Incidence and epidemiology

Infantile hemangiomas (IH) are the most common benign vascular tumor of infancy, occurring in 4% to 5% of infants. They are not usually present at birth and are diagnosed most commonly at age 3 to 6 weeks.[1-3] The lesion proliferates for an average of 5 months, stabilizes, and then involutes over several years.

Infantile hemangiomas are more common in females, non-Hispanic white patients, and premature infants. Multiple hemangiomas are more common in infants who are the product of multiple gestations.[1,4] Infantile hemangiomas are associated with advanced maternal age and placental complications.[1]

Biology

Most infantile hemangiomas occur sporadically. However, they may rarely be caused by an abnormality of chromosome 5 and present in an autosomal dominant pattern.[5] In a study that evaluated inheritance patterns of infantile hemangiomas, 34% of patients had a family history of infantile hemangioma, most commonly in a first-degree relative.[6]

Infantile hemangioma endothelial cells have proven to be clonal in nature.[7,8] Infantile hemangioma proliferation occurs during vasculogenesis (the formation of new blood vessels from angioblasts), as opposed to angiogenesis (the formation of new blood vessels from existing blood vessels). During proliferation, provasculogenic factors are expressed, such as vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), CD34, CD31, CD133, LYVE-1, and insulin-like growth factor (IGF)-2.[9-12] In involution, infantile hemangiomas express increased apoptosis.[12] During this phase, there are also increased mast cells and levels of metalloproteinase, as well as upregulation of interferon and decreased basic FGF (bFGF).[12-14] Throughout their development, endothelial cells in infantile hemangioma express a particular phenotype showing positive staining for glucose transporter (GLUT1). GLUT1 is also expressed on placental endothelial cells but is absent in other vascular tumors such as congenital hemangioma and vascular malformations.[15]

Hypoxia may have a role in the pathogenesis of hemangiomas. As described above, hemangiomas are associated with conditions related to placental hypoxia,[1] and multiple targets of hypoxia [16,17] are demonstrated in proliferating hemangiomas such as VEGF-A, GLUT1, and IGF-2.[9,11,15] The hypotheses suggest that a proliferating hemangioma is an attempt to normalize hypoxic tissue that occurred in utero.

Clinical presentation

Most infantile hemangiomas are not present at birth but precursor lesions such as telangiectasia or faint discoloration of the skin or hypopigmentation can often be seen. The lesion can be mistaken as a bruise from birth trauma or as a capillary malformation (port wine stain) (refer to Figure 1).[18,19]

Figure 1. The photos on the left depict the precursor lesion (faint color with halo). The photos on the right depict the hemangioma after proliferation (slightly raised with a brighter central color). Credit: Israel Fernandez-Pineda, M.D.

Infantile hemangiomas can be superficial in the dermis, deep in the subcutaneous tissue, combined, or in the viscera. Combined lesions are common. They are most common in the head and neck but can be anywhere on the body. They can be localized, segmental, or multiple in nature.

The cutaneous appearance of infantile hemangiomas is usually red to crimson, firm, and warm in the proliferative phase. The lesion then lightens centrally and becomes less warm and softer; it then flattens and loses its color. The process of involution can take several years and once involution has occurred, regrowth is uncommon. In two patients treated with growth hormone, regrowth after involution was noted.[20] On further investigation, growth hormone receptors were found on the infantile hemangioma cells. Although preliminary, this may advance the research into the etiology of hemangioma growth.

Permanent sequelae, such as telangiectasia, anetodermal skin, redundant skin, and a persistent superficial component, can occur after hemangioma involution (refer to Figure 2). In a retrospective cohort study of 184 hemangiomas, the overall incidence of significant sequelae was 54.9%. Sequelae were more common in combined hemangiomas, hemangiomas with a step or abrupt border, and cobblestone surface hemangiomas. Furthermore, this study revealed that the average age to hemangioma involution was 3.5 years.[21]

Figure 2. Examples of different types of sequelae. A, deep hemangioma that regressed without sequelae; B, superficial hemangioma that left only telangiectasia; C, mixed hemangioma that left anetodermic skin; D, mixed hemangioma that left redundant skin; and E, mixed hemangioma that left fibrofatty tissue. Reproduced with permission from JAMA Dermatology. 2016. 152 (11): 1239–1243. Copyright © (2016) American Medical Association. All rights reserved.

Diagnostic and staging evaluation

Infantile hemangiomas are usually diagnosed by the history and clinical appearance. Biopsy is rarely needed and performed only if there is an atypical appearance and/or atypical history and presentation. Imaging is not usually necessary, but if there is a deeper lesion without a cutaneous component, ultrasound imaging is beneficial for diagnosis because it reveals a high flow lesion with a typical Doppler wave characteristic.[22]

Infantile hemangioma with minimal or arrested growth

Infantile hemangioma with minimal or arrested growth (IH-MAG) is a variant of hemangioma that can be confused with capillary malformation or other syndromic hemangioma, such as PHACE syndrome, because of their unusual characteristics. These hemangiomas are mostly fully formed at birth and are characterized by telangiectasia and venules with light and dark areas of skin coloration (refer to Figure 3). They resolve spontaneously and are pathologically GLUT1 positive.[23]

Figure 3. Patient 4 at (A) presentation and (B) resolution. Patient 5 at (C) presentation and (D) resolution. Ma, E. H., Robertson, S. J., Chow, C. W., and Bekhor, P. S. (2017), Infantile Hemangioma with Minimal or Arrested Growth: Further Observations on Clinical and Histopathologic Findings of this Unique but Underrecognized Entity. Pediatr Dermatol, 34: 64–71. doi:10.1111/pde.13022. Used with permission.

