Decreased vascularization of retroperitoneal kaposiform hemangioendothelioma induced by treatment with sirolimus explains relief of symptoms.

Kaposiform hemangioendothelioma (KHE) is a vascular tumor with poor prognosis. We present a child with progressive disability, extreme pain, and autonomic dysfunction due to a retroperitoneal KHE where radiologic characteristics were essential for diagnosis and monitoring of response to therapy. He received sirolimus, and the symptomatology resolved completely. Repeat MRIs revealed fast marked decrease in vascularity of the tumor, although the volume was not significantly affected. We suggest that the sirolimus-induced tumor de-vascularization may explain the clinical and coagulopathy improvement.

Inhibition of phosphoinositide 3-kinase is associated with reduced angiogenesis and an altered expression of angiogenic markers in endothelioma cells.

The phosphoinositide 3-kinase (PI3k) signaling pathway is involved in the regulation of numerous cellular activities. The pathway has also been implicated in the development of various tumors. In the context of vascular tumors, the role of the PI3k signaling still needs to be established. In the present study, the effects of blocking PI3k activation on endothelioma cells derived from mice with vascular tumors were investigated using the crystal violet assay, real-time cell analysis, light microscopy, the aorta ring assay and antibody arrays. The suppression of PI3k led to the inhibition of cell growth, cell migration, as well as angiogenesis. The inhibition of these processes correlated with low Akt activity. Antibody array analysis revealed that there was a suppression of several proangiogenic molecules, including Eotaxin-1 and basic fibroblast growth factor (bFGF) in cultures treated with LY294,002, an inhibitor of PI3k. At the same time, LY294,002 increased the expression of platelet factor 4 (PF4) and the Fas ligand (FasL), molecules which have antiangiogenic properties. The results suggest that PI3k may play a role in the expression of some of the key regulatory molecules involved in angiogenesis, and perhaps in the growth of endotheliomas. As such, it is plausible that the PI3k/Akt pathway may be a target for therapeutic molecules designed for the treatment of endothelial tumors.

Cytologic diagnosis of intravascular papillary endothelial hyperplasia: a report of two cases and review of cytologic literature.

BACKGROUND: Intravascular papillary endothelial hyperplasia (IPEH), previously known as 'Masson's hemangioma', is a reactive endothelial proliferation that occurs most commonly in the vessels of the head, neck, and extremities. The cytologic findings of the lesion are varied and depend on the age of the lesion. CASES: Case 1 is a 61-year-old man who presented with a swelling on the medial aspect of the forearm. The clinical diagnosis was lipoma. Cytologic smears showed spindle cells tagging onto a rich capillary network and smaller round cells arranged around hyaline cores. The cytologic diagnosis was benign vascular tumor. On histolopathogic examination a diagnosis of IPEH was given. Case 2 is a 45-year-old man who presented with swelling on the dorsal aspect of the wrist. The cytologic diagnosis of giant cell tumor was made based on the presence of scattered spindled cells and multinucleate giant cells. The giant cells had various shapes like round or crescent and had 10-25 nuclei. The lesion was excised and a diagnosis of IPEH was rendered. CONCLUSION: These two cases highlight the varied cytomorphology of IPEH making the pinpoint diagnosis of this lesion difficult on cytologic smears.

Kaposiform hemangioendothelioma with Kasabach-Merritt phenomenon: successful treatment with embolization and vincristine in two newborns.

Kaposiform hemangioendothelioma (KHE) is a rare vascular tumor and has a high mortality in newborns when associated with Kasabach-Merritt syndrome (KMS). In two newborns with KHE and severe KMS refractory to medical treatment, emergency embolization led to clinical improvement in the acute neonatal setting by reducing tumor volume, increasing the platelet count, and improving other clotting parameters. Systemic vincristine treatment was added for further tumor control. Both patients remained symptom-free at long-term follow-up.

Usefulness of D2-40 immunohistochemistry for differentiation between kaposiform hemangioendothelioma and tufted angioma.

BACKGROUND: Recent investigations have demonstrated the utility of the monoclonal antibody D2-40 as a marker for lymphatic endothelium. D2-40 can be used on formalin-fixed and paraffin-embedded materials. Our objective was to elucidate, using D2-40 immunohistochemistry, the differences among capillary hemangiomas, and especially between kaposiform hemangioendothelioma (KHE) and tufted angioma (TA). We studied four cases of KHE, nine cases of TA, and 31 cases of other vascular tumors. Antibodies against CD31, CD34, factor VIII-related antigen, and GLUT1 were also applied. RESULTS: In KHE, D2-40 was markedly reactive for three and partially for one of four cases in the peripheral area of Kaposi's sarcoma-like proliferative capillaries and negative in the surrounding dilated vessels. In TA, D2-40 was partially positive in the surrounding dilated vessels and negative in cannonball-like proliferative capillaries. CONCLUSIONS: Our results suggest that D2-40 is a useful antibody for immunohistochemical discrimination between KHE and TA. In addition, the difference of immunostaining pattern of D2-40 is limited to the peripheral area of capillary proliferation and surrounding dilated vessels; therefore, it is suggested that KHE and TA may reflect different stages in the evolution of a single entity. Namely, they may originate from stem cells possessing the characteristics of both lymphatic and blood vessel endothelial lineages.

