by multifocal hemangiomatous and/or lymphangiomatous lesions of the skeleton with possible visceral organ involvement. The exact pathogenetic mechanism of the disease is still unknown. We describe a patient affected by CA of bone treated with surgical procedures and subsequently with intravenous aminobisphosphonates for 7 years. During the follow-up progression of lesions, the painful symptoms, markers of bone turnover, computed tomographic examination, and bone mineral density were evaluated. Aminobisphosphonate therapy showed an immediate effectiveness in reducing bone pain, with a significant decrease in circulating bone alkaline phosphatase and stable radiological findings during clinical follow-up. In addition, at baseline, high levels of bone biomarkers and cytokines (osteoprotegerin, osteopontin, and interleukin-6) capable of controlling bone metabolism and angiomatosis were identified. Aminobisphosphonate treatment produced a decrease of all these increased markers. Local cell therapy with bone marrow osteoblast precursors did not produce any measurable clinical improvement. Aminobisphosphonate therapy represents an elective treatment for bone angiomatosis syndromes, but further studies are necessary to understand the molecular basis of these disorders and of their pharmacological treatment.

Cutaneous reactive angiomatosis with combined histological pattern mimicking a cellulitis.

Cutaneous reactive angiomatoses (CRA) encompass a distinct group of rare benign reactive vascular proliferations that include reactive angioendotheliomatosis, diffuse dermal angiomatosis and reactive intralymphatic histiocytosis. The etiology of these conditions, often associated with either localized or systemic diseases, is poorly understood. We report a 72-year-old woman who presented giant diffuse cellulitis-like plaques on the right lower limb and the pelvis and a reduction of her general condition with fever. Light microscopy studies revealed combined features of reactive angioendotheliomatosis, diffuse dermal angiomatosis and reactive intralymphatic histiocytosis. A small arteriovenous fistula of the right lower leg was thought to act as trigger. Systemic corticosteroids resulted in the clinical remission of the skin lesions. Our observation provides strong evidence that reactive angioendotheliomatosis, diffuse dermal angiomatosis and reactive intralymphatic histiocytosis, previously regarded as distinct forms of CRA, may show overlapping histopathological features and most likely represent facets of the same disease.

[Chronic disseminated intravascular coagulation (DIC) markers in a patient with multiple angiomatosis during treatment with anti-angiogenics: interferon α, thalidomide and lenalidomide]. / Vývoj koagulacních markeru chronické diseminované intravaskulární koagulace (DIK) u pacienta s mnohocetnou angiomatózou v prubehu lécby antiangiogenními léky: interferonem α, thalidomidem a lenalidomidem.

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.

[Successful treatment of angiomatosis with thalidomide and interferon alpha. A description of five cases and overview of treatment of angiomatosis and proliferating hemangiomas]. / Uspesná lécba angiomatózy thalidomidem a interferonem alpha. Popis peti pripadu a prehled lécby angiomatózy a proliferujícich hemangiomu.

Our paper describes 5 patients with a vascular malformation - angiomatosis. In the first patient, a young man, angiomatosis affected the stomach, intestine, the area of mesenterium and retroperitoneum as well as mediastinum. Angiomatous mass had invaded pelvic bones and vertebrae. Treatment was initiated with interferon alpha in a maximum tolerated dose of 3 million units 3 times a week. Because of low efficacy of interferon alpha, thalidomide was added at a dose of 100 mg per day. Bone pain disappeared following a few applications of zoledronate administered in regular monthly intervals. After 3 years of concomitant administration of interferon alpha and thalidomide, we changed the regimen due to adverse effects and are administering thalidomide and interferon alternatively in 4-monthly intervals. Treatment has resulted in 50% reduction, according to imaging, of angiomatous mass, reduced intensity of disseminated intravascular coagulation and disappearance of clinical signs. The second was a case of multiple angiomatosis affecting the intestine only (multiple intestinal angiodysplasias) where we used thalidomide monotherapy. This treatment reduced blood losses and haemoglobin concentrations rose to normal levels. This male patient had consumed 120 transfusion units per year before the initiation of thalidomide. The third case was a slowly progressing vascular malformation of the face. This vascular malformation troubled its sufferer by spontaneous shortening that could not be resolved surgically because of its fragility. Two years of combined treatment with interferon a 6 million unites 3 times a week and thalidomide 100 mg daily led to a reduction and flattening of the malformation, paling of its colour and ceasing of spontaneous bleeding. This development enabled minor surgery--partial excision of this large vascular malformation. Histology examination confirmed that there was no evidence of new capillary formation. Histological examination thus confirmed efficacy of the treatment. The fourth case involved a patient with large vascular malformations affecting supraclavicular region of the neck and nape in whom radiotherapy was applied (54 Gy) leading to a reduction of the malformation mass by a at least 50%. The fifth is a case of an extensive periorbital lymphangioma that diminished following treatment with interferon alpha. These cases illustrate the benefits of combined treatment including thalidomide and interferon alpha in patients with multiple angiomatosis or large proliferating hemangioma (vascular malformation). If combined treatment with thalidomide and interferon a is not possible, it is beneficial to use thalidomide monotherapy. Radiotherapy is another alternative, although it is necessary to apply doses exceeding 50 Gy which may not be always possible.

Intravitreal ranibizumab (Lucentis) in the treatment of retinal angiomatous proliferation (RAP).