Syndromes associated with infantile hemangioma

Syndromes associated with infantile hemangioma include the following:

• PHACE syndrome: PHACE syndrome represents a spectrum of diseases and is defined by the presence of a large segmental infantile hemangioma, usually on the face or head, in association with one or more congenital malformations (refer to Figure 4). PHACE syndrome is more common in girls and in full-term, normal birth weight and singleton infants.[26-31,31] The syndrome is not rare among patients with infantile hemangiomas. A prospective study of 108 infants with large facial hemangiomas observed that 31% of patients had PHACE syndrome.[32]
  

  Figure 4. A large segmental infantile hemangioma (plaque-like) in a bearded distribution. This patient has an increased risk of PHACE syndrome, airway infantile hemangioma, and ulceration. A tracheostomy was placed secondary to a very diffuse airway hemangioma. Credit: Denise Adams, M.D.

  Consensus criteria for definite and possible PHACE syndrome were developed at an expert panel meeting, as follows:[28]

  PHACE

  -

  Posterior fossa abnormalities. Anomalies include posterior fossa malformations, including Dandy-Walker complex, cerebellar hypoplasia, atrophy, and dysgenesis/agenesis of the vermis. Effects of these anomalies include developmental delays and pituitary dysfunction.[33]

  -

  Hemangioma. A large segmental hemangioma over the face, neck, and rarely, the chest and shoulder area.

  -

  Arterial abnormalities. Cerebrovascular anomalies can include carotid artery abnormalities and absence, dilation, or narrowing of cerebral vessels. These anomalies, especially the carotid anomalies, can lead to progressive arterial occlusion and even stroke. Other neurological issues are noted in infancy and childhood.[30,31,34-36]

  -

  Cardiac abnormalities. Cardiac anomalies are most commonly coarctation of the aorta (coarctation is more proximal and affects longer segments), complex aortic arch anomalies, and ventricular and atrial septal defects.

  -

  Eye abnormalities. Ophthalmologic anomalies can include microphthalmos, retinal vascular abnormalities, persistent fetal retinal vessels, exophthalmos, coloboma, and optic nerve atrophy.

  Diagnosis of PHACE requires clinical examination, cardiac evaluation with echocardiogram, ophthalmologic evaluation, and magnetic resonance imaging (MRI)/magnetic resonance angiogram (MRA) of the head, neck, and mediastinum. Patients need to be monitored for short- and long-term effects as noted above. Other issues include speech and language delay, swallowing dysfunction, hearing loss (conductive and sensorineural), and early-onset migraines.[37-39]
  A report of two patients with retro-orbital infantile hemangioma and arteriopathy suggested a possible new presentation of PHACE syndrome.[40] For patients with proptosis, globe deviation, and strabismus, an MRI/MRA is recommended. Further workup for PHACE may be needed on the basis of central nervous system (CNS) findings.
• LUMBAR/PELVIS/SACRAL syndrome: Infantile hemangiomas located over the lumbar or sacral spine may be associated with genitourinary, anorectal anomalies, or neurological issues such as tethered cord.[41-43] The following criteria have been used to describe segmental infantile hemangioma syndrome in the lumbar, pelvic, and sacral areas. This syndrome has been described in the literature using several acronyms.

  LUMBAR

  -

  Lower-body hemangioma and other cutaneous defects.

  -

  Urogenital anomalies or ulceration.

  -

  Myelopathy.

  -

  Bony deformities.

  -

  Anorectal malformations or arterial anomalies.

  -

  Renal anomalies.

  PELVIS

  -

  Perineal hemangioma.

  -

  External genital malformations.

  -

  Lipomyelomeningocele.

  -

  Vesicorenal abnormalities.

  -

  Imperforate anus.

  -

  Skin tag.

  SACRAL

  -

  Spinal dysraphism.

  -

  Anogenital.

  -

  Cutaneous.

  -

  Renal and urologic anomalies Associated with an angioma of Lumbosacral localization.

  Segmental lesions over the gluteal cleft and lumbar spine need to be evaluated with either ultrasound or MRI, depending on the age of the patient.

Infants with more than five infantile hemangiomas need to be evaluated for visceral hemangiomas. The most common site of involvement is the liver, in which multiple or diffuse lesions can be noted.[44,45] Often these lesions are asymptomatic, but in a minority of cases, symptoms such as heart failure secondary to large vessel shunts, compartment syndrome, or profound hypothyroidism can occur due to the expression of iodothyronine deiodinase.[46] Multiple or diffuse liver hemangiomas can occur in the absence of skin lesions. (Refer to the Benign Vascular Tumors of the Liver section of this summary for more information.) Other rare potential complications of visceral hemangiomas, dependent on specific organ involvement, include gastrointestinal hemorrhage, obstructive jaundice, and CNS sequelae, caused by mass effects.

Treatment of infantile hemangioma

Treatment options for infantile hemangioma include the following:

1. Propranolol therapy.
2. Other selective beta-blocker therapy.
3. Corticosteroid therapy.
4. Pulsed dye laser therapy. Usually used for ulcerated infantile hemangiomas and residual lesions, such as telangiectasia after the proliferative period.[47] Pulsed dye laser therapy helps with pain from ulcerative infantile hemangiomas. The use of pulsed dye laser therapy as upfront treatment for infantile hemangiomas is controversial.
5. Excisional surgery. With the advent of new medical treatments, the use of surgery is reserved for ulcerated lesions, residual lesions, large periocular lesions that interfere with vision, and facial lesions with aesthetic impact that do not respond to medical therapy.[48]
6. Topical beta-blocker therapy.
7. Combined therapy for complicated hemangiomas.

