Version May 2024
INTRODUCTION — Tufted angioma and kaposiform hemangioendothelioma (KHE) are rare, vascular tumors that typically occur during infancy or early childhood. Tufted angioma, previously known as "angioblastoma of Nakagawa," is a benign tumor; the name derives from its histopathologic appearance, characterized by tufts of capillaries within the dermis [1,2]. KHE is a locally aggressive tumor that may involve superficial and deep soft tissues and, rarely, the retroperitoneum, mediastinum, and internal organs [3,4].
Tufted angioma and KHE share several histopathologic and clinical features and are thought to be part of the same neoplastic spectrum [5,6]. The most serious complication of these tumors is Kasabach-Merritt phenomenon (KMP), a life-threatening coagulopathy characterized by severe thrombocytopenia and consumption of fibrinogen and other coagulation factors [7].
Tufted angioma, KHE, and KMP will be discussed in this topic. Infantile hemangiomas, congenital hemangiomas, venous malformations, capillary malformations and associated syndromes, and Klippel-Trenaunay syndrome are discussed separately.
●Infantile hemangiomas – (See "Infantile hemangiomas: Epidemiology, pathogenesis, clinical features, and complications" and "Infantile hemangiomas: Evaluation and diagnosis" and "Infantile hemangiomas: Management".)
●Congenital hemangiomas – (See "Congenital hemangiomas: Rapidly involuting congenital hemangioma (RICH), noninvoluting congenital hemangioma (NICH), and partially involuting congenital hemangioma (PICH)".)
●Vascular malformations – (See "Venous malformations" and "Capillary malformations (port wine birthmarks) and associated syndromes" and "Klippel-Trenaunay syndrome: Clinical manifestations, diagnosis, and management".)
EPIDEMIOLOGY — Tufted angioma and KHE are rare [8,9]. Their exact incidence is unknown. Based upon the cases observed at a large referral center, the incidence of KHE has been estimated at 0.07/100,000 children per year [3].
Males and females are affected equally. Approximately 50 percent of cases are present at birth; the remainder develop after the neonatal period, most often in the first year of life. However, later onset during childhood and even in adulthood has been reported [10]. KMP occurs in approximately 70 percent of cases of KHE and 10 percent of tufted angiomas [3,11].
PATHOGENESIS — The pathogenesis of tufted angioma and KHE is poorly understood. The neoplastic spindle cells of KHE express the vascular markers CD31 and CD34, the vascular endothelial growth factor receptor 3 (VEGFR-3), a receptor required for lymphangiogenesis, and the lymphatic markers D2-40 and PROX1 [4,5,12-14]. These findings suggest that KHE may derive from the lymphatic endothelium, similarly to Kaposi sarcoma. However, in contrast with Kaposi sarcoma, human herpesvirus 8 (HHV-8) transcripts have not been identified in KHE, and there is no evidence of association with HHV-8 infection [12]. Data regarding genomic alterations in these tumors are limited, but there have been a few reports of mutations in GNA14 in some (but not all) cases [15].
CLINICAL MANIFESTATIONS
Tufted angioma — Tufted angiomas usually present as infiltrated, firm, dusky red to violaceous plaques or nodules with ill-defined borders (picture 1E). The size varies from less than 1 cm to more than 10 cm. Lesions are typically located on the arms, legs, and trunk [16]. In contrast with infantile hemangiomas, craniofacial lesions are uncommon. Lanugo hair hypertrichosis and increased sweating in the area overlying the tumor also have been described [17].
Tufted angioma typically manifests during infancy or early childhood, but cases with onset in adult life have been reported [10,18,19]. At birth, lesions are either absent or barely evident as a faint pink or brown discoloration. Over time, the tumor thickens into a plaque, often becoming dusky red or violaceous in color (picture 1E). Some develop distinct nodularity or focal papules. Eventually, lesions stabilize in size and tend to persist unchanged. However, partial or complete regression during infancy or childhood has been reported in a few cases [20,21].
Tufted angiomas are usually solitary, but multifocal or disseminated disease has been reported [22]. A rare, eruptive form has been described in immunosuppressed patients [23]. Approximately 10 percent of tufted angiomas develop KMP [11]. (See 'Kasabach-Merritt phenomenon' below.)
Kaposiform hemangioendothelioma — KHE appears as a slightly raised, expanding, subcutaneous mass with a purpuric, bruised appearance and occasional telangiectasias (picture 1A-B) [7,24,25]. Increased hair growth or sweating overlying the tumor may be evident. In some cases, the appearance of these lesions can be dramatic, with massive involvement of an entire extremity or other body parts. As the tumor grows, it infiltrates surrounding tissue planes (picture 1D).
KHE may be present at birth or develop in early childhood. Over time, especially in cases associated with severe coagulopathy, the tumor becomes indurated and firm, with a red-purple hue, ecchymoses, and petechiae (picture 1A, 1C).
