References

1. Mulliken JB, Glowacki J: Hemangiomas and vascular malformations in infants and children: a classification based on endothelial characteristics. Plast Reconstr Surg 69 (3): 412-22, 1982. [PubMed: 7063565]
2. Lokmic Z, Mitchell GM, Koh Wee Chong N, et al.: Isolation of human lymphatic malformation endothelial cells, their in vitro characterization and in vivo survival in a mouse xenograft model. Angiogenesis 17 (1): 1-15, 2014. [PubMed: 23884796]
3. Wassef M, Blei F, Adams D, et al.: Vascular Anomalies Classification: Recommendations From the International Society for the Study of Vascular Anomalies. Pediatrics 136 (1): e203-14, 2015. [PubMed: 26055853]
4. van der Vleuten CJ, Kater A, Wijnen MH, et al.: Effectiveness of sclerotherapy, surgery, and laser therapy in patients with venous malformations: a systematic review. Cardiovasc Intervent Radiol 37 (4): 977-89, 2014. [PubMed: 24196269]
5. Soblet J, Limaye N, Uebelhoer M, et al.: Variable Somatic TIE2 Mutations in Half of Sporadic Venous Malformations. Mol Syndromol 4 (4): 179-83, 2013. [PMC free article: PMC3666452] [PubMed: 23801934]
6. Luks VL, Kamitaki N, Vivero MP, et al.: Lymphatic and other vascular malformative/overgrowth disorders are caused by somatic mutations in PIK3CA. J Pediatr 166 (4): 1048-54.e1-5, 2015. [PMC free article: PMC4498659] [PubMed: 25681199]
7. Keppler-Noreuil KM, Rios JJ, Parker VE, et al.: PIK3CA-related overgrowth spectrum (PROS): diagnostic and testing eligibility criteria, differential diagnosis, and evaluation. Am J Med Genet A 167A (2): 287-95, 2015. [PMC free article: PMC4480633] [PubMed: 25557259]
8. Adams DM, Trenor CC, Hammill AM, et al.: Efficacy and Safety of Sirolimus in the Treatment of Complicated Vascular Anomalies. Pediatrics 137 (2): e20153257, 2016. [PMC free article: PMC4732362] [PubMed: 26783326]
9. Hammer J, Seront E, Duez S, et al.: Sirolimus is efficacious in treatment for extensive and/or complex slow-flow vascular malformations: a monocentric prospective phase II study. Orphanet J Rare Dis 13 (1): 191, 2018. [PMC free article: PMC6206885] [PubMed: 30373605]
10. Venot Q, Blanc T, Rabia SH, et al.: Targeted therapy in patients with PIK3CA-related overgrowth syndrome. Nature 558 (7711): 540-546, 2018. [PMC free article: PMC7610773] [PubMed: 29899452]
11. Couto JA, Huang AY, Konczyk DJ, et al.: Somatic MAP2K1 Mutations Are Associated with Extracranial Arteriovenous Malformation. Am J Hum Genet 100 (3): 546-554, 2017. [PMC free article: PMC5339083] [PubMed: 28190454]

References

1. International Society for the Study of Vascular Anomalies: ISSVA Classification of Vascular Anomalies. Milwaukee, Wi: International Society for the Study of Vascular Anomalies, 2018. Available online. Last accessed June 17, 2020.
2. Wassef M, Blei F, Adams D, et al.: Vascular Anomalies Classification: Recommendations From the International Society for the Study of Vascular Anomalies. Pediatrics 136 (1): e203-14, 2015. [PubMed: 26055853]
3. Léauté-Labrèze C, Hoeger P, Mazereeuw-Hautier J, et al.: A randomized, controlled trial of oral propranolol in infantile hemangioma. N Engl J Med 372 (8): 735-46, 2015. [PubMed: 25693013]
4. Adams DM, Trenor CC, Hammill AM, et al.: Efficacy and Safety of Sirolimus in the Treatment of Complicated Vascular Anomalies. Pediatrics 137 (2): e20153257, 2016. [PMC free article: PMC4732362] [PubMed: 26783326]
5. Fletcher CDM, Bridge JA, Hogendoorn P, et al., eds.: WHO Classification of Tumours of Soft Tissue and Bone. 4th ed. IARC Press, 2013.

