How we use angiopoietin-2 in the diagnosis and management of vascular anomalies.

The diagnosis of vascular anomalies remains challenging due to significant clinical heterogeneity and uncertain etiology. Evaluation using biopsy and/or genetic testing for somatic variants is invasive, expensive, and prone to sampling error. There is great need for noninvasive and easily measured blood laboratory biomarkers that can aid not only in diagnosis, but also management of treatments for vascular anomalies. Angiopoietin-2, a circulating blood angiogenic factor, is highly elevated in patients with kaposiform hemangioendothelioma with Kasabach-Merritt phenomenon and kaposiform lymphangiomatosis. Here, we describe our clinical experience using serum angiopoietin-2 as a biomarker for diagnosis and monitoring response to treatment.

Cost and effectiveness comparison of sirolimus versus standard treatment in Kasabach-Merritt phenomenon: a real-world evidence study in Thailand.

The conventional treatment of Kasabach-Merritt Phenomenon (KMP) consists of corticosteroids with vincristine/vinblastine or others. The aim of the study is to compare the first-year direct costs and effectiveness between sirolimus and conventional treatment. A retrospective case-control study of KMP patients was conducted at a mean age of 9 months (1 day to 12 years) between 2000 and 2022 from four tertiary centers in Thailand. The direct costs, hematologic and clinical complete response (HCR, CCR), hospitalization, length of stay, and complications were compared. Of 29 patients, 13 underwent sirolimus (four upfront and nine were refractory to the conventional). The first-year total cost had no statistically significant difference between sirolimus VS conventional treatment (8,852.63 VS 9,083.56 USD: p value: 0.94). The therapeutics achievement was the same in both HCR (244.75 VS 168.94 days; p value: 0.60) and CCR (419.77 VS 399.87 days; p value: 0.90). The subgroup analysis of the first-line sirolimus (n = 4) compared with the conventional (n = 25) showed a more reduced total cost (4,907.84 VS 9,664.05 USD; p value: 0.26) rendered net total cost of -4,756.21 USD per patient (cost saving). A more significant contrast of therapeutic achievement by reduction of both HCR (11.67 VS 224.20 days; p value: 0.36) and CCR (38.50 VS 470.88 days; p value: 0.04) was shown. The sirolimus had no difference in hospitalization, length of stay, and complications. Even though, it was unable to identify significant differences in cost-effectiveness. Sirolimus is suitable for all patients who have diagnosis of KMP either for rescue therapy or first-line treatment.

Kaposiform hemangioendothelioma presented with raynaud phenomenon: a case report.

BACKGROUND: Kaposiform hemangioendothelioma (KHE) is a rare vascular neoplasm affecting infants or young children. KHE includes a spectrum of lesions, ranging from small and superficial tumors to large and invasive lesions with Kasabach-Merritt phenomenon (KMP). Currently, no published studies have reported a KHE presenting as thrombocytopenia and Raynaud phenomenon. CASE PRESENTATION: A 2-year-old boy with right hand swelling and thrombocytopenia was admitted to our hospital. His right hand turned swelling and red, even occasionally cyanotic. This condition became worse in response to cool environments and improved with warming, and platelet counts were between 50 ~ 80 × 10^9/L. Physical examination on admission revealed the swelling and frostbite-like rash of the right-hand fingers, and the skin temperature of the right hand was lower than the left. On day 3 of admission, chest CT results showed an irregular mass on the right side of the spine. The puncture biopsy demonstrated positive CD31, D2-40, and FLI1 immunohistochemical staining, but negative GLUT1 staining, confirming the diagnosis of KHE. Furthermore, endothelin-1 (ET1) expression levels significantly increased, and eNOS and A20 expression levels significantly decreased comparing with control patients. The patient received methylprednisolone and sirolimus treatments, and his condition gradually improved during the follow-up. CONCLUSIONS: We reported the first case of KHE presenting with thrombocytopenia and Raynaud phenomenon. The development of Raynaud phenomenon could be associated with increased ET-1 and reduced eNOS and A20 expressions. Careful differential diagnosis of hidden KHE should be considered in children with thrombocytopenia and Raynaud phenomenon.