Clinical study of preoperative angiography and embolization of hypervascular neoplasms in the oral and maxillofacial region.

OBJECTIVE: The purpose of this study was to investigate the angiographic features of hypervascular head and neck neoplasms and to evaluate the effects of embolization on these lesions. METHODS: Angiograms and operation records of 25 patients with hypervascular neoplasms (23 neck paragangliomas, 1 hemangiopericytoma, and 1 hemangioendothelioma) were retrospectively analyzed, and the effects of 8 embolization procedures were estimated. RESULTS: Angiograms demonstrated that 23 neck paragangliomas (NPs) were manifested as richly vascularized lesions, and were divided into 3 types. Type I NPs (n = 2) were located cranial-laterally to the carotid bifurcation, and were removed with an intact carotid artery and injured vagus nerve. Type II (n = 17) lesions widened the bifurcations in 16 of 17 cases. During the operation, the continuity of the internal carotid arteries was preserved in 15 of 17 cases. Type III (n = 4) lesions enveloped the carotid bifurcations, and were removed together with the bifurcations in 3 of 4 cases. In 6 type II paraganglioma cases intra-arterial embolization was employed and the paragangliomas were removed with less blood loss (238 mL) than the nonembolized group (600 mL). Additionally, the infratemporal hemangiopericytoma and the parotid hemangioendothelioma were embolized and removed uneventfully. CONCLUSIONS: Angiographic studies are highly valuable for the diagnosis and preoperative analysis of hypervascular head and neck neoplasms. Also, embolization therapy may minimize intraoperative blood loss. Both methods should be employed in a team approach to lesion treatment.

Cuidados paliativos / Palliative care

No disponible

Combretastatin family member OXI4503 induces tumor vascular collapse through the induction of endothelial apoptosis.

The mechanism of tumor cell killing by OXI4503 was investigated by studying vascular functional and morphological changes post drug administration. SCID mice bearing MHEC5-T hemangioendothelioma were given a single dose of OXI4503 at 100 mg/kg. Tumor blood flow, measured by microsphere fluorescence, was reduced by 50% at 1 hr, and reached a maximum level 6-24 hr post drug treatment. Tumor vascular permeability, measured by Evan's blue and hemoglobin, increased significantly from 3 hr and peaked at 18 hr. The elevated tumor vessel permeability was accompanied by an increase in vascular endothelial growth factor (VEGF) from 1 hr post drug treatment. Immunohistochemical staining for CD31 and laminin showed that tumor blood vessels were affected as early as 3 hr but more prominent from 6 hr. From 12 hr, the vessel structure was completely destroyed. Histopathological and double immunohistochemical staining showed morphological change and induction of apoptosis in endothelial cells at 1-3 hr, followed by tumor cell necrosis from 6-72 hr. There were no statistically significant changes of Evan's blue and hemoglobin contents in liver tissue over the time course. These results suggest that OXI4503 selectively targets tumor blood vessels, and induces blood flow shutdown while it enhances tumor blood vessel permeability. The early induction of endothelial cell apoptosis leads to functional changes of tumor blood vessels and finally to the collapse of tumor vasculature, resulting in massive tumor cell necrosis. The time course of the tumor vascular response observed with OXI4503 treatment supports this drug for development as a stand alone therapy, and also lends support for the use of the drug in combination with other cancer therapies.

Oxi4503, a novel vascular targeting agent: effects on blood flow and antitumor activity in comparison to combretastatin A-4 phosphate.

