PF573,228 inhibits vascular tumor cell growth, migration as well as angiogenesis, induces apoptosis and abrogates PRAS40 and S6RP phosphorylation.

PF573,228 is a compound that targets focal adhesion kinase (FAK), a non-receptor protein kinase, which is over-expressed in various tumors. The aim of this study was to evaluate the effects of PF573,228 on the cells derived from mouse vascular tumors, namely, endothelioma cells. The treatment of endothelioma cells with PF573,228 reduced their growth with an IC50 of approximately 4.6 µmol L-1 and inhibited cell migration with an IC50 of about 0.01 µmol L-1. Microscopic studies revealed morphological attributes of apoptosis. These observations were confirmed by ELISA, which showed increased caspase-3 activity. PF573,228 also inhibited angiogenesis in a dose-dependent manner, with an IC50 of approximately 3.7 µmol L-1, and abrogated the phosphorylation of cell survival proteins, proline-rich Akt substrate (PRAS40) and S6 ribosomal protein (S6RP). Array data further revealed that PF573,228 induced caspase-3 activation, thus promoting apoptosis. Since all the processes inhibited by PF573,228 provide important support to tumor survival and progression, the drug may have a potential role in the treatment of vascular tumors.

Kaposiform hemangioendothelioma complicated by Kasabach-Merritt phenomenon: ultrastructural observation and immunohistochemistry staining reveal the trapping of blood components.

Kaposiform hemangioendothelioma (KHE), a borderline tumor of endothelial origin, is associated with Kasabach-Merritt phenomenon, characterized by profound thrombocytopenia and consumptive coagulopathy resulting from the localized intravascular coagulation (LIC) in the tumor. Previous studies have suggested that the trapping of blood components, including platelets, may underlie the LIC in KHE. However, more evidence is needed to support this hypothesis. In this study, one case of a Chinese infant with a KHE in the left arm was complicated by Kasabach-Merritt phenomenon. The tumor was partially resected and the sample was used for ultrastructural observation and immunohistochemistry staining of Glut-1. Ultrastructural observation found the trapping of erythrocytes, platelets, macrophages, and lymphocytes in the slit-like channels of the tumor nodules, and phagocytic vesicles in the cytoplasm of neoplastic cells. Immunohistochemistry staining further showed numerous Glut-1(+) erythrocytes in the channels. In conclusion, our results provided compelling morphological evidence of the trapping of blood components in KHE, which may interpret the LIC in the tumor and subsequent consumptive coagulopathy.

Primary kaposiform hemangioendothelioma of a long bone: two cases in unusual locations with long-term follow up.

Kaposiform hemangioendothelioma (KHE) is a rare vascular neoplasm of low malignant potential that mainly affects infants and adolescents. The tumor almost exclusively occurs in somatic soft tissue or the retroperitoneum. We report herein two cases of primary KHE occurring in a long bone without cutaneous changes with long-term follow up in young patients. The patients were a 9-year-old girl and 5-year-old boy presenting with lytic lesions of the femur and humerus, respectively, without cutaneous lesions. Histologically, the neoplasms were comprised of nodules of spindle- to oval-shaped cells growing in an infiltrative fashion. The neoplastic cells formed poorly canalized or slit-like blood vessels alternating with solid spindle areas. Immunohistochemical studies showed that the tumor cells expressed CD31, CD34 and Fli1, but not HHV8, LNA-1 or GLUT1. D2-40 stained the neoplastic spindle cells and lymphatic channels adjacent to vascular lobules. The girl remains well with 15 years and 6 months follow up after a second complete excision. The boy has no signs of recurrence or metastasis nearly 5 years after local complete excision. To our best knowledge, this is the first report in the English literature of primary long bone occurrences of KHE without cutaneous changes with long-term follow up.

Kaposiform hemangioendothelioma arising in the deltoid muscle without the Kasabach-Merritt phenomenon.

Kaposiform hemangioendothelioma (KHE) is a rare tumor that occurs nearly exclusively during infancy and childhood. It has features common to both capillary hemangioma and Kaposi sarcoma and for that reason many terms have been used for these tumors including "Kaposi-like infantile hemangioendothelioma" and "hemangioma with Kaposi sarcoma-like features." KHE typically presents as an ill-defined, red to purple, indurated plaque and is often complicated by the Kasabach-Merritt phenomenon (KMP), a condition of severe thrombocytopenia and consumptive coagulopathy. Knowledge of the radiological findings of this uncommon tumor might be helpful for diagnosis. We present the MRI features of a case of KHE with neither typical skin lesions nor the Kasabach-Merritt phenomenon.

