Pazopanib in advanced vascular sarcomas: an EORTC Soft Tissue and Bone Sarcoma Group (STBSG) retrospective analysis.

BACKGROUND: Pazopanib is a multitargeted tyrosine kinase inhibitor approved for the treatment of patients with selective subtypes of advanced soft tissue sarcoma (STS) who have previously received standard chemotherapy including anthracyclines. Data on the efficacy in vascular sarcomas are limited. The main objective of this study was to investigate the activity of pazopanib in vascular sarcomas. PATIENTS AND METHODS: A retrospective study of patients with advanced vascular sarcomas, including angiosarcoma (AS), epithelioid hemangioendothelioma (HE) and intimal sarcoma (IS) treated with pazopanib in real life practice at EORTC centers as well as patients treated within the EORTC phase II and III clinical trials (62043/62072) was performed. Patient and tumor characteristics were collected. Response was assessed according to RECIST 1.1. and survival analysis was performed. RESULTS: Fifty-two patients were identified, 40 (76.9%), 10 (19.2%) and two (3.8%) with AS, HE and IS, respectively. The response rate was eight (20%), two (20%) and two (100%) in the AS, HE and IS subtypes, respectively. There was no significant difference in response rate between cutaneous and non-cutaneous AS and similarly between radiation-associated and non-radiation-associated AS. Median progression-free survival (PFS) and median overall survival (OS; from commencing pazopanib) were three months (95% CI 2.1-4.4) and 9.9 months (95% CI 6.5-11.3) in AS, respectively. CONCLUSION: The activity of pazopanib in AS is comparable to its reported activity in other STS subtypes. In this study, the activity of pazopanib was similar in cutaneous/non-cutaneous and in radiation/non-radiation-associated AS. In addition, pazopanib showed promising activity in HE and IS, worthy of further evaluation.

Thalidomide for the treatment of metastatic hepatic epithelioid hemangioendothelioma: a case report with a long term follow-up.

Hepatic epithelioid hemangioendothelioma (HEH) is an unusual, low-grade malignant vascular tumor of the liver. Here we describe a case of a 40-year-old woman who presented with abdominal pain in the upper right quadrant and giant hepatomegaly, in which imaging studies and a fine-needle liver biopsy confirmed the presence of a large EHE with an isolated lung metastasis. After balancing all possible therapeutic modalities the patient was treated conservatively with thalidomide (300 mg/day). The drug was well tolerated with minimal toxicity and the patient continues on therapy 109 months after treatment was started with no disease progression. Current therapeutic options for HEH are discussed in light of the clinical case with particular emphasis on anti-angiogenic therapies.

[Epitheliod hemangioendothelioma of the lung].

The authors give a morphological and immunohistochemical description of epitheliod hemangioendothelioma of the lung in two women aged 62 and 74 years. Evident neovascularization capacity, a significant tumor cell intracytoplasmic lumen frequently packed with red blood cells, and positive immunohistochemical reactions to endothelial antigens are of prime importance in making its diagnosis.

Metastatic hepatic epithelioid hemangioendothelioma in a teenage girl.

SUMMARY: Hepatic epithelioid hemangioendothelioma (HEHE) is a rare malignant tumor characterized by its epithelioid structure and vascular endothelium origin. The clinical course of HEHE is variable, ranging from long-term survival without treatment to a rapidly progressive course with a fatal outcome. As a consequence, no standard treatment has been determined. We present a case of HEHE occurring in a 13-year-old girl, in which a novel treatment approach using antiangiogenic therapy was tried and was successful in slowing the progression of the disease.

Pathologic Angiogenesis of Malignant Vascular Sarcomas: Implications for Treatment.

Angiosarcoma, epithelioid hemangioendothelioma, and Kaposi sarcoma are classified according to the line of differentiation that these neoplastic cells most closely resemble: the endothelial cell. Although these malignant vascular sarcomas demonstrate immunohistochemical and ultrastructural features typical of this lineage, they vary dramatically in presentation and behavior, reflecting oncologic mechanisms unique to each. Antineoplastic therapies offer significant benefit, but because of the rarity of these cancers, novel therapies are slow to develop, and treatment options for these cancers remain limited. Antiangiogenic approaches that have shown benefit in other malignancies have not fully realized their promise in vascular tumors, suggesting that these tumors do not depend entirely on either angiogenic growth factors or on neighboring endothelia that are affected by these agents. Nonetheless, translational studies have begun to unravel these distinct pathologies, identifying novel translocation products, targets of oncogenic virulence factors, and genomic mutations that hijack angiogenic signaling and drive malignant growth. Concurrently, an elaborate and highly regulated model of angiogenesis and lymphangiogenesis involving vascular endothelial growth factor-receptor tyrosine kinase and TGF-ß and Notch pathways has emerged that informs treatment of these tumors as well as cancer in general. This review summarizes the literature on malignant vascular sarcomas in the context of current models of angiogenesis and, in light of recent clinical trial data, could help clinician-scientists generate novel therapeutic approaches.

Primary hepatic epithelioid hemangioendothelioma progressively responsive to interferon-alpha: is there room for novel anti-angiogenetic treatments?