Infantile Hemangioma

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).[23,24]

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.

Infantile hemangioma can be characterized as follows:

• Local: Most lesions are localized and noted to be in a well-defined area without evidence of a geometric pattern.
• Segmental: Most segmental hemangiomas occur in the head and neck region but can be seen in the genitourinary area, arm, chest, or legs. Diffuse hemangiomas of the face demonstrate defined cutaneous patterns. Several studies have evaluated the distributions of these hemangiomas and found the following four distinct patterns or segments:

  • Segment 1 involves the lateral forehead, anterior temporal scalp, and the lateral frontal scalp.
  • Segments 2 and 3 are located over the maxillary and mandibular area.
  • Segment 4 covers the medial frontal scalp, nose, and philtrum.
  Two papers have noted this observation and suggest the involvement of neural crest derivatives in facial hemangioma development.[25,26] Segmental hemangiomas commonly occur in females and are more likely associated with complications and other syndromes.[27,28] (Refer to the Syndromes associated with infantile hemangioma section of this summary for information about PHACE syndrome.)
• Multiple: More than one lesion, but noted in the past as greater than five lesions, because of the increased risk of visceral involvement (mostly the liver). Usually characterized by solitary localized lesions.

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.[29] 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.[30]

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, ultrasonography is beneficial for diagnosis because it reveals a well-circumscribed, hypoechoic, high flow lesion with a typical Doppler wave characteristic.[31] Additionally, infants with five or more cutaneous hemangiomas should undergo ultrasonography of the liver to scan for hepatic hemangioma.[32]

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 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.[33] They are mainly located on the lower body but can be present in the head and neck area; if they are segmental, they can be associated with PHACE syndrome.[34] Associated soft tissue hypertrophy may persist through childhood.[35]

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.

Airway infantile hemangioma

Airway infantile hemangiomas are usually associated with segmental hemangiomas in a bearded distribution, which may include all or some of the following—the preauricular skin, mandible, lower lip, chin, or anterior neck. It is important for an otolaryngologist to proactively assess lesions in this distribution before signs of stridor occur. The incidence of an airway infantile hemangioma increases with increased area of bearded involvement.[36] Airway infantile hemangioma can occur without skin lesions. A retrospective study of the Vascular Anomaly Database at the Children's Hospital of Pittsburgh analyzed 761 cases of infantile hemangioma. Thirteen patients (1.7%) had subglottic hemangiomas; of those 13 patients, 4 patients (30%) had bearded distributions, 2 patients (15%) had cutaneous hemangiomas, and 7 patients (55%) had no cutaneous lesions.[37] (Refer to the Propranolol therapy section of this summary for information about the treatment of airway infantile hemangiomas.)

Ophthalmologic involvement of hemangiomas

Periorbital hemangiomas can cause visual compromise.[38] This usually occurs with hemangiomas of the upper medial eyelid but any hemangioma around the eye that is large enough can distort the cornea or obstruct the visual axis. The clinician should be aware of subcutaneous periocular hemangiomas, as these lesions can extend into the orbit, causing exophthalmos or globe displacement with only limited cutaneous manifestations. Issues with these lesions include astigmatism from direct pressure of the growing hemangioma, ptosis, proptosis, and strabismus. One of the leading causes of preventable blindness in children is stimulus-deprivation amblyopia caused by hemangioma obstruction. All periorbital hemangiomas or those with any possibility of potential visual impairment should have an ophthalmologic evaluation.

Infantile hemangiomas can occur in the conjunctiva (refer to Figure 4). These hemangiomas can be associated with other ophthalmologic abnormalities and are treated with oral or topical beta-blockers.[39]

Figure 4. Proposed classification of infantile hemangiomas involving the conjunctiva. Theiler M, Baselga E, Gerth-Kahlert C, et al. Infantile hemangiomas with conjunctival involvement: An underreported occurrence. Pediatr Dermatol. 2017;34:681–685. https://doi.org/10.1111/pde.13305 Copyright © 2017 John Wiley & Sons, Inc.