Spindle cell hemangioendothelioma--a case report.

Spindle cell hemangioendothelioma is a rare vascular tumor which is presented with subcutaneous nodules and follows a benign indolent course but has a recurrent tendency, and is histologically resembling a cavernous hemangioma and Kaposi's sarcoma. We present a case of spindle cell hemangioendothelioma possessing clinical aggressiveness with painful bony erosion, histologic pleomorphism and mitoses. A 20-year-old man presented with a recurrent painful mass on the left ankle. The mass was dark brown and firm with irregular margins and measured 1.5 cm in diameter, which affected and eroded the underlying medial malleolus of the left tibia. Microscopically, the tumor was composed of cavernous endothelial-lined blood spaces and spindle cellular areas mimicking Kaposi's sarcoma. The spindle cells intermingled with plump epithelioid cells and showed a moderate degree of pleomorphism with occasional mitoses. Immunohistochemically, the spindle cells were focally positive for factor VIII-associated antigen and vimentin, and negative for S-100 protein, desmin, and epithelial membrane antigen.

Cutaneous malignant hemangioendothelioma: clinical and histopathological observations of nine patients and a review of the literature.

Nine patients with cutaneous malignant hemangioendothelioma (CMHE) were reported in Okinawa. All the patients were elderly, between 75 and 93 years of age. Four patients were males and five were female. The onset of the disease ranged from 1 to 9 months before the first visit. Eight patients had lesions on the scalp, and one, on the face and cheek. The lesions were in the form of exudative erythematous purpura, erythematous purpuric ulcers, and tumors. One patient developed a systematic metastasis involving the lungs, heart and intestine, and two patients had local metastasis to the cervical lymph nodes. Histopathologically, the tumor vessels were proliferated irregularly and showed anastomosis. The lumens were lined by large and atypical endothelial cells. Most of the specimens were infiltrated with large numbers of red blood cells. By electron microscope, Weibel-palade bodies were found inside the tumor cells located at the peripheral part of the lesion. The patients were treated by irradiation, IL-2 injection, and/or surgery. They were treated for 3 months to 2 years. Eight patients died between 4 to 24 months after the onset of disease and one has survived. The prognosis was poor.

[Polyethylene glycol-thiosulfate (PEG-Th) staining--a modification of the AgNOR method]. / Die polyethylenglykol-thiosulfat (PEG-Th)-Färbung--eine modifikation der AgNOR-Methode).

Visualization and analysis of nucleolus organizer regions (NOR) by a silverstaining is a well accepted method in cytological and histological tumor diagnostic. For specific staining of the NOR the AgNOR-method developed by HOWELL and BLACK (1980) and PLOTON et al. (1986) is performed. One major disadvantage of the AgNOR-method is the instability of the reaction products and therefore the short durability of the slide preparations. A modification of the AgNOR-method, the PEG-Th-staining, leads not only to a longer durability of the reaction products but also to a better contrast within the sections. Main characteristic of the PEG-Th-staining is a postfixation of the specific silver precipitations for 5 min in a 5% sodium thiosulfate solution. It could be proven by image analysis that there is no significant difference between the morphometric parameters evaluated on AgNOR- and PEG-Th-stained sections. Therefore results evaluated on PEG-Th-stained sections are absolutely comparable to those obtained on sections stained with the AgNOR-method thus providing the advantage of a longer durability of the reaction products and easier evaluation.

Spindle cell hemangioendothelioma. Report of three cases and review of the literature.

BACKGROUND: Spindle cell hemangioendothelioma lesions are uncommon, affect a wide age range in both sexes, and show a predilection for skin and subcutaneous tissue of the extremities. OBJECTIVE: To present three cases of spindle cell hemangioendothelioma and review the literature. METHODS: Three cases of spindle cell hemangioendothelioma are presented. RESULTS: Two of our cases first presented very early in life and progressed by local recurrences over many years. None of our cases showed evidence of metastases, but the lesions exhibited local aggressive and invasive behavior. Histologically, the lesions consist of alternating areas of dilated, thin walled cavernous vascular spaces and solid areas composed predominantly of spindle cells and clusters of epithelioid endothelial cells with intracytoplasmic vacuoles. That spindle cell hemangioendothelioma is a non-neoplastic lesion and not a neoplasm of borderline malignancy is suggested by the following observations from our cases: the repeated presence of organized intravascular thrombi in all cases, the early clinical presentation in two cases, and the presence of some degree of vascular malformation at the periphery of lesions. CONCLUSION: Both clinicians and pathologists should be aware of the existence of this lesion in order to diagnose and treat an affected patient correctly.

