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.

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.

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).

[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.

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.

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.

Graft-versus-host Disease-associated Angiomatosis Treated With Topical Timolol Solution.

INTRODUCTION: Scleroderma-like graft-versus-host disease (GVHD) is an uncommon subtype of chronic GVHD. Vascular lesions rarely arise within areas of scleroderma-like changes and until recent- ly have not been considered to be related entities. Kaffenberg et al1 have grouped this heterogeneous collection of vascular lesions under the term GVHD-associated angiomatosis. Treatment modalities thus far have been mostly ineffective. Topical timolol solution has been used in the treatment of superficial infantile hemangiomas with good success. Here the authors report the first case of GVHD-associated angiomatosis treated with topical timolol solution. METHODS AND MATERIALS: Timolol 0.5% solution was applied daily to 3 lesions on the lower extremities of their patient for 3 months. RESULTS: All lesions decreased in friability and frequency of spontaneous hemorrhage. Le- sions remained stable in size throughout treatment duration, with no growth observed in any lesion. Granulation tissue surrounding all lesions was markedly reduced after the treatment period. CONCLUSION: Topical timolol remains a promising therapeutic option in the treat- ment of GVHD-associated angiomatosis.

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.

Wyburn-Mason Syndrome Associated With Cutaneous Reactive Angiomatosis and Central Retinal Vein Occlusion.

Retinal venous occlusive events are a rare complication of arteriovenous malformations of the retina found in Wyburn-Mason syndrome. The authors present a case of a 28-year-old man diagnosed with Wyburn-Mason syndrome and cutaneous reactive angiomatosis, a reactive angioproliferative disorder induced by vascular occlusion. He developed a central retinal vein occlusion complicated by macular edema and received treatment with intravitreal bevacizumab, which led to resolution of the edema. To the best of the authors' knowledge, this is the first report of an anti- vascular endothelial growth factor agent employed as an effective treatment for macular edema in the setting of Wyburn-Mason syndrome. The association between Wyburn-Mason syndrome and cutaneous reactive angiomatosis is also a novel finding.

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.

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.

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.

Intravitreal bevacizumab versus ranibizumab for the treatment of retinal angiomatous proliferation.

PURPOSE: To evaluate the effects of intravitreal bevacizumab and ranibizumab treatments in retinal angiomatous proliferation (RAP). METHODS: Fifty patients affected by RAP were randomly assigned either to intravitreal bevacizumab injection (IVBI) or intravitreal ranibizumab injection (IVRI). After a loading phase including three consecutive monthly injections, the retreatment was administered in cases of persistent RAP. The primary outcome measures were the mean changes in BCVA between the two treatment groups, and the proportion of eyes gaining 1 and 3 lines at the end of the follow-up. Secondary outcomes included central macular thickness (CMT) changes and progression to more advanced stages of RAP. RESULTS: Fifty patients affected by stage 1 and 2 RAP were recruited. Twenty-six and 24 patients received IVBI and IVRI, respectively. At the baseline, mean best corrected visual acuity (BCVA) values were 0.59 ± 0.21 (LogMAR ± SD, approximately corresponding to 20/80 Snellen Equivalent-SE) in IVBI group and 0.66 ± 0.33 (approximately 20/90 SE) in IVRI group with no statistical difference. At 12-month examination, both groups showed a statistically significant improvement in the BCVA, with a final mean value of 0.43 ± 0.24 (approximately 20/54 SE) in IVBI group and 0.50 ± 0.32 (approximately 20/63 SE) in the IVRI group. A BCVA gain of 1 and 3 lines was registered in 20 and 8 eyes, respectively, in the IVBI group. Similarly, 17 and 7 eyes showed an improvement of 1 or 3 lines, respectively, in the IVRI group. The CMT reduced significantly from baseline to 12-month examination in both groups. A lower proportion of eyes with complete pigment epithelium detachment resolution was noted in the IVBI group than in the IVRI group (40% versus 90%). CONCLUSIONS: Our study shows that both IVBI and IVRI are equally effective in improving the BCVA over a 1-year follow-up in eyes affected by stage 1 and 2 RAP.

Escleroterapia con bleomicina en malformaciones vasculares de bajo flujo. Experiencia y revisión del tema / Bleomycin sclerotherapy for low-flow vascular malformations, our experience and literature review

Las anomalías vasculares son lesiones típicas de los pacientes pediátricos y se dividen en dos categorías: tumores vasculares y malformaciones vasculares de alto y bajo flujo. Estas últimas pueden tratarse de diversos modos: laserterapia, drenaje, aspiración, cirugía o escleroterapia, dependiendo del tipo de lesión y de su localización. Entre los agentes esclerosantes utilizados, la bleomicina ha demostrado tener buenos resultados en el tratamiento de estas lesiones. En este artículo presentamos nuestra experiencia en el tratamiento de las malformaciones vasculares de bajo flujo mediante escleroterapia con bleomicina intralesional. Desarrollamos un estudio descriptivo retrospectivo sobre 30 pacientes que presentaban malformación vascular de bajo flujo y fueron tratados con bleomicina intralesional. Los resultados fueron buenos o excelentes en 22 pacientes y regulares o malos en los 8 restantes. De acuerdo a nuestra casuística y a la literatura revisada, la escleroterapia con bleomicina es una alternativa terapéutica eficaz y segura en el tratamiento de las malformaciones vasculares de bajo flujo (AU)

Vascular anomalies are common in children and can be divided into two categories, vascular tumours and vascular malformations: high-flow or low-flow. The latter can be treated in different ways such as lasertherapy, drainage, aspiration, surgery or sclerotherapy depending on the type and location of the lesion. Among the accepted sclerosing agents, bleomycin has proven good results in the treatment of this condition. Herein we present our experience in the treatment of low-flow vascular malformations with intralesional bleomycin injection. This is a retrospective, descriptive study with 30 patients presenting a low-flow vascular malformation treated with intralesional bleomycin injection. Our results are good or excellent in 22 patients and poor in the other 8. According to our case series and the consulted literature, sclerotherapy with intralesional bleomycin injection is an effective and safe treatment for low-flow vascular malformation (AU)