In most cases, the tumor involves the extremities, resulting in musculoskeletal dysfunction with decreased range of motion or pain. Less frequent locations include the trunk and the cervicofacial region [3]. Approximately 10 percent of KHEs do not involve the skin. The retroperitoneum is the most frequent extracutaneous location, followed by muscle, bone, and thoracic cavity. Deep retroperitoneal lesions or intrathoracic lesions can cause a bluish, purpuric hue on the skin and may be mistaken for a bleeding disorder. KHE with osseous extension can occur and may uncommonly present with the bone as the primary site of involvement [26].
Over 70 percent of KHEs develop KMP [3]. The risk is highest for large, congenital lesions and lesions located in the retroperitoneum or mediastinum. (See 'Kasabach-Merritt phenomenon' below.)
Tumors without KMP usually occur in toddlers or older children and are relatively small (<8 cm in diameter) [27]. They appear as firm soft tissue masses that can be indurated, light brown, violaceous, or erythematous in color, without purpura or petechiae. These tumors can cause pain or functional impairment depending on the area of involvement [28].
Kasabach-Merritt phenomenon — KMP is a life-threatening complication occurring in approximately 70 percent of cases of KHE and 10 percent of tufted angiomas [3,11]. KMP is characterized by profound thrombocytopenia and consumption coagulopathy.
Since its first description in an infant with a "giant capillary hemangioma," the term has been used indiscriminately to describe thrombocytopenia or coagulopathy associated with any vascular anomaly [7]. However, it is now clear that KMP is a complication of tufted angioma and KHE and not of infantile or congenital hemangiomas [7,25]. These tumors can cause pain or functional impairment depending on the area of involvement [24].
Why KMP develops exclusively in the setting of tufted angioma or KHE is unclear. One hypothesis is that the abnormal endothelium and convoluted architecture of the tumor vasculature promote platelet trapping, activation, and consumption [29]. Platelet aggregation and activation result in thrombocytopenia, consumption of fibrinogen, and ongoing fibrinolysis, leading to intralesional bleeding and tumor enlargement [8].
The presenting sign of KMP is a rapid enlargement of the tumor, which becomes tense, purpuric or ecchymotic, and painful (picture 1C-D). These changes are accompanied by a rapid drop in the platelet count. The typical platelet count ranges from 3000 to 60,000/microL. Fibrinogen levels are usually <100 mg/dL; D-dimer and fibrin degradation products are elevated. The prothrombin time (PT) and the activated partial thromboplastin time (aPTT) are usually normal or minimally elevated.
Severe anemia caused by sequestration of red blood cells in the tumor may also occur. Occasionally, schistocytes (evidence of a microangiopathic hemolytic anemia) can be seen on the blood smear. (See "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)", section on 'Microangiopathic hemolytic anemia (MAHA)'.)
Despite the profound thrombocytopenia, severe hemorrhage is rare. However, trauma (eg, biopsy, surgical procedure), ulceration, infection, or delay in initiating treatment may induce progression to a more systemic coagulopathy similar to disseminated intravascular coagulation [24]. (See "Disseminated intravascular coagulation in infants and children".)
DIAGNOSIS — The diagnosis of tufted angioma and KHE is based upon the combination of clinical, histologic, and imaging features. Laboratory evaluation is essential for the diagnosis of KMP.
Clinical examination — The diagnosis of tufted angioma or KHE is suspected in an infant presenting with an atypical, indurated, vascular lesion, red to purple in color with ill-defined borders, most often located on the extremities or trunk (picture 1A, 1C-E). The presence of hypertrichosis and/or hyperhidrosis overlying the lesion is a clue to the diagnosis. (See 'Tufted angioma' above and 'Kaposiform hemangioendothelioma' above.)
Imaging studies — Magnetic resonance imaging (MRI) is important in differentiating tufted angioma and KHE from other tumors, in delineating the extent of the disease, and in documenting the response to treatment, particularly in cases with extracutaneous involvement [30-33]. T1-weighted sequences typically show a poorly circumscribed soft tissue mass with multiplanar involvement and diffuse enhancement with gadolinium. T2-weighted sequences show a diffuse, increased signal with stranding in the subcutaneous fat. Gradient sequences show mildly dilated vessels in and around the soft tissue mass. MRI can also show involvement or destruction of the adjacent bone.
Ultrasonography is used for small and superficial tumors. On ultrasonography, KHE appears as an ill-defined, focal or diffuse lesion confined to subcutaneous fat or infiltrating the subcutaneous tissue and underlying muscle. Color doppler scan shows increased vascularity with high velocity flow [34].
Laboratory evaluation — Laboratory evaluation of tufted angioma and KHE includes:
●Complete blood count with platelet count
●Fibrinogen
●D-dimer
●Prothrombin time (PT)
●Activated partial thromboplastin time (aPTT)
●International normalized ratio (INR)
A comprehensive metabolic panel including liver and kidney function tests should be performed in acutely ill patients.
