IMAGING DIAGNOSIS-MAGNETIC RESONANCE IMAGING FINDINGS IN A CAT WITH SYSTEMIC REACTIVE ANGIOENDOTHELIOMATOSIS.

A 10-year-old, castrated male domestic short-haired cat was presented with an acute history of seizures, lethargy, anorexia, vomiting, and dyspnea. Magnetic resonance imaging of the brain showed multifocal areas of gray matter T2-weighted hyperintensity. The lesions did not enhance with intravenous contrast. The cat was diagnosed at necropsy with feline systemic reactive angioendotheliomatosis, a rare vascular proliferative disorder for which a treatment has not yet been identified. This report is the first to describe associated magnetic resonance imaging changes for this disease.

Pseudomyogenic hemangioendothelioma secondary to fibrous dysplasia of the left lower extremity in a 14-year-old female: a case report.

BACKGROUND: Pseudomyogenic hemangioendothelioma is a rare soft tissue tumor usually found in young adults, predominantly males. Fibrous dysplasia is a common benign bone tumor, which accounts for 5~7 % of all the primary benign bone tumors. However, pseudomyogenic hemangioendothelioma secondary to fibrous dysplasia is extremely rare. To the best of our knowledge, this is the first case of pseudomyogenic hemangioendothelioma secondary to fibrous dysplasia. CASE PRESENTATION: This study describes a case of a 14-year-old female who suffered from pseudomyogenic hemangioendothelioma secondary to fibrous dysplasia of the left lower extremity. The patient underwent two operations successively due to pathological fractures in the left femur and tibia in a local hospital. She was diagnosed with fibrous dysplasia according to the postoperative pathological examinations. However, less than 1 year later, she was diagnosed with a recurrence of fibrous dysplasia in her left femur during a follow-up in our hospital. She underwent a curettage and grafting in the left femur. Postoperative pathological examinations demonstrated the diagnosis of fibrous dysplasia. Nevertheless, she presented to our clinic with a chief complaint of pain and swelling in her left tibia and calcaneus 4 months later. The patient underwent fine-needle aspiration in her left tibia. According to the histological and immunohistochemical findings, the diagnosis of pseudomyogenic hemangioendothelioma was confirmed by an expert pathology consultant. Finally, the patient had to undergo an amputation of the left thigh. Postoperative pathological examinations confirmed the diagnosis of pseudomyogenic hemangioendothelioma. Postoperative follow-up at 3 months disclosed no evidence of recurrent disease and no residual side effects from therapy. CONCLUSIONS: Pseudomyogenic hemangioendothelioma is a rare endothelial neoplasm which often mimics myoid and epithelioid tumors morphologically. For the diagnosis, the immunostaining is very important but not decisive and enough. Analysis based on any single factor or incomplete information may easily lead to arbitrary conclusion. Clinical information including age, gender, tumor location, disease course, and recurrence is important for appropriate diagnosis, and full understanding of the tumor is indispensable.

Thalassemia major between liver and heart: Where we are now.

The aim of the study was to assess the current state in terms of liver and heart iron overload as well as of liver and heart related morbidity and mortality in a large cohort of thalassemia patients. Myocardial iron loading was present in 28.9% patients, which was severe in 3.2%. Liver iron was normal in 9.3% and severe in 15%. The rate of cardiac deaths started to decrease between 2000 and 2003 and dropped significantly afterwards. The prescription of combination therapy soon after the hospital admission for decompensated heart failure was associated with a decrease in the short-term mortality. In 111 adult patients who underwent liver elastometry, 14 HCVRNA positive subjects and 2 HCVRNA negative, had stiffness values suggestive of cirrhosis. No cases of hepatocarcinoma were reported. Liver "iron free foci" occurred in a HCV negative patient and the occurrence of a malignant epithelioid hemangioendothelioma led to liver transplantation in another. The study suggests that a subset of patients continues to develop progressive hemosiderosis that may lead to cardiac disease and death. Beyond its key role in preventing myocardial iron overload, liver iron chelation is essential for hampering the onset of hepatic tumors, which may not be limited to hepatocarcinoma.