Treatment options under clinical evaluation for infantile hemangiomas

Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.

The following are examples of national and/or institutional clinical trials that are currently being conducted:

1. NCT02505971 (Nadolol Versus Propranolol in Children With Infantile Hemangioma): This randomized, controlled, double-blinded study at Toronto Sick Kids is evaluating the efficacy and safety of both groups (nadolol and propranolol). Inclusion is for patients with hemangiomas that require systemic treatment.
2. NCT02913612 (Efficacy, Safety, and Pharmacokinetics of Topical Timolol in Infants With Infantile Hemangioma [TIM01]): This is a multicenter, double-masked, randomized, efficacy, safety, and pharmacokinetic study. Timolol maleate 0.25% is being compared with timolol maleate 0.5%.

Focal vascular lesions (congenital hemangiomas)

Focal lesions of the liver are usually congenital hemangiomas (RICH or NICH) (refer to Figure 6). RICH can present with symptoms of heart failure and mild to moderate coagulopathy.

Treatment options for focal vascular lesions include the following:

1. Supportive management.
2. Embolization for symptomatic shunting. These procedures need to be performed by interventional radiologists with expertise in vascular anomalies.[89]
3. Surgery. Patients with focal symptomatic hepatic congenital hemangioma unresponsive to supportive management or radiological intervention may be surgical candidates for resection. This is a rare circumstance and needs to be evaluated by an interdisciplinary vascular anomaly team.

No medication has proven to be an effective treatment for these lesions, and infants need to be supported during this initial period until involution begins.[45] These lesions may be diagnosed prenatally. In rare situations, maternal treatment with medications such as steroids appeared to be effective but, more likely, natural involution may have been responsible.[90]

Figure 6. Single liver lesion (intrahepatic congenital hemangioma). MRI image of a congenital hemangioma. Note the central enhancement, which is typical for an intrahepatic congenital hemangioma. Credit: Denise Adams, M.D.

Multiple liver lesions (infantile hemangiomas)

Multifocal hepatic lesions are infantile hemangiomas. Multifocal lesions may not need to be treated if the patient is asymptomatic, and they typically follow the same proliferative and involution course as cutaneous hemangiomas.[45] These lesions are monitored closely and if there is growth, propranolol therapy should be considered. If propranolol is needed, doses of up to 2 mg/kg per day are effective.

Diffuse liver lesions (infantile hemangiomas)

Diffuse liver lesions can be very serious (refer to Figure 7). Complications include hypothyroidism caused by the expression of iodothyronine deiodinase, congestive heart failure, and compartment syndrome.[44,45,91,92]

Figure 7. Diffuse liver lesions with classical imaging on CT. Note the peripheral enhancement in early contrast phase. Credit: Denise Adams, M.D.

Treatment options for diffuse liver lesions may include the following:

1. Propranolol: Beta-blockers are the most common treatment for diffuse and some multifocal infantile hemangiomas of the liver. Treatment doses of 2 to 3 mg/kg per day are indicated.[51]
2. Chemotherapy: Steroids, cyclophosphamide, and vincristine have been used to treat diffuse liver infantile hemangioma.[45,93,94]
3. Transplant: If a patient does not respond to medical management, a transplant may be indicated.[95] Transplantation is considered only for patients with severe diffuse lesions who have multisystem organ failure and there is insufficient time for effective pharmacologic therapy.

There have been isolated reports of malignancy in patients with diffuse hepatic infantile hemangiomas.[96] It is not clear if all cases were transformation of a benign lesion to a malignant phenotype; however, if the lesion does not respond to standard therapy, biopsy should be considered. Further evaluation and consensus is needed to assess whether these patients need to be monitored over a longer period of time with liver ultrasound. (Refer to the Angiosarcoma of the Soft Tissue section of this summary for more information.)

The differential diagnosis of vascular liver lesions always includes malignant liver tumors; thus, alpha-fetoprotein (AFP) should be included in the initial lab work. AFP can be elevated above baseline in congenital and infantile hemangiomas of the liver, but will rapidly fall to normal levels in 1 to 2 months, although there are no prospective studies investigating AFP elevation.[97,98] Some hypervascular hepatoblastomas in neonates with congestive heart failure have been mistaken for infantile hemangiomas. Other tumors in the differential diagnosis include angiosarcoma, metastatic neuroblastoma, and mesenchymal hamartomas. If there is any question about the diagnosis, a biopsy is recommended, although bleeding is a risk of the procedure.[99]

Clinical presentation

Spindle cell hemangiomas, initially called spindle cell hemangioendotheliomas, often occur as superficial (skin and subcutis), painful lesions involving distal extremities in children and adults.[100,101] The tumors appear as red-brown or bluish lesions that can begin as a single nodule and develop into multifocal painful lesions over years. The lesions can be seen in Maffucci syndrome (cutaneous spindle cell hemangiomas occurring with cartilaginous tumors, enchondromas) and Klippel-Trenaunay syndrome (capillary/lymphatic/venous malformations), generalized lymphatic anomalies, lymphedema, and organized thrombus.[102,103]

These tumors are well circumscribed, occasionally contain phleboliths, and consist of cavernous blood spaces alternating with areas of nodular spindle cell proliferation. A significant percentage of spindle cell hemangiomas are completely intravascular. The vein containing the tumor is abnormal, as are blood vessels apart from the tumor mass.[102,103]

Treatment of spindle cell hemangioma

There is no standard treatment for spindle cell hemangioma because it has not been studied in clinical trials. Surgical removal is usually curative, although there is a risk of recurrence.[102,103]

Clinical presentation

Epithelioid hemangiomas are benign lesions that usually occur in the skin and subcutis but can occur in other areas such as the bone, with focal and multifocal lesions.[102,104] Epithelioid hemangiomas may be a reactive process, as they can be associated with local trauma and can develop in pregnancy. Patients usually present with local swelling and pain at the involved site. In the bone, they present as well-defined lytic lesions that involve the metaphysis and diaphysis of long bones.[102,105] They can have a mixed lytic and sclerotic pattern of bone destruction.