Congenital Hemangiomas

Congenital hemangiomas are benign vascular tumors that proliferate in utero. Development of these lesions is complete at birth. Histologically, these lesions are GLUT1 negative, unlike infantile hemangiomas. They are usually cutaneous, but can be found in the viscera. Complications include hemorrhage, transient heart failure, and transient coagulopathy.[117]

To the clinician unfamiliar with these lesions, congenital hemangiomas can be difficult to diagnose. Diagnostic criteria include a purpuric lesion fully formed at birth, frequently with a halo around the lesion, with high flow noted on ultrasound imaging. Essential to the diagnosis is observation of stability or decrease in size over time. These lesions do not enlarge unless there is hemorrhage into the tumor.

Somatic activating mutations of GNAQ and GNA11 have been found to be associated with congenital hemangiomas.[118] Additional research is necessary to assess the significance of these findings, as this may aid in diagnosis and pathophysiology.

Congenital hemangiomas are divided into the following three forms:

• Rapidly involuting congenital hemangiomas (RICH). These lesions are large high-flow lesions that are completely formed at birth but rapidly involute by 12 to 15 months. They can ulcerate and bleed and can cause transient heart failure and mild coagulopathy. After involution, usually some residual changes in the skin are present (refer to Figure 6).[119-122] In a retrospective case series of congenital hemangiomas, several high-risk ultrasound findings were noted for RICH. Venous lakes were associated with cardiac failure, and an increased risk of bleeding was noted with venous lakes and venous ectasia. Infants with RICH should be evaluated with ultrasonography and monitored closely if these high-risk features are noted.[123]
  

  Figure 6. Typical appearance of a cutaneous congenital hemangioma at birth. Note the pedunculated mass. This RICH lesion involuted over time but some residual skin changes remained. Credit: Denise Adams, M.D.

• Partial involuting congenital hemangiomas (PICH). These lesions are completely formed at birth and involute only partially.[124]
• Non-involuting congenital hemangiomas (NICH). These lesions are formed at birth and never involute. Depending on the location of the lesions and whether they cause functional impairment, the lesions may need to be removed surgically.[125,126]

Benign Vascular Tumors of the Liver

In the literature, vascular liver tumors are usually classified as liver hemangioendotheliomas, a broad classification no longer in use. These tumors are classified according to their clinical characteristics and radiologic assessment.

Lesions are usually divided into the following three categories:[66]

• Focal vascular lesions (congenital hemangiomas).
• Multiple liver lesions (infantile hemangiomas).
• Diffuse liver lesions (infantile hemangiomas).

On MRI, vascular liver tumors are hyperintense on T2 imaging and hypointense on T1 imaging, with postcontrast imaging demonstrating early peripheral enhancement with eventual diffuse enhancement.[66]

Focal vascular lesions (congenital hemangiomas)

Focal lesions of the liver are usually congenital hemangiomas (RICH or NICH) (refer to Figure 7). RICH can present with symptoms of heart failure and mild to moderate coagulopathy, but are typically detected by antenatal ultrasonography or as an asymptomatic mass in the newborn period.

Treatment options for focal vascular lesions include the following:

1. Supportive management. Most lesions are asymptomatic and can be monitored through involution using ultrasonography.
2. Embolization is considered for severe symptomatic shunting that is unresponsive to treatment for congestive heart failure. These procedures need to be performed by interventional radiologists with expertise in vascular anomalies.[127]
3. Surgery. Patients with massive 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. Indication for surgical removal includes rupture, bleeding, and nonresolving coagulopathy. Two patients were reported to require surgical resection after the development of clinically significant ascites as their RICH involuted.[128,129]

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.[66] 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.[130]

Figure 7. 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.