Medical management of tumors associated with Kasabach-Merritt phenomenon: an expert survey.

Kasabach-Merritt phenomenon (KMP) is a rare consumptive coagulopathy characterized by profound thrombocytopenia and hypofibrinogenemia occurring in association with the vascular tumors kaposiform hemangioendothelioma (KHE) and tufted angioma (TA). Treatment remains challenging without consensus on the optimal medical management. The authors compiled expert opinions regarding management to establish treatment recommendations. Twenty-seven vascular anomalies centers in the United States and Canada were surveyed using 2 representative cases of KHE/TA with and without KMP. Overall response rate was 92% (25/27) with 88% completion (24/27). Most sites (23/25; 92%) do not have a standard of practice for management. The most frequent initial therapy for KHE+KMP was a combination of systemic corticosteroids and vincristine (VCR) (12/24 centers; 50%) followed by corticosteroids alone (29%). Second-line treatments were VCR (38%), rapamycin (21%), and propranolol (21%). Management of KHE/TA without KMP was variable; initial treatments included systemic corticosteroids (8/24; 33%) alone or with VCR (9/24; 38%), monitoring without medication (33%), VCR (8%), propranolol (8%), aspirin (4%), and rapamycin (4%). This survey highlights certain trends in the management of KMP-associated tumors, without standard protocols and consensus.

Comprehensive Analyses of Coagulation Parameters in Patients with Vascular Anomalies.

BACKGROUND: Vascular anomalies comprise a diverse group of rare diseases with altered blood flow and are often associated with coagulation disorders. The most common example is a localized intravascular coagulopathy in venous malformations leading to elevated D-dimers. In severe cases, this may progress to a disseminated intravascular coagulopathy with subsequent consumption of fibrinogen and thrombocytes predisposing to serious bleeding. A separate coagulopathy is the Kasabach-Merritt phenomenon in kaposiform hemangioendothelioma characterized by platelet trapping leading to thrombocytopenia and eventually consumptive coagulopathy. Our previous work showed impaired von Willebrand factor and platelet aggregometry due to abnormal blood flow, i.e., in ventricular assist devices or extracorporeal membrane oxygenation. With altered blood flow also present in vascular anomalies, we hypothesized that, in particular, the von Willebrand factor parameters and the platelet function may be similarly impacted. METHODS: We prospectively recruited 73 patients with different vascular anomaly entities and analyzed their coagulation parameters. RESULTS: Acquired von Willebrand syndrome was observed in both of our patients with Kasabach-Merritt phenomenon. In six out of nine patients with complex lymphatic anomalies, both the vWF antigen and activity were upregulated. Platelet aggregometry was impaired in both patients with Kasabach-Merritt phenomenon and in seven out of eight patients with an arteriovenous malformation. CONCLUSIONS: The analysis of coagulation parameters in our patients with vascular anomalies advanced our understanding of the underlying pathophysiologies of the observed coagulopathies. This may lead to new treatment options for the, in part, life-threatening bleeding risks in these patients in the future.

Induction of the angiogenic phenotype by Hox D3.

Angiogenesis is characterized by distinct phenotypic changes in vascular endothelial cells (EC). Evidence is provided that the Hox D3 homeobox gene mediates conversion of endothelium from the resting to the angiogenic/invasive state. Stimulation of EC with basic fibroblast growth factor (bFGF) resulted in increased expression of Hox D3, integrin alphavbeta3, and the urokinase plasminogen activator (uPA). Hox D3 antisense blocked the ability of bFGF to induce uPA and integrin alphavbeta3 expression, yet had no effect on EC cell proliferation or bFGF-mediated cyclin D1 expression. Expression of Hox D3, in the absence of bFGF, resulted in enhanced expression of integrin alphavbeta3 and uPA. In fact, sustained expression of Hox D3 in vivo on the chick chorioallantoic membrane retained EC in this invasive state and prevented vessel maturation leading to vascular malformations and endotheliomas. Therefore, Hox D3 regulates EC gene expression associated with the invasive stage of angiogenesis.