BACKGROUND: Retinal angiomatous proliferation (RAP) is a distinct variant of neovascular age-related macular degeneration (AMD). The aim of this study is to evaluate the functional and anatomic outcome after intravitreal ranibizumab (Lucentis) treatment in patients with RAP. METHODS: Prospective study of consecutive patients with newly diagnosed or recurrent RAP treated with intravitreal ranibizumab at the Jules Gonin Eye Hospital between March 2006 and December 2007. Baseline and monthly follow-up visits included best-corrected visual acuity (BCVA), fundus exam and optical coherence tomography. Fluorescein and indocyanine green angiography were performed at baseline and repeated at least every 3 months. RESULTS: Thirty-one eyes of 31 patients were treated with 0.5 mg of intravitreal ranibizumab for RAP between March 2006 and December 2007. The mean age of the patients was 82.6 years (SD:4.9). The mean number of intravitreal injections administered for each patient was 5 (SD: 2.4, range 3 to 12). The mean follow up was 13.4 months (SD: 3, range 10 to 22). The baseline mean logMAR BCVA was 0.72 (SD: 0.45) (decimal equivalent of 0.2). The mean logMAR BCVA was improved significantly (P < 0.0001) at the last follow-up to 0.45, SD: 0.3 (decimal equivalent 0.35). The visual acuity (VA) improved by a mean of 2.7 lines (SD 2.5). Mean baseline central macular thickness (CMT) was 376 microm, and decreased significantly to a mean of 224 microm (P < 0.001) at the last follow-up. Mean reduction of CMT was 152 microm (SD: 58). An average of 81.5% of the total visual improvement and 85% of the total CMT reduction occurred during the first post-operative month after one intravitreal injection of ranibizumab. During follow-up, an RPE tear occurred in one eye (3.2%) of the study group. No injection complications or systemic drug-related side-effects were noted during the follow-up period. CONCLUSIONS: Intravitreal ranibizumab injections appeared to be an effective and safe treatment for RAP, resulting in visual gain and reduction in macular thickness. Further long-term studies to evaluate the efficacy of intravitreal ranibizumab in RAP are warranted.

Efficacy of intravitreal bevacizumab to treat retinal angiomatous proliferation stage II and III.

PURPOSE: To evaluate the efficacy of intravitreal bevacizumab to treat retinal angiomatous proliferation (RAP) stages II and III. METHODS: A retrospective, interventional, nonrandomized multicentric study was performed. The files, optical coherence tomography (OCT) scans, indocyanine green, and fluorescein angiograms of patients with RAP stages II and III who had been treated by intravitreal bevacizumab were retrospectively examined. Final visual acuity, number of injections, and appearance of adverse events were considered as main outcome indicators. RESULTS: Twenty-six eyes from 24 patients (9 male and 15 female) were treated by intravitreal bevacizumab. Fourteen eyes presented RAP stage II and 12 eyes presented RAP stage III. Mean age was 76+/-9 and 79+/-6 years, respectively. Mean initial best-corrected visual acuity (BCVA) was logMAR 0.60+/-0.24 and 1.13+/-0.37, respectively. Mean BCVA was 0.62+/-0.26 and 1.06+/-0.37, respectively, at 6 months (p=0.96 and 0.10, respectively, Student t test for paired data) and 0.63+/-0.26 and 1.04+/-0.37, respectively, at 12 months (p=0.82 and p=0.06, respectively, Student t test for paired data). The average number of injections during the first year was 3.4 and 3.2, respectively. CONCLUSIONS: Intravitreal bevacizumab may stabilize visual acuity during the first year in RAP lesion stage II and III. Visual prognosis seems to be better in RAP II lesions.

Eruptive cherry angiomas and skin melanoma: a fortuitous association?

The aim of the study was to assess the association between eruptive cherry angiomas (CAs) and malignant melanoma (MM). Secondary objectives included investigating (i) this association in different age subgroups, and (ii) the association of eruptive CAs with other variables such as malignant tumours, in general, and immunosuppressive treatments. This cross-sectional study involved all patients referred to the outpatient Dermatology-Oncology Units of the universities of Ferrara and Bologna, Italy, and submitted to total body skin examination. These patients were included in a previously collected series. We recorded age, sex, cutaneous and noncutaneous malignancies, immunosuppressive treatments, and presence of CAs. CAs were arbitrarily considered as 'eruptive' when more than or equal to 10. Variables significantly associated with eruptive CAs were included in the logistic regression analysis, also stratified by age. A total of 1693 patients were included in the present study: 500 patients had malignancies, 460 malignant skin tumours, 263 had MM; 150 patients were immunosuppressed; 804 (47.49%) patients had eruptive CAs. In the whole study population, age, immunosuppressive treatment, MM, other skin and nonskin malignant tumours were significantly associated with eruptive CAs at the multivariate analysis. Multivariate analysis in each age subgroup revealed that the association between MM and eruptive CAs was highly significant in younger patients (≤50 years), significant in the 51-70 year-old subgroup, whereas it lost significance in older patients. These findings suggest an association between MM and eruptive CAs, particularly in the lower and intermediate age groups. Both the nature of this association and its possible impact in clinical practice, especially in MM screening, are yet to be established.

Reversible skeletal changes after treatment with bevacizumab in a child with cutaneovisceral angiomatosis with thrombocytopenia syndrome.

Cutaneovisceral angiomatosis with thrombocytopenia (CAT) syndrome is a rare vascular disorder of the skin and gastrointestinal tract for which there is no standard treatment. We present a case in which a child with CAT syndrome was treated with bevacizumab, a vascular endothelial growth factor inhibitor, and subsequently developed asymptomatic metaphyseal bone lesions. Though not previously described as a side effect, we hypothesize that the use of bevacizumab in a child with active epiphyseal growth plates caused these radiographic lesions. Because of the potential for altered bone growth and metabolism, children receiving VEGF inhibitors should be monitored closely for bony toxicity.