Diffuse liver lesions (infantile hemangiomas)

Diffuse liver lesions are very serious (refer to Figure 8). Complications include hypothyroidism caused by the expression of iodothyronine deiodinase, high-output or congestive heart failure, and abdominal compartment syndrome.[65,66,131,132]

Figure 8. 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.[77]
2. Thyroid hormone replacement: Thyroid hormone replacement therapy must be aggressive if hypothyroidism is diagnosed; treatment with higher doses of hormones may be needed because the deficiency is caused by the aggressive consumption of the hormone by the tumor.[67]
3. Chemotherapy: Steroids, cyclophosphamide, and vincristine have been used to treat diffuse liver infantile hemangioma.[66,133,134]
4. Transplant: If a patient does not respond to medical management, a transplant may be indicated.[135] Transplant 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.[136] 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 ultrasonography. (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 is very high in all newborns, but will rapidly fall to normal levels in several months. AFP levels should rapidly diminish, but failure to do so or a rising trend of AFP should elicit concern for hepatoblastoma. There are no prospective studies investigating AFP elevation in hemangioma.[137,138] 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.[139]

Spindle Cell Hemangioma

Epithelioid Hemangioma

Pyogenic Granuloma (Lobular Capillary Hemangioma)

Angiofibroma

Juvenile Nasopharyngeal Angiofibroma

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Kaposiform Hemangioendothelioma and Tufted Angioma

Kaposiform hemangioendothelioma (KHE) and tufted angioma are rare vascular tumors that typically occur during infancy or early childhood but have been reported in adults. Both tumors are thought to be a spectrum of the same disease, because both can be locally aggressive and cause Kasabach-Merritt phenomenon, a serious life-threatening coagulopathy characterized by profound thrombocytopenia and hypofibrinogenemia. They are discussed here as a single entity, kaposiform hemangioendothelioma.

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 9). 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 expansive and contiguous. Local lymph nodes may be involved, but there are no reports of distant metastasis. Rare multifocal presentations have been reported, mostly in the bone.[1-3]

Figure 9. Kaposiform hemangioendothelioma with Kasabach-Merritt phenomenon. The lesion is indurated, firm, and warm with petechiae and purpura. Credit: Denise Adams, M.D.

Fifty to seventy percent of patients with kaposiform hemangioendothelioma develop Kasabach-Merritt phenomenon (KMP), 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, serious bleeding, and even death. 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 anomalies specialist.[3] The risk of developing Kasabach-Merritt phenomenon is highest in patients with congenital lesions, lesions larger than 8 cm, and when kaposiform hemangioendothelioma arises in the retroperitoneum or mediastinum.[3,12] The mortality rate is unclear but it has been reported to be as high as 30%.[3,12]