[The characteristics of the nucleolar organizer in tumors of the choroid of the eye]. / Kharakteristika iadryshkogo organizatora v opukholiakh sosudistoi obolochki glaza.

26 intraocular melanomas were studied histologically, ultrastructurally and morphometrically. For the first time the impregnation method was used for visualization of the nucleolar organizer (NO) in the cells of eye tumors using silver salts on the deparaffined sections. The efficiency and reliability of this method in the determination of the degree of malignancy of intraocular melanomas are demonstrated. A correlation existed between long-term postoperative results and the nucleolar organizer index (NO number/number of nuclei). The method can be practiced in any pathohistologic laboratory.

Epithelioid hemangioendothelioma of the clitoris: a case report with immunohistochemical and ultrastructural findings.

A 30-year-old woman was referred for evaluation of a small nodule of the clitoris. This was subsequently diagnosed as epithelioid hemangioendothelioma. This rare vascular tumor of intermediate malignancy has not been previously described in the vulva. The patient underwent a modified radical vulvectomy and bilateral inguinal lymph node dissection, and subsequently received photon therapy. She is alive with no evidence of disease 27 months after diagnosis.

Spindle cell hemangioendothelioma exhibits the ultrastructural features of reactive vascular proliferation rather than of angiosarcoma.

A patient with spindle cell hemangioendotheliomas was followed from 1964 to the present time, allowing the authors the opportunity to examine the lesions in the early, mature, and old phases. Organizing thrombi of different stages associated with slit-like vascular proliferation were always observed, whereas cavernous vascular spaces predominated as the lesions became older. Each spindle cell hemangioendothelioma initially developed relatively rapidly and was sometimes painful but then persisted as a silent nodule for decades. Transmission and scanning electron microscopic studies revealed that endothelial cells tended to digitate into the slit-like proliferating channels, became attached to other cells by means of tight junctions, and thus obstructed the channels at sites where thrombi developed repeatedly. The vascular spaces, ranging in nature from slit-like to cavernous, were outlined further by a relatively sparse mantle of ramified or dendritic interstitial cells that corresponded to spindle cells. Most of the cells appeared simply to be fibroblasts, but they developed the features of pericytes when they were close to the endothelial lining of well-developed vascular lumens. Large vascular spaces and phleboliths were surrounded by smooth muscle cells. Approximately 20% of the interstitial cells were dendritic macrophages characterized by phagocytic activity, presence of many lysosomes, and Factor XIIIa expression. The long and characteristic clinical course, the histologic evidence that thrombosis and its organization was continually occurring within the lesions, and the ultrastructural finding that spindle cell hemangioendotheliomas were composed of different microvascular segments from capillaries to veins, suggest that spindle cell hemangioendotheliomas may develop from a cycle of recanalization after thrombosis that occurs repeatedly because of the unique endothelial growth that was noted. This is in contrast with the previous conception that they were low-grade angiosarcomas.

Spindle cell haemangioendothelioma: probably a benign vascular lesion not a low-grade angiosarcoma. A clinicopathological, ultrastructural and immunohistochemical study.

Ten cases of spindle cell haemangioendothelioma (SCH) were analysed clinicopathologically, including an immunohistochemical survey of seven cases and ultrastructural observations on one. There were seven females and three males, ranging from 16 to 76 years of age. All but one lesion developed on the extremities, predominantly on the hands and feet. Six of the ten patients presented multiple nodules or papules which gradually increased in size and number over a long duration. Among them, four patients had undergone operations twice or more, but no metastatic foci were recognized. Histologically, the lesions were composed of dilated vascular spaces and a proliferation of bland-appearing spindle cells and interspersed epithelioid endothelial cells. Ultrastructural and immunohistochemical studies demonstrated that the spindle cells were mainly made up of fibroblastic cells admixed with pericyte-like cells and macrophages. Smooth muscle cells and primitive mesenchymal cells were also present. The clinical and microscopic features suggest that SCH may be a benign vasoformative lesion of a heterochronological multicentric origin.