Primary hepatic epithelioid hemangioendothelioma (HEH) is a rare, low-grade malignant neoplasm of endothelial origin, with an unpredictable clinical course and prognosis. No standard therapeutic strategies are still available for HEH, due to the infrequency of the disease and to its variable natural history that limit the identification of the most effective treatment. In the absence of metastatic disease, surgical resection or liver transplantation represent the treatment of choice for HEH, while several antineoplastic agents have been proposed in the presence of metastatic nonresectable disesase. Herein, we describe the biological characterization and the clinical course of a primary HEH progressively responsive to treatment with intermediate doses of interferon-alpha (IFN)-alpha2a. Furthermore, based on the newly-identified expression of endoglin (CD105) on HEH, we discuss the clinical potential of novel anti-angiogenetic approaches to the disease.

Expression of FKBP12 in benign and malignant vascular endothelium: an immunohistochemical study on conventional sections and tissue microarrays.

FKBP12 is a cytosolic FK506 binding protein that interacts with calcineurin and thereby mediates the immunosuppressive effects of FK506. Because initial immunohistochemical staining showed abundant expression of FKBP12 in vascular endothelial cells, we evaluated whether it could serve as a marker for vascular neoplasms. We performed immunohistochemical staining of conventional sections from formalin-fixed, paraffin-embedded tissue from 59 benign and malignant vascular neoplasms using a polyclonal rabbit antiserum against FKBP12. Western blot analysis of tissue from 6 angiosarcomas showed a single band at 12 kD, consistent with the published molecular weight for the FKBP12 protein. Together, CD31, CD34, and FKBP12 identified all 59 vascular neoplasms in this study. Specificity of immunohistochemical staining was assessed on 1,321 tissues represented on 7 tissue microarrays. All proteins were occasionally expressed in non-vascular tissue. Six of 8 vascular neoplasms represented on the arrays stained for FKBP12, as did normal vessels in numerous cores. The polyclonal antiserum shows comparable sensitivity (94.9%) and specificity (96.5%) to CD34 and CD31 and may be a useful additional marker for vascular differentiation. Because we have evaluated a large number of tissues by tissue microarray, we anticipate that our estimate of the specificity of immunostaining for FKBP12 as a marker for vascular endothelium will be accurate. In addition, our findings may explain the toxic effects of FK506 on vascular endothelium of the kidney.

Long-term durable response to lenalidomide in a patient with hepatic epithelioid hemangioendothelioma.

Epithelioid hemangioendothelioma (EH) is a rare tumor arising from the vascular endothelial cells of soft tissue or visceral organs. The most common visceral site is the liver, where it is often involved in a multifocal manner known as hepatic EH (HEH). Surgical resection with curative intent represents the gold standard therapy. When surgery is not feasible, or in cases of metastatic disease, no standard medical treatment is currently indicated. In small series, drugs with anti-angiogenic activity (such as bevacizumab, sorafenib, thalidomide, and lenalidomide) have been proposed with promising results. We describe a 73-year-old man with multifocal non-resectable HEH treated with lenalidomide. Disease status was evaluated by abdominal ultrasound and magnetic resonance every four months. The patient was treated for a total of 39 mo with prolonged disease stabilization and, at the time of writing, is still under treatment with a good tolerance profile. During a short period of treatment discontinuation, the disease showed slight progression that immediately resolved after the reintroduction of lenalidomide. Lenalidomide may represent a valid treatment option for HEH due to its anti-angiogenic and antineoplastic activities. This preliminary result merits further study in a large series.

On the discriminatory value of anti-HPCA-1 (CD-34) in the differential diagnosis of benign and malignant cutaneous vascular proliferations.

The staining pattern of monoclonal antibody anti-HPCA-1 (CD-34) was studied in 95 cases of benign and malignant cutaneous vascular proliferations and compared with other vascular endothelium-associated antigenic markers in paraffin-embedded tissues. The proliferating vessels in 22 cutaneous capillary hemangiomas, 8 lobular capillary hemangiomas, and 1 case of papillary intravascular endothelial hyperplasia stained strongly positively for anti-HPCA-1, and the intensity of the reaction was paralleled by that of factor VIII-related antigen (FVIII), Ulex europaeus lectin-1 (UEA), and vimentin (VIM). The vessels in 10 cases of granulation tissue, 6 cases of cavernous hemangioma, 6 cases of angiokeratoma, 5 cases of angiolymphoid hyperplasia with eosinophilia (epithelioid hemangioma), and 3 cases of bacillary angiomatosis showed a lack of reactivity with anti-HPCA-1 and staining of variable intensity with the other markers. Twenty cases of Kaposi's sarcoma (seven patch, five plaque, eight nodular stage) showed strong labeling with anti-HPCA-1 in small, well-formed vessels scattered among the spindle-cell proliferation, and four of these cases showed focal positivity of scattered spindle cells. Nine cases of cutaneous angiosarcoma, two cases of low-grade epithelioid angiosarcoma, and one case of spindle-cell hemangioendothelioma were negative for anti-HPCA-1 and showed variable reactivity for FVIII and UEA; all cases stained strongly positively for VIM. The results of this study indicate that although anti-HPCA-1 shows a high sensitivity for the staining of normal vascular endothelium, its specificity may be restricted to mature, well-formed vessels, therefore rendering its discriminatory value very limited for the identification of poorly differentiated vascular endothelial neoplasms.