The use of mTOR inhibitors for the treatment of kaposiform hemangioendothelioma. A systematic review.

BACKGROUND: Kaposiform hemangioendothelioma (KHE) is a locally aggressive and potentially lethal vascular tumor of infancy. Current consensus recommendations include the use of vincristine and/or systemic steroids as first-line treatment. Mammalian target of rapamycin (mTOR) inhibitors represent a promising therapy for patients with KHE. The goal of our study is to critically assess the existing literature on outcomes of patients with KHE treated with mTOR inhibitors. METHODS: We conducted a literature search from 1 January 2000, to 30 April 2022. Articles reporting outcomes of patients treated with mTOR inhibitors for KHE were included. Descriptive statistics were used to describe and summarize the outcomes of the treatment. RESULTS: We included 327 patients with a mean age at diagnosis of 9.1 months (SD ± 9). Patients were treated with an mTOR inhibitor for a mean of 15.2 months (SD ± 4.1). A total of 315 (96.3%) patients had positive outcomes including improvement of the tumor size, symptoms and/or laboratory parameters in 227 (85%) and complete remission in 38 (12%). Seven (2%) patients did not respond to treatment and seven (2%) died of sepsis (4), Kasabach-Merritt phenomenon complications (1), cardiac and liver failure due to ductus arteriosus (1), or metastatic disease (1). CONCLUSION: This systematic review supports the efficacy and safety of mTOR inhibitors for KHE. Their use resulted in positive outcomes in terms of decreased symptoms, reduction in tumor size and improvement in biochemical parameters with a mortality rate of 2%. According to these findings, we suggest revised consensus treatment guidelines for KHE with mTOR inhibitors potentially considered first-line therapy.

Kaposiform hemangioendothelioma of the heart: a case report and literature review.

Kaposiform hemangioendothelioma is a rare tumour of vascular origin that rarely occurs in the heart. We provided a rare case of a 26-day-old infant with tachypnoea. Echocardiography showed a solid tumour in the pericardial cavity and a large amount of pericardial effusion. The solid tumour was confirmed by surgery, and the pathology was kaposiform hemangioendothelioma. We analysed this case and reviewed the related literature to explore the clinical features and echocardiographic manifestations to improve the understanding, diagnosis, and treatment of this disease for clinicians and sonographers.

Recent advances in the diagnosis, classification and molecular pathogenesis of cutaneous mesenchymal neoplasms.

The diagnosis of cutaneous mesenchymal neoplasms remains challenging, due to a combination of overlapping histological features, the rarity of some diagnoses and often inadequate sampling in superficial biopsies. Here, we describe recent advances in cutaneous mesenchymal neoplasms. We discuss improvements in our understanding of the molecular pathogenesis of non-neural granular cell tumour, epithelioid fibrous histiocytoma, composite and retiform haemangioendothelioma and dermatofibrosarcoma protuberans. We also discuss recently described tumour types, including some discovered via molecular testing: EWSR1::SMAD3-rearranged fibroblastic tumour, clear cell neoplasm with MITF::CREM rearrangement and melanocytoma with CRCT1::TRIM11 rearrangement, and some discovered via traditional histopathology: superficial CD34-positive fibroblastic tumour, plexiform myofibroblastoma and clear cell neoplasm with melanocytic differentiation and ACTIN::MITF translocation.

Composite hemangioendothelioma in the cervical spine with kaposiform hemangioendothelioma features in an elderly patient: a case report.

BACKGROUND: Composite hemangioendothelioma (CHE) is an intermediate group of tumors with features between hemangioma and angiosarcoma both histologically and biologically. CHE is predominant in young and middle-aged adults, but very infrequently affects the spine. We describe the case of primary CHE in the cervical spine exhibiting kaposiform hemangioendothelioma (KHE)-like components that was associated with cervical myelopathy with vertebral body destruction in an elderly woman. We retrospectively reviewed the case of a primary cervical spinal tumor, diagnosed as CHE with KHE-like components in pathological findings, associated with cervical myelopathy and cervical vertebral body destruction. CASE PRESENTATION: An 80-year-old woman presented with progressive cervical myelopathy caused by a cervical spine tumor. Preoperative cervical MRI revealed a neoplastic lesion invading the cervical spine that strongly compressed the spinal cord, causing right upper-limb paralysis. We performed partial tumor resection along with posterior decompression and fixation. Postoperatively, pathological findings showed that the tumor was CHE with KHE-like features. Following radiotherapy, no recurrences have been observed in 21 months. CONCLUSIONS: This is the first report of CHE with features of KHE in the spine of an elderly patient. Posterior decompression and fusion of the cervical spine and subsequent radiotherapy resulted in a good outcome.