Malignant hemangioendotheliomas produced by subcutaneous inoculation of Balb/3T3 cells attached to glass beads.

The Balb/3T3 mouse embryo cell line has been frequently used in cancer research as representative of nontumorigenic cells with the characteristic in vitro properties of postconfluence inhibition of cell division, low saturation density, and anchorage dependence. On the reasoning that anchorage dependence might also apply in vivo, each of nine mice were subcutaneously inoculated with an average of 15,400 Balb/3T3 cells attached to two glass beads 3 millimeters in diameter. After 8 weeks, all the mice had developed large bloody tumors that microscopically proved to be hemangioendotheliomas. Ther inoculation of Balb/3T3 cells alone or beads alone produced no tumors. Transplants of each tumor into normal mice grew to kill the animal within 6 weeks. Tumor cells from collagenase-disaggregated tumor tissue had a plating efficiency of 21.2 percent compared to that of normal adult subcutaneous fibroblasts of less than 0.1 percent. The tumor cells in vitro closely resembled Balb/3T3 cells in appearance and were tumorigenic at a dose of 10-4 cells. A second, repeat experiment produced the same type of tumors grossly and microscopically in 17 of 25 mice between 99 and 211 days after inoculation of the Balb/3T3 cells attached to glass beads. These findings require a reassessment of the postulate that low saturation density, postconfluence of cell division, and anchorage dependence are characteristic in vitro properties only of nonneoplastic cells.

Polymorphous hemangioendothelioma in a child with acquired immunodeficiency syndrome (AIDS).

Polymorphous hemangioendotheliomas (PH) are rare and borderline malignant tumors that are among the wide range of vascular tumors. We report here a 13-year-old male presenting with a history of weight loss, opportunistic infections, and lymphadenopathy. He was determined to be HIV positive and to have acquired immunodeficiency syndrome (AIDS). A biopsy of a femoral node was diagnostic of PH. His systemic lymphadenopathy appeared to resolve with anti-retroviral therapy. This tumor should be considered within the differential diagnoses of pediatric and immunocompromised patients.

Hepatic haemangioendothelioma: a vertical association with biliary atresia?

Haemangioendotheliomas (HAE) are the commonest vascular tumours of the liver in infancy and are characterised by solitary or multifocal lesions often arising in conjunction with cutaneous haemangiomas. The authors report on a 4-month-old infant with massive hepatomegaly and hypothyroidism due to multifocal HAE whose mother had been born with biliary atresia. As the incidence of biliary atresia in the UK is about 1 in 16 000 live births, the association reported here seems more than co-incidental. This report reviews the literature and discusses potential aetiologies to explain this rare association.

Development of Kasabach-Merritt phenomenon following vaccination: More than a coincidence?

Kasabach-Merritt phenomenon (KMP) occurred uniquely in patients with kaposiform hemangioendothelioma (KHE) and tufted angioma (TA). We report the clinical characteristics of two patients with KHE involving the right upper arm. The patients demonstrated rapid enlargement of the lesion with severe KMP shortly after vaccination. Sirolimus was used to treat the KHE with KMP. The patients showed a quick normalization of the platelet level. The follow-up examination revealed that the size of the mass was significantly decreased. This report raises the intriguing possibility that extrinsic factors may contribute to the development of KMP in the context of an already existing KHE.

Resolution of reactive angioendotheliomatosis in an arteriovenous fistula with innominate vein angioplasty.