The detection of severe thrombocytopenia, hypofibrinogenemia, and elevated D-dimer suggests the diagnosis of KMP. However, other rare tumors of infancy (eg, congenital hemangiomas, hemangiopericytoma, infantile fibrosarcoma, angiosarcoma) and venous malformations may be associated with thrombocytopenia and coagulopathy. (See 'Differential diagnosis' below.)
Biopsy — Whenever possible, histologic confirmation of the diagnosis of tufted angioma or KHE should be considered, since therapy is often needed for a prolonged period of time. However, the presence of a highly vascular tumor together with thrombocytopenia and coagulopathy, although not an absolute contraindication for biopsy, greatly increases the risk of bleeding from a biopsy.
If clinical and imaging findings are highly suggestive of the diagnosis, deferring biopsy is an option. If a biopsy is deemed necessary in a patient with severe coagulopathy, relevant specialists (ie, hematologist, surgeon, anesthesiologist) should be involved in careful planning to minimize complications, and the biopsy should be performed in the operating room or interventional radiology suite. Supportive care with platelet transfusions, cryoprecipitate, and other products may be needed pre- and postoperatively and during the procedure.
Histopathology — The diagnosis of tufted angioma is confirmed by the finding of multiple discrete lobules of tightly packed capillaries (tufts) scattered in the dermis and sometimes in the subcutis in a so-called "cannonball" pattern (picture 2) [35]. These capillary tufts are surrounded by cleft-like, semilunar, empty, vascular spaces. Thin-walled, lymphatic spaces may be seen throughout the dermis. Mitoses are rare.
The finding of dilated, thin-walled vessels surrounded by coalescing lobules or sheets of tightly packed, spindled or more rounded endothelial cells, with an infiltrative pattern in the dermis, subcutaneous fat, and muscles, is diagnostic of KHE (picture 3). Slit-like lumina reminiscent of Kaposi sarcoma may be seen. Mixed with these areas are nests of rounded epithelioid cells of vascular origin and aggregates of capillaries with round or irregularly shaped lumens containing platelet-rich fibrin thrombi. There is usually the presence of abnormal, lymphatic spaces either within or at the periphery of the lesion. The rate of mitosis is variable but usually low.
Immunohistochemical studies reveal that the endothelial cells express the vascular markers CD31 and CD34 and the vascular endothelial growth factor receptor 3 (VEGFR-3), a marker of lymphangiogenesis, in both tufted angioma and KHE. The lymphatic markers D2-40 and PROX1 are also positive, supporting the concept of "lymphothelial" tumors arising from the lymphatic endothelium [4,5,12,13]. Of note, GLUT1, the marker for infantile hemangiomas, is always negative.
The significant morphologic overlap between tufted angioma and KHE suggests that they may be part of a continuum, in which superficial, cutaneous lesions show the classical findings of tufted angioma and lesions infiltrating the subcutaneous tissues or involving visceral sites have the features of KHE [6,36,37].
DIFFERENTIAL DIAGNOSIS — The differential diagnosis of tufted angioma and KHE includes:
●Infantile hemangiomas – Infantile hemangiomas are not completely formed at birth, are more commonly located in the head and neck area, and have a predilection for females (picture 4A-B). They are not associated with a coagulopathy. On histology, they exhibit lobulated masses of proliferating endothelial cells and strong expression of GLUT1. (See "Infantile hemangiomas: Epidemiology, pathogenesis, clinical features, and complications".)
●Congenital hemangiomas – Congenital hemangiomas are vascular tumors that are fully formed at birth (picture 5A-B). Rapidly involuting congenital hemangioma (RICH) can cause platelet trapping with mild thrombocytopenia and hypofibrinogenemia, which resolve spontaneously over a few weeks. Clinically, RICH can be quite difficult to distinguish from those KHEs that present as tumors at birth. Histologically, RICH differs in having lobules of capillary proliferations embedded in a fibrous stroma without spindle cell or lymphatic ectasias. (See "Congenital hemangiomas: Rapidly involuting congenital hemangioma (RICH), noninvoluting congenital hemangioma (NICH), and partially involuting congenital hemangioma (PICH)".)
●Kaposiform lymphangiomatosis – Kaposiform lymphangiomatosis (KLA) is a new entity classified under the heading of lymphatic anomaly that is distinct from generalized lymphatic anomaly and KHE in its histology, clinical course, and outcome [38,39]. Histologically, KLA is characterized by diffuse, lymphatic malformation with focal areas of "kaposiform" spindle cells versus the diffuse nature of the spindle cells in KHE. Somatic activating variants in NRAS have been found in KLA specimens [40]. Clinically, KLA can be multifocal or diffuse throughout the lung and/or abdomen. Other organ involvement can occur, including soft tissue, bone, spleen, liver, and brain. The disorder is associated with hemorrhagic pleural effusions and/or ascites. Patients can have mild to severe coagulopathy similar to KHE, including thrombocytopenia and hypofibrinogenemia. Vincristine, steroids, and sirolimus have all been used for treatment; however, the mortality is high despite aggressive therapy [38,41-43].