Primary cardiac composite hemangioendothelioma with calcification mimicking a right atrial myxoma: A rare entity.

Composite hemangioendothelioma (CHE) is a rare vascular tumor which shows varying combination of benign, low-grade, and malignant vascular components on pathology. CHE is usually located on the surface of the dermis and subcutaneous tissue of the extremities. We report an unusual case of CHE in the heart.

The First Case of Composite Hemangioendothelioma in The Heart.

Composite hemangioendothelioma (CHE) is an extremely rare vascular neoplasm that is characterized by an admixture of benign, low-grade malignant, and malignant vascular components. It is usually located superficially in the dermis and subcutis of the extremities, and other sites involved include the head and neck region, oral mucosa, and viscera of the kidney and spleen. CHE has a low-grade malignant potential because it is locally aggressive. Here, we report a case of CHE in the heart in a 46-year-old man, who presented with a palpable mass arising from his right ventricle. Echocardiogram imaging revealed a 13.3 × 14.2 mm mass with high-signal intensity. Excision was performed, and microscopic examination revealed a heterogeneous mixture of vascular components, consisting of spindle-cell hemangioma, retiform hemangioendothelioma, and epithelioid-like hemangioendothelioma areas. To our knowledge, this is the first report on the behavior of this distinctive vascular neoplasm occurring in the right ventricle. Due to the unclear biological behavior of CHE in the heart and the paucity of cases, no further therapy was undertaken despite the risk of local recurrence and distant metastasis. The result of a six-month follow-up after surgery was disease-free.

Intravascular Papillary Endothelial Hyperplasia of the Mandible: A Rare Entity.

ABSTRACT: Intravascular papillary endothelial hyperplasia (IPEH) is a lesion characterized by the proliferation of endothelial cells within the lumen of the vessel, it was first described by Masson in 1923.The pathogenesis of Masson's tumor is still unknown, currently the most accredited hypothesis is the reactive 1. Clinically and symptomatologically it can have different presentations, it is, therefore, of fundamental importance to make a correct differential diagnosis. Diagnosis is mainly based on histological criteria. Intravascular papillary endothelial hyperplasia usually occurs in the skin and subcutaneous tissues, less commonly in the skeleton. The present is the fifth case of intravascular papillary endothelial hyperplasia of the mandible.

Kaposiform hemangioendothelioma further broadens the phenotype of PIK3CA-related overgrowth spectrum.

Kaposiform hemangioendothelioma (KHE) is a rare locally aggressive mixed vascular tumor, with typical onset in early childhood and characterized by progressive angio- and lymphangiogenesis. Its etiopathogenesis and molecular bases are still unclear. Here, we report the first case of congenital KHE harboring a PIK3CA mosaic pathogenic variant (c.323G > A, p.Arg108His) in a boy with very subtle PIK3CA-related overgrowth spectrum (PROS) features. This finding provides insights into the pathophysiology of KHE, offering targeted therapeutic options by inhibition of the PI3K/Akt/mTOR pathway. We propose the inclusion of this mixed lymphatic and vascular anomaly within the PROS.

Intravascular papillary endothelial hyperplasia in the oral mucosa and jawbones: A collaborative study of 20 cases and a systematic review.