On pathologic evaluation, they have small caliber capillaries with eosinophilic, vacuolated cytoplasm and large oval, grooved, and lobulated nuclei. The endothelial cells are plump and are mature, well-formed vessels surrounded by multiple epithelioid endothelial cells within abundant cytoplasm. They lack cellular atypia and mitotic activity.[102,104,105]

Treatment of epithelioid hemangioma

There is no standard treatment for epithelioid hemangioma because it has not been studied in clinical trials. Treatment consists of curettage, sclerotherapy, and resection, or rarely, radiation therapy.[102,105]

Clinical presentation

Pyogenic granuloma, known as lobular capillary hemangioma, is a benign reactive lesion that can present at any age, including infancy, although it is most common in older children and young adults. They can present as single or multiple lesions.[106-109] These lesions can arise spontaneously, in sites of trauma, or within capillary and arteriovenous malformations. Pyogenic granulomas have also been associated with medications including oral contraceptives and retinoids. Most occur as solitary growths, but multiple (grouped) or rarely disseminated lesions have been described. These lesions appear as small or large, smooth or lobulated vascular nodules that can grow rapidly, sometimes over weeks to months and have a tendency to bleed profusely.

Histologically, these lesions are composed of capillaries and venules with plump endothelial cells separated into lobules by fibromyxoid stroma. Some untreated lesions eventually atrophy, become fibromatous, and slowly regress.

Treatment of pyogenic granuloma

Treatment often consists of full-thickness excision, curettage, or laser photocoagulation, but recurrence is common.[110] A small case series of four patients with acquired ocular surface pyogenic granulomas were treated with topical timolol 0.5% twice daily for 21 days. In all cases, complete resolution with no recurrence occurred for at least 3 months. More studies are needed to validate these findings.[111]

Clinical presentation

Angiofibromas are rare, benign neoplasms in the pediatric population. Typically, they are cutaneous lesions associated with tuberous sclerosis, appearing as red papules on the face.

Treatment of angiofibroma

Excision of the tumor, laser treatments, and topical treatments, such as sirolimus, have been used.[112,113]

Clinical presentation

Juvenile nasopharyngeal angiofibromas (JNA) account for 0.5% of all head and neck tumors.[114] Histologically, juvenile nasopharyngeal angiofibromas are benign vascular tumors but they can be locally destructive, spreading from the nasal cavity to the nasopharynx, paranasal sinuses, and orbit skull base, with intracranial extension. Some publications have suggested a hormonal influence on juvenile nasopharyngeal angiofibroma, with emphasis on the molecular mechanisms involved.[115,116]

Treatment of juvenile nasopharyngeal angiofibroma

Surgical excision is the treatment of choice but this can be challenging because of the extent of the lesion. A single-institution retrospective review of juvenile nasopharyngeal angiofibromas identified 37 patients with lateral extension.[117] Anterior lateral extension to the pterygopalatine fossa occurred in 36 patients (97%) and further to the infratemporal fossa in 20 patients (54%). In 16 patients (43%), posterior lateral spread was observed (posterior to the pterygoid process and/or between its plates). The recurrence rate was 29.7% (11 of 37 patients). The recurrence rate in patients with anterior and/or posterior lateral extension was significantly higher than in patients with anterior lateral extension only.

Juvenile nasopharyngeal angiofibromas have also been treated with radiation therapy, chemotherapy, alpha-interferon therapy, and sirolimus.[118-121]

Incidence

The exact incidence of kaposiform hemangioendothelioma is unknown but is estimated to be 0.07 cases per 100,000 children per year.[1-3] The lesions affect both sexes equally, with most developing in the neonatal period, one-half presenting at birth, and others presenting during childhood or adulthood.[4]

Pathology

Kaposiform hemangioendothelioma is characterized by sheets of spindle cells with an infiltrative pattern in the dermis, subcutaneous fat, and muscle. There are often areas of fibrosis, with dilated thin-walled vessels infiltrated around the areas of spindle cells. 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. Tufted angioma is characterized by multiple, discrete lobules of tightly packed capillaries (tufts) scattered in the dermis and sometimes in the subcutis, so called cannonball pattern.[5] Mitoses are rare.

The pathogenesis is poorly understood. There is some evidence that kaposiform hemangioendothelioma may be derived from lymphatic endothelium, as the spindle cell expresses the vascular markers CD31 and CD34, the vascular endothelial growth factor receptor-3, a receptor required for lymphangiogenesis, and the lymphatic markers D2-40 and PROX1.[5-7] There is no evidence of association with human herpesvirus 8 infection as is present in Kaposi sarcoma.[7]

Clinical presentation

Kaposiform hemangioendothelioma most frequently involves the extremities and less frequently involves the trunk and head and neck area.[3] Most lesions involve the skin (refer to Figure 8). Deeper lesions (retroperitoneum, thoracic cavity, and muscle) can appear as a bluish-purpuric hue on the skin, whereas superficial lesions can be firm, purpuric or ecchymotic, and painful. Lesions are usually unifocal and growth is contiguous. Local lymph nodes may be involved, but they never metastasize. Rare multifocal presentations have been reported mostly in the bone.[1-3]

Figure 8. Kaposiform hemangioendothelioma with Kasabach-Merritt phenomenon. The lesion is indurated, firm, and warm with petechiae and purpura. Credit: Denise Adams, M.D.