●Infantile myofibromatosis – Formerly known as infantile hemangiopericytoma [44-46], infantile myofibromatosis is a rare soft tissue tumor that can contain two different clinical entities, the adult type and the infantile type, with the latter occurring in the first year of life [47]. In newborns and infants, the tumor may present as a multilobulated mass in the subcutis (picture 6). Consumption coagulopathy and bleeding may occur and mimic KMP. Histology reveals well-circumscribed nodules of round-shaped and spindle-shaped cells with variable cytologic atypia and haphazard, perivascular orientation and an increased number of thin-walled, branching "staghorn" vessels. (See "Skin nodules in newborns and infants", section on 'Infantile myofibromatosis'.)
●Infantile fibrosarcoma – Infantile fibrosarcoma is a rare, malignant tumor that can be present at birth or develop in the first years of life. Lesions present as rounded, firm tumors fixed to the deep tissue planes [48]. Congenital lesions may mimic KHE, particularly when associated with thrombocytopenia and coagulopathy. Histology is required for a precise diagnosis. (See "Skin nodules in newborns and infants", section on 'Infantile fibrosarcoma'.)
●Venous malformations – Venous malformations are slow-flow vascular malformations that usually present at birth as soft, compressible, blue masses that enlarge when the affected area is in a dependent position or with physical activity or crying. Venous malformations can be multifocal or diffuse. Imaging studies, including Doppler ultrasonography and MRI, are helpful in distinguishing venous malformations from vascular tumors [49]. In extensive venous malformations (multifocal or diffuse), localized intravascular clotting results in consumption coagulopathy, with elevated D-dimers and low fibrinogen. However, in contrast with KMP, thrombocytopenia is mild, with platelet counts rarely lower than 50,000 to 60,000/microL. (See "Venous malformations".)
●Angiosarcomas – Angiosarcomas are extremely rare in children, but cases have been reported in neonates and toddlers, with presentation of multiple cutaneous lesions and liver lesions, some of which are GLUT1 positive [17,18,36,37,50]. Large lesions and multiple lesions have been associated with coagulopathy.
●Kaposi sarcoma – Kaposi sarcoma is exceedingly rare in children born outside of Africa. Histologically, Kaposi sarcoma presents with extensive, vascular proliferation in the dermis with multiple dilated, vascular spaces and solid cords and fascicles of spindle cells arranged between the jagged, vascular channels. The viral genome of human herpesvirus 8 (HHV-8) is detectable in Kaposi sarcoma lesions at all stages, regardless of the clinical variant [51,52]. Coagulopathy is not common in these lesions. (See "Classic Kaposi sarcoma: Clinical features, staging, diagnosis, and treatment" and "AIDS-related Kaposi sarcoma: Clinical manifestations and diagnosis".)
MANAGEMENT — The approach to the treatment of tufted angioma and KHE must be individualized, based upon the size, location, presence of symptoms (eg, tenderness or functional compromise), and presence or absence of thrombocytopenia and coagulopathy (KMP).
Guidelines for the management of complicated KHE were proposed in 2013 by an American and Canadian multidisciplinary expert panel, based upon a review of the available evidence, expert opinion, and clinical experience [53]. At the time, sirolimus was just beginning to emerge as a treatment for vascular anomalies. Its role as a therapy for KHE and KMP has been subsequently emphasized. (See 'Sirolimus plus systemic corticosteroids' below.)
Patients without Kasabach-Merritt phenomenon — Several forms of treatment have been proposed for tufted angioma and KHE that are not complicated by KMP. They include surgical excision, pulsed dye laser (for superficial, stain-like tumors), topical agents (eg, sirolimus, tacrolimus), systemic agents including corticosteroids, vincristine, and sirolimus. The efficacy of these various treatment modalities has not been evaluated in randomized trials or large observational studies. Limited evidence is based upon small case series, single case reports, and clinical experience.
Asymptomatic tumors without Kasabach-Merritt phenomenon
●Observation – For tumors of any size that are asymptomatic, do not involve vital organs, do not cause functional compromise, and are not disfiguring, observation may be an option. Spontaneous regression of tufted angioma during infancy or early childhood has been reported in a few patients [20,54-56]. In a series of five patients with KHE without KMP who did not receive any treatment, two tumors regressed spontaneously within two years, and three tumors remained stable after a follow-up time of 15 months to 6.5 years [27].
●Surgical excision – Surgical excision, if feasible, is the treatment of choice for patients who desire definitive treatment.