BACKGROUND: Intravascular papillary endothelial hyperplasia is an unusual vascular lesion characterized by the proliferation of endothelial cells. The aim of this study was to determine the frequency and general features of this lesion. METHODS: Biopsy records of three oral pathology services were reviewed for intravascular papillary endothelial hyperplasia cases from 1959 to 2020. In addition, a systematic review of case reports and case series was carried out in eight electronic databases. RESULTS: Of the 65 205 retrieved cases, 20 (0.03%) were diagnosed as intravascular papillary endothelial hyperplasia. Mean patient age was 46.55 years, and females (12 cases/60%) were more affected. The lower lip (9 cases/47.36%) was the most commonly affected site, and the lesions were generally asymptomatic (7 cases/63.63%). Clinically, 90% of the lesions presented (18 cases) as a nodule, with a mean size of 1.13 cm. The clinical diagnostic hypotheses most frequently raised were mucocele (6 cases/37.50%) and hemangioma (5 cases/31.25%). An excisional biopsy was chosen in all cases for treatment. Forty-nine studies of the systematic review were included, yielding 105 cases. The literature showed similarity in all variables. CONCLUSION: Despite the uncommon frequency, clinicians and oral pathologists should familiarize themselves with the similarities between intravascular papillary endothelial hyperplasia and some other lesions in terms of clinical and histological features.

Intravascular pseudolymphomatous angiosarcoma: A new finding potentially mistaken for intravascular lymphoma.

Pseudolymphomatous infiltrates associated with angiosarcoma are a rarely reported phenomenon. Recognition of this reactive process is critical to making an accurate diagnosis, both in diagnosing the angiosarcoma and in avoiding an incorrect diagnosis of lymphoma. Here, we present a novel histopathologic pattern, angiosarcoma with a prominently intravascular atypical lymphoid component, mimicking intravascular T-cell lymphoma. Interestingly, serial biopsies in this case revealed a progressive increase in lymphocyte density and intravascular component over time. Despite prior reports of improved progression-free survival and overall survival of patients with pseudolymphomatous angiosarcoma, this patient showed rapid disease progression.

Intracranial kaposiform hemangioendothelioma presenting as epistaxis: a rare case report with review of literature.

INTRODUCTION: Kaposiform hemangioendothelioma (KHE) is a rare vascular tumor of intermediate malignancy with tendency for local invasion and recurrence. The tumor almost exclusively occurs in children, especially in infants. Intracranial KHE are extremely rare with only two cases reported in the literature. REPORT: We report the clinical and pathological features of this rare tumor arising from basitemporal region in a 21-month child. Our case did not present with Kasabach-Merritt phenomenon. Histopathological examination confirmed the diagnosis of KHE. CONCLUSION: KHE should be considered in the differential diagnosis of intracranial extra-axial neoplasm in children, and histopathological examination plays an important role in distinguishing KHE from its morphologic mimics. It is essential to diagnose KHE due to its locally aggressive nature.

Hepatic hemangioendothelioma of infancy: clinical features of a large cohort of patients and proposed management.

PURPOSE: The management of hepatic hemangioendothelioma (HHE) may be challenging. We aimed to review a large cohort of children who presented to our centers with symptomatic HHE in the last 16 years. METHODS: We collected age at presentation, clinical features, histology, diagnostic process, management and outcome. RESULTS: Twenty seven patients (male/female 5/22), median age 13 days (1-1530) presented with hepatomegaly (24/27), cardiac failure (10/27), cutaneous hemangiomas (8/27), fever and anemia (6/27 each), vomiting (5/27), splenomegaly (4/27). The lesion was focal, multifocal, or diffuse in 9 patients of each group. The management included medical treatment (8/27), embolization (8/27), resection (3/27), observation (6/27), transplantation (2/27). After 16 months' follow-up (30 days-11 years), 23/27 (85%) were alive. Diffuse lesions (4/4), cardiac failure (4/4), type II histology (4/4), age older than 6 months at diagnosis (3/4) predicted mortality (all p < 0.01). Histology showed type 1 lesion in 3/8, type 2 in 3/8, and type 3 in 2/8 with foci of angiosarcoma. CONCLUSION: Most patients with symptomatic HHE can be managed successfully with a combination of medical, radiological and surgical treatments. Patients with diffuse lesions, late presentation, cardiac failure and type II histology have a poor outcome. LEVEL OF EVIDENCE: Diagnostic level IV. Therapeutic level IV.

The histopathology of congenital haemangioma and its clinical correlations: a long-term follow-up study of 55 cases.