Oxi4503, which is the diphosphate prodrug of combretastatin A1, is a novel vascular targeting agent from the combretastatin family. Another member of this family, Combretastatin A-4 phosphate (CA4P), is a well-characterized vascular targeting agent already being evaluated in clinical trials. The potential for tumor vascular targeting by Oxi4503 was assessed in a mouse system. This approach aims to shut down the established tumor vasculature, leading to the development of extensive tumor cell necrosis. The vascular effects of Oxi4503 were assessed in the s.c. implanted MDA-MB-231 adenocarcinoma and the MHEC5-T hemangio-endothelioma in SCID mice and in a range of normal tissues. Blood flow was measured by i.v. injection of fluorescence beads, while quantitative fluorescence microscopy was used to measure the spatial heterogeneity of blood flow in tumor sections. Oxi4503 induced the shutdown of tumor blood vessels in a dose-dependent pattern with an ED50 at 3 mg/kg in contrast to 43 mg/kg of CA4P. Quantitative fluorescence microscopy showed that Oxi4503 increased the spatial heterogeneity in tumor blood flow. Oxi4503 affected peripheral tumor regions less than central regions, although this was not as pronounced as seen with CA4P, where only central regions were affected. The vascular shutdown induced by administration of Oxi4503 at a dose of 6 mg/kg resulted in extensive cell loss 24 hours following treatment, which translated into a significant effect on tumor growth. Tumor growth was completely repressed at doses above 12.5 mg/kg of Oxi4503, while doses above 25 mg/kg showed tumor regression and even complete regression in some animals. These results are promising for the use of Oxi4503 as a tumor vascular targeting agent. Moreover the potent antitumor effect when administered as a single agent suggests a different activity profile than CA4P.

Inhibition of fibroblast growth factor-2-induced vascular tumor formation by the acyclic nucleoside phosphonate cidofovir.

Cidofovir [(S)-HPMPC; (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine] is an antiviral drug that has been approved for the treatment of cytomegalovirus retinitis in AIDS patients. Cidofovir also possesses potent inhibitory activity against various human papillomavirus-induced tumors in animal models and patients. In addition, cidofovir inhibits the development of murine polyomavirus-induced hemangiomas in rats by an as-yet-uncharacterized, antivirus-independent mechanism. Here we report the inhibitory effect of cidofovir on the development of virus-independent vascular tumors originated by basic fibroblast growth factor (FGF2)-overexpressing endothelial cells (FGF2-T-MAE cells). In vitro, cidofovir was cytostatic to FGF2-T-MAE cells at a 50% cytostatic concentration of 6.7 microg/ml. Cidofovir concentrations >25 microg/ml resulted in cytotoxicity because of induction of apoptosis. Cidofovir did not affect FGF2-T-MAE cell sprouting in three-dimensional fibrin gel and morphogenesis on Matrigel at noncytotoxic concentrations. In vivo, cidofovir (100 microg/egg) completely suppressed hemangioma formation on the chick chorioallantoic membrane (CAM) induced by intra-allantoic injection of FGF2-T-MAE cells, without affecting the formation of normal CAM vessels. Accordingly, cidofovir applied locally at 200 microg/disc, reduced neovascularization on the CAM by only 35%. Intratumoral or systemic administration of cidofovir caused a significant inhibition of the growth of s.c., i.p., or intracerebral FGF2-T-MAE xenografts in nude mice and severe combined immunodeficient mice. Drug-induced apoptosis was observed in FGF2-T-MAE tumors as soon as 2 days after the beginning of treatment. In conclusion, cidofovir appears to inhibit the growth of endothelium-derived tumors via induction of apoptosis without exerting a direct antiangiogenic activity.

[Endovascular papillary angioendothelioma]. / Endovaskuliarnaia papilliarnaia angioéndotelioma.

One case of a rare vascular tumor which occurs mainly in the childhood is presented. The tumor has a tendency to recurrence and metastases into the regional lymph nodes in spite of a relatively mature structure.

Vascular endothelial growth factor receptor-3 (VEGFR-3): a marker of vascular tumors with presumed lymphatic differentiation, including Kaposi's sarcoma, kaposiform and Dabska-type hemangioendotheliomas, and a subset of angiosarcomas.

Recently, a novel monoclonal antibody to vascular endothelial growth factor receptor 3 (VEGFR-3), a tyrosine kinase receptor expressed almost exclusively by lymphatic endothelium in the adult, has been shown to react with a small number of cases of Kaposi's sarcoma (KS) and cutaneous lymphangiomas. We sought to extend these studies to a large number of well-characterized vascular neoplasms to evaluate diagnostic uses of this antibody and to determine whether it defines them in a thematic fashion. Formalin-fixed, paraffin-embedded sections from 70 vascular tumors were immunostained with antibodies to VEGFR-3 von Willebrand factor (vWF), and CD31. Anti-VEGFR-3 was positive in 23 of 24 KS, 8 of 16 angiosarcomas (AS), 6 of 6 kaposiform hemangioendotheliomas, 4 of 4 Dabska tumors, and 2 of 13 hemangiomas. Positively staining angiosarcomas were characterized either by a prominent lymphocytic component, a hobnail endothelial cell similar to that encountered in the Dabska tumor, or spindled areas resembling KS. No VEGFR-3 expression was noted in any cases of epithelioid hemangioendothelioma, pyogenic granuloma, littoral angioma, or stasis dermatitis. vWF expression was seen in 10 of 13 KS; 13 of 14 AS; 4 of 5 kaposiform hemangioendotheliomas; and all Dabska tumors, hemangiomas, lymphangiomas, epithelioid hemangioendotheliomas, vascular malformations, stasis dermatitis, and splenic littoral angiomas. CD31 expression was present in 12 of 13 KS, 13 of 14 AS, and in all other cases. Expression of VEGFR-3 is a very sensitive marker of KS, kaposiform, and Dabska-type hemangioendotheliomas, suggesting that all show at least partial lymphatic endothelial differentiation. Expression of VEGFR-3 does not reliably discriminate KS from AS. However, the expression of VEGFR-3 by certain AS having Kaposi-like areas, a prominent lymphocytic infiltrate, or hobnail endothelium may define subset(s) having phenotypic, if not pathogenetic and biologic, differences.