Seventy percent of patients with kaposiform hemangioendothelioma develop Kasabach-Merritt phenomenon, which is a life-threatening complication characterized by profound thrombocytopenia (range, 3,000/µL–60,000/µL) and profound hypofibrinogenemia (<1 g/L). D-dimer and fibrin degradation products are elevated. Severe anemia can occur secondary to tumor sequestration. Severe hemorrhage is rare; however, trauma (biopsy, surgical procedure), ulceration, infection, or delay in initiating treatment may induce progression to disseminated intravascular coagulation and serious bleeding and death can occur. Aggressive replacement of blood products, especially platelets, can increase the size of the lesion, causing significant pain and should only be considered with active bleeding and under the direction of a vascular anomaly specialist.[3]

Diagnostic evaluation

The diagnosis is based on the combination of clinical, histologic, and imaging features. Laboratory evaluation is essential for the diagnosis of Kasabach-Merritt phenomenon. Whenever possible, histologic confirmation should be obtained, because prolonged therapy is often needed. However, if clinical and imaging findings are highly suggestive of the diagnosis, deferring biopsy is an option but needs to be planned with an interdisciplinary approach.

Magnetic resonance imaging is the imaging preference. T1-weighted sequences typically show a poorly circumscribed soft tissue mass with soft tissue and dermal thickening 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.[3]

Treatment of kaposiform hemangioendothelioma and tufted angioma

Treatment varies according to severity; there is no evidence-based standard of care. An American and Canadian multidisciplinary expert panel published guidelines for the management of complicated kaposiform hemangioendothelioma.[8] A number of treatment therapies have been reported but none have been uniformly effective.[9,10]

Treatment options for kaposiform hemangioendothelioma include the following:[8-17]

1. Steroid therapy.
2. Antiplatelet agent (aspirin) therapy.
3. Alpha-interferon.
4. Antifibrinolytic agent therapy.
5. Chemotherapy, including vincristine, cyclophosphamide, actinomycin, and methotrexate used alone or in combination.
6. Propranolol therapy.
7. Surgical excision with or without embolization.
8. Sirolimus as a single agent or in combination with steroids.

Initial treatment is most commonly steroids followed by vincristine. A retrospective review identified 37 children with kaposiform hemangioendothelioma whose lesions did not respond to steroids.[11][Level of evidence: 3iiiDiv] Twenty-six kaposiform hemangioendothelioma lesions achieved complete remission, with platelet counts reaching normal levels within 7.6 ± 5.2 weeks after vincristine treatment.

Propranolol therapy has been reported as a treatment option for kaposiform hemangioendothelioma. Its use is based on the positive results of propranolol for other more benign vascular tumors. Results have been mixed, with a report of improved effectiveness using higher doses of propranolol.[18,19] Preliminary results indicate that propranolol should be reserved for patients with kaposiform hemangioendothelioma without Kasabach-Merritt phenomenon and with smaller, less complicated lesions.

Secondary to promising case reports, case series and a prospective clinical trial, sirolimus may be considered an alternative first-line therapy for kaposiform hemangioendothelioma.[14,15,20] There are limited studies investigating its effect on kaposiform hemangioendothelioma/tufted angioma without Kasabach-Merritt phenomenon.

Reports that support the use of sirolimus include the following:

1. In a prospective study that assessed the efficacy and safety of sirolimus for the treatment of complicated vascular anomalies, 13 patients with kaposiform hemangioendothelioma were treated.[21]

   • In patients with kaposiform hemangioendothelioma and Kasabach-Merritt phenomenon, ten of ten patients had a partial response, with normalization of their platelet count and fibrinogen at the end of six and 12 courses.
   • In three of three patients with kaposiform hemangioendothelioma without Kasabach-Merritt phenomenon, one patient with multifocal bony disease had disease progression while the other two patients revealed a partial response at the end of course 12. Side effects were minimal in this group of young patients and no patient with kaposiform hemangioendothelioma required a dose adjustment or was removed from study secondary to toxicity.
2. A single case report of a child with kaposiform hemangioendothelioma who developed recurrence of pain and fibrosis years after initial therapy and was treated with sirolimus for 26 months observed the following:[20]

   • The patient's contracture and range of motion improved, the lesion shrank, and the child was well 2 years later.
3. In a multicenter, retrospective cohort study, 52 Chinese patients with progressive kaposiform hemangioendothelioma were analyzed. Thirty-seven patients (71%) had Kasabach-Merritt phenomenon. Those without Kasabach-Merritt phenomenon received sirolimus alone, and 21 of the patients with Kasabach-Merritt phenomenon received a combination of sirolimus and prednisone.[22]

   • Overall, 96% and 98% of patients demonstrated improvement in notable symptoms and/or had improved complications at 6 and 12 months, respectively.

Additional studies are needed to determine the long-term efficacy and safety of sirolimus for the treatment of vascular tumors associated with Kasabach-Merritt phenomenon.

Surgical excision may be possible for lesions that are smaller, have failed medical management, or are life threatening. Embolization may be performed in conjunction with surgery or medical therapy; usually it is a temporizing measure.

The mortality associated with this tumor is primarily from the extensive coagulopathy associated with Kasabach-Merritt phenomenon.