INTRODUCTION: Arteriovenous fistulae (AVF)-associated reactive angioendotheliomatosis (RAE) is a very rare entity (three previously reported cases in the literature) that can manifest as extremity wounds. RAE's etiopathology is unknown. CASE DESCRIPTION: We report a case of severe limb-threatening upper extremity wound with pathology-proven RAE. This lesion was previously refractory to standard wound care. There was no evidence of limb ischemia or steal syndrome, previously deemed to be the underlying cause of AVF-associated RAE in other reports. CONCLUSIONS: Successful endovascular treatment of an ipsilateral innominate vein stenosis led to reduction of venous hypertension, resolution of associated arm edema, and subsequent wound healing. We therefore propose that venous engorgement and hypertension from central venous stenosis is the likely underlying cause for AVF-associated RAE. If this rare entity is encountered in the setting of AVF, there is utility in treating the wound as a sentinel lesion and venography should be conducted to rule out central venous pathology. Vascular intervention complements aggressive local wound management and biopsy is requisite for prompt diagnosis.

Masson's tumour in the right parietal lobe after stereotactic radiosurgery for cerebellar AVM: case report and review.

We present a 50-year-old patient who had undergone stereotactic radiosurgery for a cerebellar vermian arteriovenous malformation. On routine surveillance MR imaging a lesion suggestive of a meningioma was demonstrated and removed. Histologically it was found to be intravascular papillary endothelial hyperplasia (Masson's tumour). The characteristic radiological and histological findings are presented. Aspects of management of this rare tumour are discussed. Given that cases are often found in combination with a vascular abnormality, we discuss the possibility of a change in local haemodynamics after radiosurgery promoting development of this tumour.

Vascular tumors of infancy and childhood: beyond capillary hemangioma.

Vascular tumors of infancy and childhood represent a number of clinicopathologically distinct entities for which precise histopathological diagnosis is often essential in determining effective therapeutic approach. Unfortunately, pathologists and clinicians alike have traditionally tended to lump these tumors, in addition to small vessel vascular malformations, under overly generic terms like capillary hemangioma that do little, if anything, to guide proper clinical management. In the last decade this nosologic oversimplification has begun to wane as important new diagnostic tools and better understanding of etiology have evolved, facilitated by international recognition of the need for a multidisciplinary approach in dealing with these perplexing and often clinically devastating lesions. This article provides a brief historical perspective on this progress, and then focuses on the current clinical, histological, and immunophenotypical features that distinguish the major types of vascular tumors of infancy and childhood, also reviewing new evidence regarding their mechanisms of pathogenesis.

Carcinogenic activity of Symphytum officinale.

The carcinogenicity of Symphytum officinale L., Russian comfrey, used as a green vegetable or tonic, was studied in inbred ACI rats. Three groups of 19--28 rats each were fed comfrey leaves for 480--600 days; four additional groups of 15--24 rats were fed comfrey roots for varying lengths of time. A control group was given a normal diet. Hepatocellular adenomas were induced in all experimental groups that received the diets containing comfrey roots and leaves. Hemangioendothelial sarcoma of the liver was infrequently induced.

Vasoformative sarcomas arising from BALB/3T3 cells attached to solid substrates.

The BALB/3T3 mouse embryo cell line, noted for its marked postconfluence inhibition of proliferation, anchorage dependence, and high serum requirement, and frequently studied as a prototype nontumorigenic "fibroblast" line that is compared with tumorigenic sublines transformed with various agents, produced tumors within 2 to 3 months when an average of 3 X 10(4) cells were implanted s.c. attached to 1- X 5- X 10-mm polycarbonate platelets. Plastic platelets alone produced no tumors after 1 year of observation. The tumors, as well as others arising from implants of BALB/3T3 cells attached to 3-mm glass beads, were given the histological diagnosis of "vasoformative saroma" because the tumor cells frequently formed vascular channels. The vasoformative pattern and the results of specific staining for reticulin and collagen support the likelihood that BALB/3T3 cells originated from endothelial cells rather than from fibroblasts. That the tumors were derived from BALB/3T3 cells and not host cells was proved when tumors arising in BALB/c X C57BL/6 F1 hybrids were shown to be transplantable to BALB/c but not to C57BL/6 mice. The cultured tumor cells showed loss of both postconfluence inhibition of proliferation and anchorage dependence. Evidence of the induction of endogenous oncornaviruses was obtained in only one of four tumors tested. These tumors also exhibited tumor-unique transplantation rejection antigens. We conclude that BALB/3T3 cells are preneoplastic and give rise to different spontaneously transformed clones bearing unique tumor rejection antigens when implanted in vivo attached to a solid substrate.