●Topical therapies – Topical sirolimus and topical tacrolimus have been reported as beneficial in a limited number of cases, but their place as therapeutic agents for superficial KHE or tufted angioma is uncertain. In two small case series, topical sirolimus was reported to be effective in causing fading and improvement of local symptoms of tufted angiomas [57,58]. Topical sirolimus 0.2% gel is available by prescription in the United States; however, prior reports used higher concentrations compounded for topical use.
Topical tacrolimus 0.1%, commonly used as a steroid-sparing treatment for atopic dermatitis, has also been reported to be effective in treating superficial KHE and tufted angioma in a small case series (six patients) and in a case report [59,60]. The mechanisms for its benefits may include local anti-inflammatory effects as well as inhibition of local angiogenic factors.
Symptomatic tumors without Kasabach-Merritt phenomenon — For patients with tumors that are relatively well localized but are causing symptoms, disfigurement, or functional compromise, surgical excision, if feasible, is the preferred treatment [17,56]. However, since the tumor margins are often poorly defined, complete surgical excision may not be possible, and medical therapy is needed.
There is no consensus on the pharmacologic treatment of nonresectable tumors that have a high risk of functional compromise. Our approach would be to start medical therapy prior to surgery:
●For tufted angioma, we suggest aspirin 5 mg/kg per day as first-line therapy [61].
●For KHE, in accord with an expert consensus panel, we suggest oral prednisone or prednisolone 2 mg/kg per day as first-line therapy [53]. Adjunctive therapies include aspirin at an antiplatelet dose of 2 to 5 mg/kg per day or sirolimus. The dosing and duration of sirolimus treatment are discussed below. (See 'Sirolimus plus systemic corticosteroids' below.)
Other treatments that have been used alone or in combination for tumors without KMP include vincristine, propranolol, interferon-alpha, and ticlopidine [27,61-65]. However, no single regimen has been studied in comparative prospective trials, and information on long-term outcomes and complete resolution of the tumor is lacking.
Patients with Kasabach-Merritt phenomenon
General considerations — Infants with tufted angioma or KHE and associated KMP are at very high risk for complications. Their management primarily involves the treatment of the tumor responsible for the coagulopathy and supportive measures to maintain hemostasis.
In 2013, an expert panel recommended steroids and vincristine as first-line treatment for KHE/KMP [53]. However, subsequent numerous case reports, case series, and a prospective clinical trial have shown very encouraging results with the mammalian (mechanistic) target of rapamycin (mTOR) inhibitor sirolimus, suggesting that it should be considered the preferred first-line therapy [28,63,66-73]. Thus, most clinicians treating KHE with KMP are using sirolimus with or without systemic corticosteroids as first-line treatment, both because it can be orally administered (as opposed to the need for a central line for administration of vincristine) and because the coagulopathy of KMP improves much more rapidly with sirolimus. (See 'Sirolimus plus systemic corticosteroids' below.)
First-line therapy
Sirolimus plus systemic corticosteroids — For large, nonresectable KHE with KMP, we suggest treatment with sirolimus plus systemic corticosteroids as the initial treatment followed by sirolimus as monotherapy. Because sirolimus is an immunosuppressant, we recommend Pneumocystis pneumonia prophylaxis, especially in infants and toddlers (see "Treatment and prevention of Pneumocystis pneumonia in patients without HIV", section on 'Prophylaxis'):
●Oral corticosteroid dosing – Oral prednisolone 2 mg/kg per day is given for two weeks and the weaned over one to two months.
●Sirolimus dosing – Sirolimus is typically given orally at the dose of 0.8 to 1 mg/m2 per dose twice daily in children aged 12 months and older, with close pharmacokinetic monitoring [74]. Blood levels of sirolimus should not be higher than 10 to 13 ng/mL. In newborns, lower doses are required with more frequent monitoring (table 1) [75,76]. Trough blood levels should be checked weekly, until stable at least twice in a row, and monthly thereafter. Levels should also be monitored with illness. Neonates and infants may need twice-weekly monitoring of trough levels initially. Careful consideration is needed in dosing sirolimus in pediatric patients to achieve the target dose of approximately 10 to 13 ng/mL. Close monitoring of the serum levels should be performed, and dose adjustments should be made accordingly [75,77]. The suggested dosing regimens are derived in part from the phase 2 prospective study (table 1) [28]. Neonates and infants need a lower dosing regimen secondary to physiologic differences in drug metabolism [75,77].
●Duration of treatment – Multiple reports have noted a rapid response of hematologic parameters within one to three weeks of sirolimus therapy [28,66-68,78]. However, a concern raised in several reports is the phenomenon of "relapse" or worsening of clinical status (increase in the size of the lesion, change in color, pain or, rarely, increase in D-dimer, drop in platelets and/or fibrinogen) after the medication is discontinued or during a "weaning schedule." This can happen relatively quickly even after dramatic clinical response, raising the issue of whether longer-term maintenance therapy with sirolimus may be needed in some cases [79].