AIMS: Congenital haemangiomas (CHs) can be subdivided into different subtypes [rapidly involuting CHs (RICHs), non-involuting CHs (NICHs), and partially involuting CHs (PICHs)]. During the first few days of life, RICHs may be associated with transient but sometimes marked thrombocytopenia. We sought to assess the histological aspects and clinicopathological correlations of the three subtypes. METHODS AND RESULTS: We assessed the histopathological features of 10 RICHs, 25 NICHs, and 20 PICHs, described the patients' long-term clinical outcomes, and assessed clinicopathological correlations. All CHs were located in the dermis and hypodermis, and comprised both capillary lobules (with three distinct histopathological patterns) and extralobular large vessels. Most of the extralobular vessels were abnormal veins and abnormal lymphatic vessels. We did not observe significant correlations between the CH subtype, the histopathological pattern, and the time of the histopathological assessment. Interestingly, unexpected intralobular expression of podoplanin was found in neonatal biopsies of five RICHs and PICHs. Four of these five patients had concomitant thrombocytopenia. The podoplanin staining intensity decreased over time as the thrombocytopenia resolved and the tumour shrank. CONCLUSION: The histopathological features were similar in all three subtypes of CH, and were related to the time since disease onset; we consider that RICH, PICH and NICH form a single entity and differ only in their involuting potential. Along with the transient expression of intralobular podoplanin observed in some specimens from the newborn, the lobular architecture might lead to misdiagnosis of tufted haemangioma or kaposiform haemangioendothelioma.

Sirolimus Treatment of an Infant With Intrathoracic Kaposiform Hemangioendothelioma Complicated by Life-threatening Pleural and Pericardial Effusions.

Kaposiform hemangioendothelioma (KHE) is a rare infiltrative vascular tumor that may be associated with Kasabach-Merritt Phenomenon (KMP), which is a consumptive coagulopathy with potentially life-threatening thrombocytopenia. Management of KHE and KMP is challenging, and currently, there are no standardized validated treatment protocols. Mammalian target of rapamycin inhibitors have been shown to be effective in the treatment of KHE. We describe a term male who presented as a diagnostic dilemma with life-threatening pleural and pericardial effusions and severe thrombocytopenia. After extensive work-up the etiology for his condition was determined to be KHE with KMP. The patient was commenced on sirolimus and responded well to therapy with resolution of KMP.

Kaposiform haemangioendothelioma: clinical features, complications and risk factors for Kasabach-Merritt phenomenon.

BACKGROUND: Few studies have reported the clinical features, complications and predictors of Kasabach-Merritt phenomenon (KMP) associated with Kaposiform haemangioendothelioma (KHE). OBJECTIVES: To determine the clinical characteristics present at diagnosis and to identify features that may aid clinicians in managing KHE. METHODS: We conducted a cohort study of 146 patients diagnosed with KHE. RESULTS: KHE precursors or lesions were present at birth in 52·1% of patients. In 91·8% of patients, lesions developed within the first year of life. The median age at diagnosis of KHE was 2·3 months (interquartile range 1·0-6·0). The extremities were the dominant location, representing 50·7% of all KHEs. Among KHEs in the cohort, 63·0% were mixed lesions (cutaneous lesions with deep infiltration). Approximately 70% of patients showed KMP. A KHE diagnosis was delayed by ≥ 1 month in 65·7% of patients with KMP. Patients with KMP were more likely to have major complications than patients without KMP (P = 0·023). Young age (< 6 months), trunk location, large lesion size (> 5·0 cm) and mixed lesion type were associated with KMP in a univariate analysis. In the multivariate analysis, only age [odds ratio (OR) 11·9, 95% confidence interval (CI) 4·07-34·8; P < 0·001], large lesion size (OR 5·08, 95% CI 2·24-11·5; P < 0·001) and mixed lesion type (OR 2·96, 95% CI 1·23-7·13; P = 0·016) were associated with KMP. CONCLUSIONS: Most KHEs appeared before 12 months of age. KHEs are associated with various major complications, which can occur in combination and develop early in the disease process. Young age, large lesion size and mixed lesion type are important predictors of KMP.