Even with therapy, these lesions do not fully regress and can recur; worsened symptomatology (pain, inflammation) can occur with age, especially around the time of puberty.[23]

Long-term effects include chronic pain, lymphedema, heart failure, and orthopedic issues.[23] These lesions prove to be a difficult dilemma for the practitioner because they have a varied clinical spectrum and response to therapy.

Treatment options under clinical evaluation for kaposiform hemangioendothelioma

Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.

The following is an example of national and/or institutional clinical trial that is currently being conducted:

1. NCT02110069 (A Study to Compare Vincristine to Sirolimus for Treatment of High-Risk Vascular Tumors): This is a study comparing vincristine with sirolimus for the treatment of high-risk kaposiform hemangioendothelioma. A multicenter adaptive study design determining efficacy (initially defined as the time to hematologic response) by comparing vincristine with sirolimus therapy while patients are on a steroid wean.

Incidence and outcome

Pseudomyogenic hemangioendothelioma is a rare, newly designated, distinct vascular tumor. It is characterized as an intermediate-grade tumor with moderately aggressive local spread and rare distant metastatic disease.

Pathology and biology

Pseudomyogenic hemangioendothelioma is characterized by loose fascicles of plump spindle and epithelioid cells with abundant eosinophils, cytoplasm, and coexpression of keratins and endothelial markers.[1-3] The etiology for this tumor is unclear, although a balanced translocation t(7;19) resulting in the SERPINE1-FOSB fusion gene was reported.[4]

Clinical presentation and diagnostic evaluation

The tumor usually presents in young men aged 20 to 50 years.[1,2] Multifocal disease occurs in 70% of patients. Sites of involvement include the dermis, subcutis, and bones. Patients usually present with pain or a soft tissue mass.[1,5]

Treatment of pseudomyogenic hemangioendothelioma

Most patients are treated with surgery, including amputation with multifocal bony disease.[1] In reported cases, chemotherapy has had limited response. Recently, the mammalian target of rapamycin (mTOR) inhibitors have been considered as treatment options.[6,7]

Pathology and clinical presentation

Retiform hemangioendotheliomas are slow growing, exophytic, flat tumors found in young adults and occasionally children.[8] They are usually located in the limbs and trunk. Histologically, they are located in the dermis and subcutaneous tissue. Vessels exhibit a pattern resembling the rete testis and are lined by protruding endothelial cells. They do not express lymphatic markers but stain positive for endothelial markers.[9]

Prognostic factors

Local recurrences are common, but distinct metastases are extremely rare.[9]

Treatment of retiform hemangioendothelioma

Surgical excision with adequate surgical tumor margins and monitoring for local recurrence is the treatment for this tumor. There are case reports of the use of radiation therapy and chemotherapy for inoperable and recurrent tumors.[10-13]

Pathology and clinical presentation

Papillary intralymphatic angioendothelioma, also known as Dabska tumor, can occur in the adult and pediatric population.[14] The lesions occur in the dermis and subcutis on all body parts and there have been some reports of lymph node involvement. They can be large or small raised purplish firm nodules.

Pathologically, they reveal intravascular growth of well-differentiated endothelial cells in a columnar configuration. They have thickened hyaline walls with hobnailed endothelium. Vascular endothelial growth factor receptor type 3, a marker for lymphatic endothelium, is positive in most cases. There is minimal cytologic atypia.[15] Some are associated with vascular malformations.

Treatment of papillary intralymphatic angioendothelioma

Surgical excision is the treatment of choice.[16]

Pathology and clinical presentation

Composite hemangioendothelioma is a very rare vascular tumor classified because of the combined benign and malignant vascular components. Usually, combined epithelioid and retiform variants are noted but some tumors have three components (epithelioid, retiform, and spindle cell).[17] Angiosarcoma foci have been noted. Pathology reveals positivity for CD31, factor VIII, and vimentin.[17,18] Rarely, D-240 is positive with a Ki-67 index of approximately 20%.[17]

This tumor usually occurs in the dermis and subcutis of the distal extremities but has been found in other areas such as the head, neck, and mediastinum.[17] They have been reported in all age groups.[17]

Prognostic factors

Composite hemangioendotheliomas recur locally and rarely metastasize.[17,18] Regional lymph nodes are the most likely site of metastasis and need imaging evaluation.[17]

Treatment of composite hemangioendothelioma

Surgical removal is the treatment of choice, although radiation therapy and chemotherapy have been used for metastatic disease.[19,20]

Pathology and clinical presentation

Kaposi sarcoma (KS) is a rare malignant vascular tumor associated with a viral etiology (human herpesvirus 8).[21] The skin lesions were first described in 1872 by Moritz Kaposi. The incidence has increased worldwide secondary to the HIV-AIDS epidemic. It is an extremely rare diagnosis in children. Epidemic and iatrogenic forms of Kaposi sarcoma in children result from profound acquired T-cell deficiency that results from HIV infection and rare immune disorders.

A retrospective study has investigated the presentation of Kaposi sarcoma in children in endemic areas of Africa. Children usually present with cutaneous lesions, lymphadenopathy, and intrathoracic and oral lesions. Cutaneous lesions initially appear as red, purple, or brown macules, later developing into plaques and then nodules.[22-24]

Kaposi sarcoma is exceedingly rare in the pediatric population and is usually associated with immunocompromised states such as HIV infection or solid organ transplant.

Treatment of Kaposi sarcoma

Children with Kaposi sarcoma have responded to treatment with chemotherapy regimens, including bleomycin, vincristine, and taxanes, although there are no prospective clinical trials. Other treatment options have been based on adult studies (see below).