Invading and metastasizing cardiac hemangioendothelial neoplasms in a cohort of the fish Rivulus marmoratus: unusually high prevalence, histopathology, and possible etiologies.

An unusually high, unprecedented prevalence of cardiac hemangioendotheliomata, including hemangiomas, hemangioendotheliomas, and hemangioendotheliosarcomas, was found in a laboratory cohort of the small, teleost fish Rivulus marmoratus. The neoplasms occurred in 51 of 204 fish (25%) used in a carcinogenicity study of butylated hydroxyanisole fed in a lyophilized chicken liver diet for up to 9 months. The cardiac neoplasms occurred in approximately equal numbers of both control (fed lyophilized chicken liver but not exposed to butylated hydroxyanisole) and exposed (fed 0.8% butylated hydroxyanisole in chicken liver) fish. The neoplasms occurred in the bulbus arteriosus and ventricle (accompanied by an intense epicarditis), and in some cases, in the gills. At least one case of hemangioma was characterized by cavernous vessels in the bulbar wall. Hemangioendothelioma cases consisted of pleomorphic endothelial cells that formed continuous tracts and anastomosing, typical vascular channels of varying sizes. The hemangioendotheliosarcomas consisted of atypical, spindle, polygonal, or round endothelial cells that formed solid tumor masses that contained abnormal vessels with atypical endothelium tufting into their lumina. Some fish had neoplasm cases containing varying regions with mixtures of the above features. Incipient neoplasms occurred on/in the semilunar valves, and their cells appeared to invade the adjacent walls of the bulbus and/or the ventricle. The gill lesions represented possible metastatic neoplasms, probably formed by atypical endothelial cells that exfoliated from the edges of cardiac neoplasms into the lumina of the ventricle or bulbus and were then pumped to the arterioles of the gills via the ventral aorta. Fish examined from the original colony in the laboratory and from the wild had no neoplasms. Possible causes are discussed, and studies are under way in an attempt to determine the etiology of the neoplasm and to evaluate Rivulus marmoratus as a possible model organism for study of these types of cardiac neoplasms.

Reduction of N-nitrosodiethylamine carcinogenesis in rats by lipotrope or amino acid supplementation of a marginally deficient diet.

In studies in this and other laboratories, induction of hepatocardinoma by several different chemical carcinogens was enhanced in rats fed diets deficient in lipotropes (choline, methionine, folic acid), amino acids, and niacin, and high in fat. In some cases, specific supplementation with lipotropes blocked carcinogenesis. In studies reported here, specific supplementation of a marginally deficient diet that enhanced carcinogenesis in rats, with the amino acids or lipotropes in which it was deficient, significantly decreased induction of hepatocarcinoma by N-nitrosodiethylamine. Niacin supplementation decreased hepatocarcinoma incidence only slight; the addition of beef fat to an adequate diet did not enhance tumor induction. Rats fed the amino acid- or lipotrope-supplemented diets had an increased incidence of hepatic hemangioendothelial sarcomas, compared to deficient rats or to rats fed the adequate control diet. Methionine was contained in both the amino acid and the lipotrope supplement and probably was responsible for reducing hepatocarcinoma incidence. Methionine has been found to have an anticarcinogenic effect in other studies and also to block the depletion of hepatic folate stores that is induced by N-nitrosodiethylamine. Interactions between carcinogens, S-adenosylmethionine, and folate may be significant in hepatic or other tissue carcinogenesis. One of more hepatic microsomal oxidases were depressed in rats fed any of the high-fat diets but were not correlated with tumor incidence.