References

1. Rodriguez V, Lee A, Witman PM, et al.: Kasabach-merritt phenomenon: case series and retrospective review of the mayo clinic experience. J Pediatr Hematol Oncol 31 (7): 522-6, 2009. [PubMed: 19564750]
2. Ryan C, Price V, John P, et al.: Kasabach-Merritt phenomenon: a single centre experience. Eur J Haematol 84 (2): 97-104, 2010. [PubMed: 19889011]
3. Croteau SE, Liang MG, Kozakewich HP, et al.: Kaposiform hemangioendothelioma: atypical features and risks of Kasabach-Merritt phenomenon in 107 referrals. J Pediatr 162 (1): 142-7, 2013. [PMC free article: PMC3494787] [PubMed: 22871490]
4. Lee B, Chiu M, Soriano T, et al.: Adult-onset tufted angioma: a case report and review of the literature. Cutis 78 (5): 341-5, 2006. [PubMed: 17186794]
5. Enjolras O, Soupre V, Picard A: Uncommon benign infantile vascular tumors. Adv Dermatol 24: 105-24, 2008. [PubMed: 19263597]
6. Zukerberg LR, Nickoloff BJ, Weiss SW: Kaposiform hemangioendothelioma of infancy and childhood. An aggressive neoplasm associated with Kasabach-Merritt syndrome and lymphangiomatosis. Am J Surg Pathol 17 (4): 321-8, 1993. [PubMed: 8494101]
7. Arai E, Kuramochi A, Tsuchida T, et al.: Usefulness of D2-40 immunohistochemistry for differentiation between kaposiform hemangioendothelioma and tufted angioma. J Cutan Pathol 33 (7): 492-7, 2006. [PubMed: 16872472]
8. Lim YH, Bacchiocchi A, Qiu J, et al.: GNA14 Somatic Mutation Causes Congenital and Sporadic Vascular Tumors by MAPK Activation. Am J Hum Genet 99 (2): 443-50, 2016. [PMC free article: PMC4974082] [PubMed: 27476652]
9. Lim YH, Fraile C, Antaya RJ, et al.: Tufted angioma with associated Kasabach-Merritt phenomenon caused by somatic mutation in GNA14. Pediatr Dermatol 36 (6): 963-964, 2019. [PMC free article: PMC7039697] [PubMed: 31423605]
10. Le Cras TD, Mobberley-Schuman PS, Broering M, et al.: Angiopoietins as serum biomarkers for lymphatic anomalies. Angiogenesis 20 (1): 163-173, 2017. [PubMed: 27990590]
11. Saharinen P, Eklund L, Alitalo K: Therapeutic targeting of the angiopoietin-TIE pathway. Nat Rev Drug Discov 16 (9): 635-661, 2017. [PubMed: 28529319]
12. Ji Y, Yang K, Peng S, et al.: Kaposiform haemangioendothelioma: clinical features, complications and risk factors for Kasabach-Merritt phenomenon. Br J Dermatol 179 (2): 457-463, 2018. [PubMed: 29603128]
13. Gong X, Ying H, Zhang Z, et al.: Ultrasonography and magnetic resonance imaging features of kaposiform hemangioendothelioma and tufted angioma. J Dermatol 46 (10): 835-842, 2019. [PubMed: 31373042]
14. Burleigh A, Kanigsberg N, Lam JM: Topical rapamycin (sirolimus) for the treatment of uncomplicated tufted angiomas in two children and review of the literature. Pediatr Dermatol 35 (5): e286-e290, 2018. [PubMed: 30015406]
15. Zhang X, Yang K, Chen S, et al.: Tacrolimus ointment for the treatment of superficial kaposiform hemangioendothelioma and tufted angioma. J Dermatol 46 (10): 898-901, 2019. [PubMed: 31373046]
16. Osio A, Fraitag S, Hadj-Rabia S, et al.: Clinical spectrum of tufted angiomas in childhood: a report of 13 cases and a review of the literature. Arch Dermatol 146 (7): 758-63, 2010. [PubMed: 20644037]
17. Ji Y, Chen S, Yang K, et al.: Kaposiform hemangioendothelioma: current knowledge and future perspectives. Orphanet J Rare Dis 15 (1): 39, 2020. [PMC free article: PMC6998257] [PubMed: 32014025]
18. Drolet BA, Trenor CC, Brandão LR, et al.: Consensus-derived practice standards plan for complicated Kaposiform hemangioendothelioma. J Pediatr 163 (1): 285-91, 2013. [PubMed: 23796341]
19. Haisley-Royster C, Enjolras O, Frieden IJ, et al.: Kasabach-merritt phenomenon: a retrospective study of treatment with vincristine. J Pediatr Hematol Oncol 24 (6): 459-62, 2002 Aug-Sep. [PubMed: 12218593]