[Systemic proliferating angioendotheliomatosis]. / Angioendotheliomatosis proliferans systematisata.

A 75-year-old female patient with neurological disturbances and numerous erythematous skin infiltrates is presented. Angioendotheliomatosis proliferans systematisata was diagnosed on histological detection of intravascular tumour cells in the cutaneous blood vessels. On immunohistochemistry and electron microscopy, the mononuclear tumour cells were identified as atypical B-lymphocytes. Our results provide further evidence that angioendotheliomatosis proliferans systematisata is a malignant angiotropic lymphoma with neurocutaneous manifestation.

Cellular hemangiomas ("hemangioendotheliomas") in infants. Light microscopic, immunohistochemical, and ultrastructural observations.

Cellular hemangiomas of infancy, also known as "infantile hemangioendotheliomas," are benign tumors whose dense cellularity may lead to confusion with soft tissue sarcomas. Ultrastructural and immunohistologic study revealed considerable cellular heterogeneity in these lesions despite the monomorphous appearance revealed by routine histologic preparations. Pericytes and endothelial cells are predominant, but fibroblasts and mast cells are regularly present in these tumors. An interstitially located cell of uncertain identification, expressing factor XIIIa and a macrophage marker, not previously noted, comprises an important segment of the cell population. The cell composition reflects the dynamic potential of these lesions, whose natural tendency is to grow, then to become stable, and finally to involute.

Atypical tumor of the mediastinum: epithelioid hemangioendothelioma containing metaplastic bone and osteoclastlike giant cells.

A 66-year-old woman presented with a superior-anterior mediastinal mass that contained considerable calcification by computed tomography. Initial biopsy interpretation was inconclusive but suggested a giant cell sarcoma of soft parts because the tumor contained atypical epithelioid cells and osteoclastlike giant cells. After radiation and chemotherapy, the tumor was removed. It contained large epithelioid cells, pale chondroid areas, metaplastic bone, and osteoclastlike giant cells. Immunohistochemical and electron microscopic studies revealed the epithelioid cells to be factor VIII positive and to contain abundant intermediate filaments, micropinocytotic vesicles, Weibel-Palade bodies, basal lamina, and primitive cell-cell junctions. These epithelioid cells also stained for muscle-specific actin (HHF-35), yet were negative for desmin and cytokeratins (CAM 5.2 and AE1/3). The findings were most consistent with those reported to occur in epithelioid hemangioendothelioma.

Spindle cell haemangioendothelioma: a clinicopathological and immunohistochemical study indicative of a non-neoplastic lesion.

Spindle cell haemangioendothelioma is an uncommon vascular lesion, of which 35 cases have been previously reported. A further 20 cases are reported herein. These lesions affected a wide age range in both sexes, and showed a predilection for the extremities. Twelve patients had multiple lesions and, in these cases, local progression over many years but no true recurrence was typical. None of the 20 patients developed metastases, but one later developed an angiosarcoma. Individual cases were associated with congenital lymphoedema. Klippel-Trenaunay syndrome and early-onset varicose veins. Histologically, in addition to the admixture of cavernous spaces and solid spindle cell/epithelioid cell areas, the presence both of irregularly distributed and perivascular smooth muscle cells and of malformed variably-sized vessels at the periphery of almost every lesion was noted in each case. Reticulin staining, immunohistochemistry and electronmicroscopy revealed the presence of primitive vessel formation and partial endothelial differentiation in the solid spindle cell areas. Combining these data with those from previously published series, it is suggested that spindle cell haemangioendothelioma is a non-neoplastic lesion (rather than a borderline malignancy as it is currently regarded) and that its development correlates with histological and/or clinical evidence of a malformed vasculature at the affected site.

Is there a role for pericytic cells in the vascular bed of infantile hemangioendothelioma of the liver?

Electron microscopic examination of an infantile hemangioendothelioma (IHE) type I of the liver, appearing in a five month old child, showed a high density of pericytes in the walls of the neoplastic vessels. These vessels, in part of the IHE patients, establish an important arteriovenous shunt leading to high output, congestive cardiac failure. It is unclear whether functions ascribed to pericytes, such as participation in microvascular contractility or as suppressors of endothelial cell proliferation are involved in two noteworthy aspects of the present case. The child exhibited no congestive heart failure and the multiple nodular lesions underwent spontaneous regression.