Most clinicians will treat high-risk patients for two years and then wean the dose of sirolimus over six months. Patients who "relapse" usually require a lower dose of sirolimus to maintain relief of symptoms.
Long-term data on the duration of response to sirolimus, dosing regimens needed during maintenance treatment, and long-term toxicity are limited. Long-term follow-up data of a phase 2 sirolimus study were reported by one of the authors in 2018 [80]. Of 10 patients with KHE and KMP, five were still on small doses of sirolimus five years after the initial year of therapy. No patient had any long-term toxicities.
●Adverse effects – Common adverse effects of sirolimus for infants include mouth sores, abdominal upset, poor oral feeding, immunosuppression, irritability, and the need for modification of vaccination schedules.
●Supporting evidence – Growing evidence from several case series, a phase 2 trial, and a randomized trial supports the efficacy of sirolimus as monotherapy or in combination with oral corticosteroids for KHE with KMP [28,66-69,78,79,81-84], including cases refractory to previous therapy with vincristine [85]:
•In a phase 2 clinical trial evaluating the safety and efficacy of sirolimus for the treatment of complicated vascular anomalies (including, but not limited to, KHE) in 61 children, sirolimus induced a partial response (complete response of hematologic parameters with partial tumor response) in all patients with KHE/KMP [28]. Sirolimus was given at the dose of 0.8 mg/m2 twice daily, with careful monitoring and adjustment to keep serum levels between 10 to 15 ng/mL using pharmacodynamic modeling. Patients also received supportive care, including Pneumocystis pneumonia prophylaxis.
•A subsequent randomized trial that included 73 patients aged 0 to 14 years with KHE and KMP compared combined therapy with sirolimus plus prednisolone with sirolimus monotherapy [78]. Patients received sirolimus at a starting dose of 0.8 mg/m2 twice daily and concurrent prednisolone 2 mg/kg per day or sirolimus alone. Patients who showed stabilization or improvement continued treatment for 12 months and were followed for two years. More patients in the combined therapy group than in the monotherapy group achieved the primary outcome of a durable platelet response at week 4 (95 versus 67 percent, difference 28 percent; 95% CI 10.0-44.7). Complete and nearly complete tumor involution compared with baseline was demonstrated in 81 percent of patients in the combined therapy group versus 58 percent of those in the monotherapy group (difference 23 percent; 95% CI 1.7-41.4). Adverse events occurred with equal frequency in the two groups and included upper respiratory tract infection, mucositis, and nausea/vomiting.
Second-line therapy
Vincristine — Vincristine, a chemotherapy agent that promotes endothelial apoptosis, was used in the past as a first-line or early second-line therapy in combination with a tapering dose of systemic corticosteroids [86]. However, vincristine has fallen into disfavor, given the longer time to response, need for a central line, and risk of neurotoxicity and other adverse events.
It can be used as an adjunctive treatment in severe, refractory cases with incomplete response to sirolimus and systemic corticosteroids:
●Administration – Vincristine is given at a weekly dose of 0.025 to 0.05 mg/kg for infants <10 kg and 1 to 1.5 mg/m2 for infants >10 kg for two months [53,87]. Vincristine is a vesicant and should be given through a central venous line.
If a response is noted (hematologic response, complete regression, or reduction in size of the tumor), the administration interval can be increased to every two weeks for two months and then to every three weeks for two months. In one case series, the average time to platelet increase was two months, and the average time to decrease in tumor size was four months [86].
●Duration of treatment – Vincristine is typically administered for 20 to 24 weeks, based upon the response to treatment and acceptable, therapy-related toxicity.
●Adverse effects – Adverse effects of vincristine include peripheral polyneuropathy, abdominal autonomic dysfunction (constipation), and vocal cord paralysis, and it needs to be given via a central line as it is a vesicant [86,88]. (See "Overview of neurologic complications of conventional non-platinum cancer chemotherapy", section on 'Vincristine'.)
●Supporting evidence – Several systematic reviews and meta-analyses of observational studies and one small, randomized trial evaluated the efficacy of vincristine for the treatment of KHE with KMP:
•In a meta-analysis that included 15 studies with 244 patients comparing the efficacy of several treatments, the pooled response rate for vincristine was 0.72 (95% CI 0.64-0.79) compared with 0.27 (95% CI 0.17-0.36) for systemic corticosteroids [89].
•Another meta-analysis of seven studies (123 patients) published between 2009 and 2017 showed that compared with systemic corticosteroids, vincristine was more likely to induce hematologic and tumor response (pooled relative risk 2.08, 95% CI 1.38-3.16) [90]. The authors also reviewed 20 additional studies of systemic corticosteroids (15 studies) and vincristine (5 studies), reporting an overall response rate higher for vincristine than for corticosteroids (86 versus 55 percent, respectively). Adverse events were more frequent with corticosteroids than vincristine (52 and 18 percent, respectively).