Infantile hemangioendothelioma. A case report.

The case of a 3-month-old boy with a hepatic infantile hemangioendothelioma is reported. There was no previous history of disease and no symptoms, only an incidentally found abdominal mass. The case is presented as an example of establishing the diagnosis, deciding upon the treatment, and performing the follow-up using only non-invasive imaging techniques.

Interferon alpha-2b at low doses as long-term antiangiogenic treatment of a metastatic intracranial hemangioendothelioma: a case report.

We describe a case of intracranial haemangioendothelioma in a 20-year old female patient who presented severe neurological symptoms and relapsed after two surgical interventions. The patient was treated with low doses of recombinant interferon alpha-2b (1 MUI three times a week) after surgical resection which led to recovery of daily function and work activity. To our knowledge, this is the ninth patient reported with intracranial hemangioendothelioma, but the only one having diffuse and painful bone metastases resolved by treatment with interferon. After 30 months the patient is free from symptoms and recurrence. The effectiveness shown by recombinant interferon alpha-2b against vascular neoplasms prompted us to look for the possible biological basis of such a property.

Hemangioendothelioma of the spleen: imaging findings at color Doppler, US, and CT.

The ultrasonographic, color Doppler, and computed tomography findings of an unusual vascular primary tumor of the spleen are reported. A brief clinical and histopathological analysis of this entity is discussed and the differential diagnosis of other primary lesions of the spleen is attempted.

The antiangiogenic agents TNP-470 and 2-methoxyestradiol inhibit the growth of angiosarcoma in mice.

BACKGROUND: Endothelial malignancies, such as angiosarcoma and hemangioendothelioma, are often resistant to chemotherapy and surgery, and may result in death. Improved means of therapy are needed for these disorders. OBJECTIVE: We wanted to determine whether angiosarcoma can be treated with angiogenesis inhibitors in mice. METHODS: Mice were inoculated with a cell line that gives rise to angiosarcoma and were treated with the angiogenesis inhibitors 2-methoxyestradiol and TNP-470. Response to therapy was monitored by measurement of tumors. RESULTS: TNP-470 caused an 84% reduction in tumor size, and 2-methoxyestradiol caused a 68% reduction in tumor size. CONCLUSION: Angiogenesis inhibitors are highly effective in treatment of angiosarcoma in mice. Clinical trials of these agents in humans with angiosarcoma and hemangioendothelioma are warranted.

A new "anonymous" type of haemangioendothelioma.

BACKGROUND: Our report may contribute to a better understanding of the different possible presentations of endothelial tumors. METHODS AND RESULTS: We report a new type of haemangioendotheliomatous tumor of uncertain aggressiveness arisen in a benign haemangioma of the scalp and represented by a proliferation of small- and medium-sized arborescent vessels whose walls were totally replaced by endothelial-like, atypical cells. CONCLUSIONS: The features of our case do not fit those of the many types previously reported in the literature. As regards the name, we prefer to consider this new variety as an anonymous type in order to avoid further confusion on a topic deserving a drastic review.

Retiform hemangioendothelioma. A new case in a child with diffuse endovascular papillary endothelial proliferation.

We present a new case of retiform hemangioendothelioma (RH), an entity first described by Calonje et al. in 1994. The tumor was intradermal and located on the toe of an 11-year-old boy. Histologically, in addition to the distinctive retiform pattern of proliferating vessels in RH there are intraluminal papillae with hyaline cores similar to those seen in malignant endovascular papillary angioendothelioma (Dabska's tumor), but usually they are infrequent, focal and poorly developed. In our case, these papillary structures were well formed and distributed in a diffuse way. They were most conspicuous in superficial areas where the blood vessels were dilated. In deep areas, where the pattern of neoplastic vessels was retiform, the papillae filled their lumina totally, resembling solid cords. Our case shares the clinical and morphologic features of both retiform hemangioendothelioma and Dabska's tumor, supporting a relationship between these two kinds of neoplasms. The benign behavior of this case, with no recurrence or metastases over a 4-year follow-up, corresponds to the low malignancy of this kind of vascular neoplasm.