Because Kaposi sarcoma is rare in the pediatric population, there are no evidence-based studies. Even in adults, the evidence and quality of studies is inferior and it is difficult to recommend particular treatment regimens. Fifty-six Malawian children aged 3 to 12 years with Kaposi sarcoma were treated with six courses of vincristine, bleomycin, and oral etoposide. This was a high-risk population because 48 of the patients (86%) were HIV positive, of whom 36 (77%) were on antiretroviral therapy. Quality of life improved in 45 patients (80%). Eighteen patients (32%) had a complete remission. At 12 months, the overall survival rate was 71%, and the event-free survival rate was 50%.[25][Level of evidence: 3iiA]

In a systematic review of treatment for classic Kaposi sarcoma, 26 articles published from 1980 to 2010 were reviewed; articles describing populations at high risk secondary to previous transplantation and endemic and epidemic Kaposi sarcoma were excluded.[26] All articles had a minimum of five patients per intervention. A greater than 50% decrease in the size of the lesions or lymphedema was considered a response. The quality of the articles was considered poor, primarily because of lack of uniform staging criteria and variable means of assessing response. The following response rates for systemic treatments were noted:

• Pegylated doxorubicin—71% to 100%.
• Vinca alkaloids—58% to 90%.
• Etoposide—74% to 76%.
• Taxanes—93% to 100%.
• Gemcitabine—100%.
• Vinblastine and bleomycin—97%.
• Interferon alfa-2—71% to 100%.

For local therapies, the following response rates were reported:

• Intralesional vincristine—62%.
• Intralesional interferon alfa-2—50% to 90%.
• Imiquimod—56%.
• Radiation therapy—63% to 93%.

(Refer to the PDQ summary on Kaposi Sarcoma Treatment for information about the treatment of Kaposi sarcoma in adults.)

Incidence and outcome

This tumor was first described in soft tissue by Weiss and Enzinger in 1982. Epithelioid hemangioendotheliomas can occur at younger ages, but the peak incidence is in the fourth and fifth decades of life. The tumors can have an indolent or very aggressive course, with overall survival of 73% at 5 years. There are case reports of patients with untreated multiple lesions who have a very benign course compared with other patients who have a very aggressive course. Some pathologists have tried to stratify patients to evaluate risks and adjust treatment, but more research is needed.[1-7]

The presence of effusions, tumor size larger than 3 cm, and a high mitotic index (>3 mitoses/50 high-power fields) have been associated with unfavorable outcomes.[3]

Pathology and biology

A WWTR1-CAMTA1 gene fusion has been found in a large percentage of patients; less commonly, a YAP1-TFE3 gene fusion has been reported.[1] These fusions are not directly targetable with current medicines. Monoclonality has been described in multiple liver lesions, suggesting a metastatic process.

Histologically, these lesions are characterized as epithelioid lesions arranged in nests, strands, and trabecular patterns, with infrequent vascular spaces. Features that may be associated with aggressive clinical behavior include cellular atypia, one or more mitoses per 10 high-power fields, an increased proportion of spindled cells, focal necrosis, and metaplastic bone formation.[3]

The number of pediatric patients reported in the literature is limited.

Clinical presentation and diagnostic evaluation

Common sites of involvement are liver alone (21%), liver plus lung (18%), lung alone (12%), and bone alone (14%).[3,8,9] Clinical presentation depends on site of involvement, as follows:

• Liver: Hepatic nodules have central vascularity on ultrasound, contrast-enhancing lesions by computed tomography, and low T1 signal and moderate T2 signal on magnetic resonance imaging.
• Lung: Pulmonary epithelioid hemangioendothelioma may be an asymptomatic finding on chest x-ray or be associated with pleuritic pain, hemoptysis, anemia, and fibrosis.
• Bone: Bone metastasis may be associated with pathologic fracture. On x-rays, they are well-defined osteolytic lesions and can be multiple or solitary.
• Soft tissue: Thirty percent of soft tissue cases are associated with metastases, and when present, can have a very aggressive course, with limited response to chemotherapy.
• Skin: Cutaneous lesions can be raised and nodular or can be warm red-brown plaques.

Treatment of epithelioid hemangioendothelioma

Treatment options for epithelioid hemangioendothelioma include the following:

1. Observation.
2. Surgery.
3. Immunotherapy.
4. Targeted therapy.
5. Chemotherapy.

For indolent cases, observation is warranted. For more aggressive cases, multiple medications have been used, including interferon, thalidomide, sorafenib, pazopanib, and sirolimus.[10] The most aggressive cases are treated with angiosarcoma-type chemotherapy. Surgery is used when possible. Liver transplantation has been used with aggressive liver lesions, both with and without metastases.[3,11-14]

Treatment options under clinical evaluation for epithelioid hemangioendothelioma

Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.

The following are examples of national and/or institutional clinical trials that are currently being conducted:

1. NCT03148275 (Trametinib in Treating Patients with Epithelioid Hemangioendothelioma That Is Metastatic, Locally Advanced, or Cannot Be Removed by Surgery): This is a phase II trial assessing the efficacy of trametinib, with patient-reported outcomes as secondary aims.
2. NCT01532687 (Gemcitabine Hydrochloride With or Without Pazopanib Hydrochloride in Treating Patients With Refractory Soft Tissue Sarcoma): This randomized phase II trial studies how well gemcitabine hydrochloride works with or without pazopanib hydrochloride in treating patients with refractory soft tissue sarcoma.