•A multicenter, randomized trial evaluated the efficacy of vincristine versus systemic corticosteroids in 59 patients with KHE or tufted angioma, of whom 50 had KMP [91]. Patients received methylprednisolone 4 mg/kg/day, switched to every other day after a response was noted and then tapered in four to six weeks, or vincristine 0.05 mg/kg weekly four times, then monthly six times, with additional doses added if needed. At one month, more patients in the vincristine group than in the corticosteroid group experienced improvement in thrombocytopenia and tumor texture (80 versus 44 percent and 69 versus 31 percent, respectively). The overall improvement rate (based on percentage change from baseline of a composite score based on platelet count; fibrinogen levels; and tumor size, texture, and appearance) was greater in the vincristine group than in the corticosteroid group (60 versus 34.5 percent, respectively), although the difference was not statistically significant.
In a small number of patients, vincristine has been used in combination with antiplatelet agents [88,92,93]. In a retrospective study, 11 children aged 0 to 36 months were treated with vincristine 0.05 mg/kg weekly for four months [88]. Aspirin 10 mg/kg per day and ticlopidine 10 mg/kg per day were also given and continued for a total of 14 months. An increase in platelet count to 100,000 or more was observed in all children within three weeks of starting treatment. All patients were alive and clinically free of disease after a median follow-up of 4.5 years (range 2 to 17 years).
Other therapies — Antiplatelet agents (eg, aspirin, ticlopidine) are usually used in combination with other treatments such as systemic corticosteroids and vincristine [88]. Aspirin is used in the setting of platelet trapping and consumption to prevent platelet activation and aggregation, a critical pathophysiologic mechanism in the development and perpetuation of KMP [29].
An antifibrinolytic agent (tranexamic acid or aminocaproic acid) has been used in a few cases of KMP with mixed results [94-97].
Propranolol has been suggested as a possible treatment for tufted angioma and KHE, given its remarkable efficacy in the treatment of infantile hemangiomas. However, in a small case series of 11 patients, improvement was noted only in four patients [64].
Hemostasis support — Although platelet counts in KMP can be alarmingly low (eg, 3000 to 5000/microL), clinicians should not treat "the numbers" but "the patient" [9]. Despite the profound thrombocytopenia, life-threatening hemorrhages are rare. However, severe bleeding can occur in patients with visceral involvement or disseminated intravascular coagulation and in those who have multiorgan failure [98]:
●Platelet transfusions – Platelets should not be given unless the patient is actively bleeding or in preparation for surgery. In patients undergoing surgical procedures, platelets should be infused during the procedure. The effects of platelet transfusions are very transitory and can actually induce a rapid and, at times, sustained increase in the size of the tumor, probably secondary to increased platelet trapping and clotting within small vessels of the tumor [53].
●Cryoprecipitate – Cryoprecipitate for the correction of hypofibrinogenemia should be given with careful consideration in the following circumstances:
•Active bleeding
•Before surgical procedures
•Platelet count <10,000/microL
•Fibrinogen <100 mg/dL
•To stabilize the endothelium in critical infants with multiorgan system failure
●Coagulation factor replacement – In case of active bleeding, recombinant human factor VIIa can be used at a dose of 90 mcg/kg [99]. (See "Recombinant factor VIIa: Administration and adverse effects", section on 'Off-label uses'.)
Infants with disseminated intravascular coagulation and prolonged prothrombin time (PT) and activated partial thromboplastin time (aPTT) may need the replacement of the other coagulation factors with fresh frozen plasma (see "Disseminated intravascular coagulation in infants and children"). Despite abnormal coagulation parameters that sometimes include abnormal PT, aPTT, and international normalized ratio (INR), heparin and low molecular weight heparin should not be used in the management of KMP because it is a unique form of coagulopathy, different from other forms of disseminated intravascular coagulation or localized intravascular coagulopathy, with platelet trapping as its primary inciting event.
●Packed red blood cell transfusion – Transfusion of packed red blood cells should be given if the patient has symptomatic anemia. (See "Red blood cell transfusion in infants and children: Selection of blood products".)
Surgical treatment — Tufted angiomas and KHE associated with KMP are usually large and infiltrative lesions that do not allow a complete surgical excision. However, for small or localized tumors or tumors whose size has been reduced by pharmacologic therapy, surgical excision is a treatment option [100-102]. Surgical excision may be a second-line approach for tumors that have failed medical management or for imminently life-threatening tumors when the time to response to medical therapy is considered too long [53].
Embolization — In patients with symptomatic or high-risk tumors, embolization may be helpful in decreasing the blood flow to the lesion before initiating a pharmacologic treatment [103-105]. A case series of 34 infants who received transarterial embolization from two to five times each found that the feeding arteries of KHE were numerous, small, and not easily embolized and that platelet increases were either absent or transient [106].