Vascular transformation of sinuses in lymph nodes. A study of its morphological spectrum and distinction from Kaposi's sarcoma.

Vascular transformation of lymph node sinuses (VTS) is characterized by conversion of nodal sinuses into capillary-like channels, often accompanied by fibrosis. A detailed study of this entity, based on 76 cases, showed that the morphologic spectrum was much broader than that originally described. The vasoproliferative process caused variable expansion of the subcapsular, intermediate, and medullary sinuses of the lymph nodes and involved single or multiple lymph nodes in a diffuse or segmental fashion. The proliferated vessels formed anastomosing narrow clefts, rounded spaces of different sizes, plexiform channels, or solid spindled to plump cellular foci and often were associated with variable degrees of sclerosis. The vascular spaces were empty, filled with lymph-like fluid, congested with blood, or occasionally thrombosed; extravasation of red cells was common. Several patterns were commonly observed in an individual case. Less common features included perivascular fibrin deposition and the presence of eosinophilic globules. Vascular thrombosis was identified only rarely in extranodal vessels available for histologic assessment. The more cellular forms of this vascular transformation may be mistaken for Kaposi's sarcoma, but can be distinguished from it by the pure sinusoidal distribution, a lack of well-formed spindle cell fascicles, the associated fibrosis, the maturation of the spindle cells into well-formed vascular channels toward the capsular aspect, and the failure of this process to involve the capsule itself, which is frequently affected by Kaposi's sarcoma.

Spindle cell hemangioendothelioma. An analysis of 78 cases with reassessment of its pathogenesis and biologic behavior.

Seventy-eight cases of spindle cell hemangioendothelioma (SCH) were studied to reevaluate its pathogenesis and determine its long-term behavior. Most of the original findings were confirmed by this study. The tumor occurred at all ages (8-78 years; median, 32 years; mean, 34 years). Males and females were equally affected. The tumor developed as a superficially located mass of the distal extremities (upper, 32 cases; lower, 30 cases). Four patients (5%) also had Maffucci's syndrome. The lesions were circumscribed red-brown masses occasionally containing phleboliths that consisted of cavernous blood spaces alternating with cellular areas consisting of collapsed vascular spaces separated by spindled fibroblastic cells. Often the endothelium lining the collapsed blood spaces appeared epithelioid with cytoplasmic vacuolization. The spindled fibroblastic cells lacked significant atypia and had at most a low level of mitotic activity. As a significant departure from what was originally reported, more than half of these cases (58%) were partially or completely intravascular. The vein containing the tumor often had an irregularly attenuated wall with small intimal herniations and intimal papillae traversing the lumen. Similar intimal changes in adjacent vessels suggest that SCH grows as a multifocal or contiguous process within vessels. Follow-up information was obtained in 40 cases, ranging from 1 month to 40 years (mean, 5.4 years). Despite conservative excisions in most patients (simple excision, 83%; wide local excision, 13%; amputation, 2%), prognosis was excellent. Fifty-eight percent experienced recurrences, but no patient developed metastasis and no patient died of the direct effects of the tumor, although one patient with Maffucci's syndrome developed a concurrent angiosarcoma. We conclude that SCH is a primary benign vascular neoplasm or malformation similar to angiomatosis in which alterations in blood flow might explain some of the secondary features. Areas of diminished blood flow result in vascular collapse with formation of the "cellular" zones, and areas of vascular engorgement with stasis promote thrombosis and organization. Local "recurrences" probably represent contiguous spread along or multifocal involvement of a vessel. Because there is no evidence that this lesion has metastatic potential, we suggest that the lesion be designated spindle cell hemangioma for solitary lesions and spindle cell hemangiomatosis for multifocal lesions.