Incidence

Angiosarcoma is a rare (accounting for 2% of sarcomas), aggressive, vascular tumor that can arise in any part of the body, but is more common in the soft tissue. Angiosarcoma has an estimated incidence of 2 cases per 1 million; in the United States, it annually affects approximately 600 people who are typically aged 60 to 70 years.[15]

Angiosarcomas are extremely rare in children and it is unclear if the pathophysiology of this tumor is different in the pediatric population. Cases have been reported in neonates and toddlers, with presentation of multiple cutaneous lesions and liver lesions, some of which are GLUT1 positive.[16-19] Most angiosarcomas involve the skin and superficial soft tissue, although the liver, spleen, and lung can be affected; bone is rarely affected.

Risk factors

Established risk factors include vinyl chloride exposure, radiation exposure, and chronic lymphedema from any cause, including Stewart-Treves syndrome.[20]

Pathology and biology

Angiosarcomas are largely aneuploid tumors. The rare cases of angiosarcoma that arise from benign lesions such as hemangiomas have a distinct pathway that needs to be investigated. MYC amplification is seen in radiation-induced angiosarcoma. KDR-VEGFR2 mutations and FLT4-VEGFR3 amplifications have been seen with a frequency of less than 50%.[20]

Histopathologic diagnosis can be very difficult because there can be areas of varied atypia. The common feature is an irregular network of channels in a dissective pattern along dermal collagen bundles. There is varied cellular shape, size, mitosis, endothelial multilayering, and papillary formation. Epithelioid cells can also be present. Necrosis and hemorrhage are common. Tumors stain for factor VIII, CD31, and CD34. Some liver lesions can mimic infantile hemangiomas and have focal GLUT1 positivity. Nomenclature of these liver lesions has been difficult and confusing with use of terminology from 1971 (e.g., type I hemangioendothelioma: infantile hemangioma; type II hemangioendothelioma: low-grade angiosarcoma; type III hemangioendothelioma: high-grade angiosarcoma).[17]

Treatment of angiosarcoma of the soft tissue

Treatment options for angiosarcoma of the soft tissue include the following:

1. Surgery (localized disease).
2. Radiation therapy (localized cutaneous disease in adults).
3. Surgery, chemotherapy, and radiation therapy (metastatic disease).

Localized disease is cured by aggressive surgery. Complete surgical excision appears to be crucial for angiosarcomas and lymphangiosarcomas despite evidence of tumor shrinkage in some patients who were treated with local or systemic therapy.[18,21-23] A review of 222 patients (median age, 62 years; range, age 15–90 years) showed an overall disease-specific survival (DSS) rate of 38% at 5 years. Five-year DSS was 44% in 138 patients with localized, resected tumors but only 16% in 43 patients with metastases at diagnosis.[23] Data on liver transplantation for localized angiosarcoma are limited.[24][Level of evidence: 3iiA]

Localized disease, especially cutaneous angiosarcoma, can be treated with radiation therapy. Most of these reported cases are in adults.[25]

Multimodal treatment with surgery, systemic chemotherapy, and radiation therapy is used for metastatic disease, although it is rarely curative.[26] Disease control is the objective in metastatic angiosarcoma, with published progression-free survival rates between 3 months and 7 months [27] and a median overall survival (OS) rate of 14 months to 18 months.[28] In both adults and children, 5-year OS rates between 20% and 35% are reported.[18,19,29]

In a child diagnosed with angiosarcoma secondary to malignant transformation from infantile hemangioma, response to treatment with bevacizumab, a monoclonal antibody against vascular endothelial growth factor, combined with systemic chemotherapy, has been reported.[16,26] A report of eight cases of liver angiosarcoma in children highlighted the misuse of the term hemangioendothelioma and the importance of early diagnosis and treatment of these tumors.[30]

Biologic agents that inhibit angiogenesis have shown activity in adults with angiosarcoma.[17,29]

Treatment options under clinical evaluation for angiosarcoma of the soft tissue

Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.

The following are examples of national and/or institutional clinical trials that are currently being conducted:

1. ARST1321 (NCT02180867) (Radiation Therapy With or Without Combination Chemotherapy or Pazopanib Hydrochloride Before Surgery in Treating Patients With Newly Diagnosed Nonrhabdomyosarcoma Soft Tissue Sarcomas That Can be Removed by Surgery [PAZNTIS]): This study will first determine the feasibility of adding a tyrosine kinase inhibitor in combination with radiation therapy or chemotherapy (ifosfamide/etoposide) and radiation therapy in pediatric and adult patients newly diagnosed with unresected intermediate-risk and high-risk nonrhabdomyosarcomatous soft tissue sarcoma. Subsequently, this trial will compare the rates of near-complete pathologic response (>90% necrosis) of: 1) preoperative pazopanib plus chemoradiation therapy versus preoperative chemoradiation therapy alone for potentially resectable (>5 cm), grade 3 intermediate-risk to high-risk chemotherapy-sensitive adult and pediatric nonrhabdomyosarcomatous soft tissue sarcoma; and 2) pazopanib plus preoperative radiation therapy versus preoperative radiation therapy alone for potentially resectable intermediate-risk to high-risk adult and pediatric nonrhabdomyosarcomatous soft tissue sarcoma. Patients with angiosarcoma of the soft tissue are eligible for this trial.
2. NCT01532687 (Gemcitabine Hydrochloride With or Without Pazopanib Hydrochloride in Treating Patients With Refractory Soft Tissue Sarcoma): This randomized phase II trial studies how well gemcitabine hydrochloride works with or without pazopanib hydrochloride in treating patients with refractory soft tissue sarcoma.