Radiation therapy — Low-dose radiotherapy is rarely used for the treatment of KMP. Because of the risk of secondary malignancies, radiotherapy should be considered a last resort treatment for tumors that are unresponsive to other therapies [107-112].
PROGNOSIS — Tufted angioma and KHE can undergo spontaneous or treatment-induced regression but never resolve completely [20,21]. A study evaluating patients 10 years after their diagnosis found active tumor on radiologic imaging and repeat biopsy in most patients [37].
In the past, a mortality rate of 12 to 24 percent has been reported among patients with KMP. However, mortality rates have decreased over time due to improved pharmacologic therapy and better supportive care [24]. The leading causes of death include hemorrhage, sepsis, organ failure, or invasion of vital structures. Hemorrhage is more common in retroperitoneal and intrapleural tumors [36,70,107].
The cutaneous outcome of tufted angioma and KHE includes three types of residual lesions: vascular stains with papules, soft tissue swelling with telangiectasias, and fibrotic subcutaneous infiltrate. Long-term complications that can significantly impair quality of life include lymphedema, recurrent inflammation, pain, and orthopedic issues (eg, contractures, scoliosis, impaired function) [113]. Late complications often arise around puberty [114].
SUMMARY AND RECOMMENDATIONS
●Definition – Tufted angioma and kaposiform hemangioendothelioma (KHE) are rare, vascular tumors that typically occur during infancy or early childhood. They may be associated with Kasabach-Merritt phenomenon (KMP), a life-threatening complication characterized by severe thrombocytopenia and coagulopathy. (See 'Introduction' above.)
●Clinical presentation:
•Tufted angioma usually presents as infiltrated, firm, dusky red to violaceous plaques or nodules with ill-defined borders (picture 1E).
•KHE appears as a subcutaneous mass with a purpuric, bruised appearance (picture 1A). (See 'Clinical manifestations' above.)
●Kasabach-Merritt phenomenon – KMP is characterized by profound thrombocytopenia and coagulopathy, due to platelet trapping in the tumor and consumption of fibrinogen. The presenting sign is a rapid enlargement of the tumor, which becomes tense, purpuric or ecchymotic, and painful (picture 1C). (See 'Kasabach-Merritt phenomenon' above.)
●Diagnosis – The diagnosis of tufted angioma or KHE is suspected in a child presenting with an atypical, vascular lesion, red to purple in color with ill-defined borders, most often located on the extremities or trunk (picture 1A, 1C-E). A biopsy for histologic and immunohistochemical evaluation may be necessary to confirm the diagnosis.
Laboratory findings of severe thrombocytopenia, hypofibrinogenemia, and elevated D-dimer suggest the diagnosis of KMP. (See 'Diagnosis' above.)
●Management of patients without Kasabach-Merritt phenomenon:
•Asymptomatic tumors – For patients without KMP who have small, localized tumors, observation for spontaneous regression may be an option for lesions that are asymptomatic, do not cause functional compromise, and are not disfiguring. Surgical excision, if feasible, is the treatment of choice for patients who desire definitive treatment. (See 'Asymptomatic tumors without Kasabach-Merritt phenomenon' above.)
•Symptomatic tumors – For patients with tumors causing pain or functional impairment, surgical excision, if feasible, is the preferred treatment. However, as complete resection cannot be performed in many cases, medical therapy is needed before attempting surgery:
-For tufted angiomas, we suggest aspirin 5 mg/kg per day (Grade 2C).
-For KHE, we suggest oral prednisone or prednisolone 2 mg/kg per day as first-line therapy (Grade 2C). Aspirin 2 to 5 mg/kg per day and sirolimus can be given as adjunctive therapies. (See 'Patients without Kasabach-Merritt phenomenon' above.)
●Management of patients with Kasabach-Merritt phenomenon – For large, nonresectable tumors with KMP, we recommend initial treatment with sirolimus and systemic corticosteroids (Grade 1C) (see 'Patients with Kasabach-Merritt phenomenon' above):
•Sirolimus is typically given at the dose of 0.8 mg/m2 per dose with close monitoring of blood levels and supportive care. Neonates and infants may need a lower dosing regimen due to physiologic differences in drug metabolism (table 1).
•Oral prednisolone 2 mg/kg/day is given for two weeks and then weaned over a two- to four-week period.
Pneumocystis pneumonia prophylaxis must be given to infants and toddlers. (See "Treatment and prevention of Pneumocystis pneumonia in patients without HIV", section on 'Prophylaxis'.)
●Hemostasis support – The need for hemostasis support, in particular platelet transfusion and fibrinogen replacement, should be based upon careful evaluation of the acuteness of the clinical presentation and the patient's needs (eg, active bleeding, upcoming surgery). (See 'Hemostasis support' above.)
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