20. Hauer J, Graubner U, Konstantopoulos N, et al.: Effective treatment of kaposiform hemangioendotheliomas associated with Kasabach-Merritt phenomenon using four-drug regimen. Pediatr Blood Cancer 49 (6): 852-4, 2007. [PubMed: 16411198]
21. Wang Z, Li K, Yao W, et al.: Steroid-resistant kaposiform hemangioendothelioma: a retrospective study of 37 patients treated with vincristine and long-term follow-up. Pediatr Blood Cancer 62 (4): 577-80, 2015. [PubMed: 25346262]
22. Fernandez-Pineda I, Lopez-Gutierrez JC, Ramirez G, et al.: Vincristine-ticlopidine-aspirin: an effective therapy in children with Kasabach-Merritt phenomenon associated with vascular tumors. Pediatr Hematol Oncol 27 (8): 641-5, 2010. [PubMed: 20863161]
23. Fernandez-Pineda I, Lopez-Gutierrez JC, Chocarro G, et al.: Long-term outcome of vincristine-aspirin-ticlopidine (VAT) therapy for vascular tumors associated with Kasabach-Merritt phenomenon. Pediatr Blood Cancer 60 (9): 1478-81, 2013. [PubMed: 23609996]
24. Kai L, Wang Z, Yao W, et al.: Sirolimus, a promising treatment for refractory Kaposiform hemangioendothelioma. J Cancer Res Clin Oncol 140 (3): 471-6, 2014. [PubMed: 24464150]
25. Hammill AM, Wentzel M, Gupta A, et al.: Sirolimus for the treatment of complicated vascular anomalies in children. Pediatr Blood Cancer 57 (6): 1018-24, 2011. [PubMed: 21445948]
26. Blatt J, Stavas J, Moats-Staats B, et al.: Treatment of childhood kaposiform hemangioendothelioma with sirolimus. Pediatr Blood Cancer 55 (7): 1396-8, 2010. [PubMed: 20730884]
27. Ji Y, Chen S, Xiang B, et al.: Sirolimus for the treatment of progressive kaposiform hemangioendothelioma: A multicenter retrospective study. Int J Cancer 141 (4): 848-855, 2017. [PubMed: 28486787]
28. Adams DM, Trenor CC, Hammill AM, et al.: Efficacy and Safety of Sirolimus in the Treatment of Complicated Vascular Anomalies. Pediatrics 137 (2): e20153257, 2016. [PMC free article: PMC4732362] [PubMed: 26783326]
29. López V, Martí N, Pereda C, et al.: Successful management of Kaposiform hemangioendothelioma with Kasabach-Merritt phenomenon using vincristine and ticlopidine. Pediatr Dermatol 26 (3): 365-6, 2009 May-Jun. [PubMed: 19706115]
30. Oza VS, Mamlouk MD, Hess CP, et al.: Role of Sirolimus in Advanced Kaposiform Hemangioendothelioma. Pediatr Dermatol 33 (2): e88-92, 2016 Mar-Apr. [PubMed: 26864138]
31. Wang Z, Yao W, Sun H, et al.: Sirolimus therapy for kaposiform hemangioendothelioma with long-term follow-up. J Dermatol 46 (11): 956-961, 2019. [PubMed: 31489702]
32. Zhang G, Chen H, Gao Y, et al.: Sirolimus for treatment of Kaposiform haemangioendothelioma with Kasabach-Merritt phenomenon: a retrospective cohort study. Br J Dermatol 178 (5): 1213-1214, 2018. [PubMed: 29388191]
33. Mariani LG, Schmitt IR, Garcia CD, et al.: Low dose sirolimus treatment for refractory tufted angioma and congenital kaposiform hemangioendothelioma, both with Kasabach-Merritt phenomenon. Pediatr Blood Cancer 66 (8): e27810, 2019. [PubMed: 31087627]
34. Ying H, Qiao C, Yang X, et al.: A Case Report of 2 Sirolimus-Related Deaths Among Infants With Kaposiform Hemangioendotheliomas. Pediatrics 141 (Suppl 5): S425-S429, 2018. [PubMed: 29610165]
35. Russell TB, Rinker EK, Dillingham CS, et al.: Pneumocystis Jirovecii Pneumonia During Sirolimus Therapy for Kaposiform Hemangioendothelioma. Pediatrics 141 (Suppl 5): S421-S424, 2018. [PubMed: 29610164]
36. Filippi L, Tamburini A, Berti E, et al.: Successful Propranolol Treatment of a Kaposiform Hemangioendothelioma Apparently Resistant to Propranolol. Pediatr Blood Cancer 63 (7): 1290-2, 2016. [PubMed: 27100060]
37. Wang Z, Li K, Dong K, et al.: Variable response to propranolol treatment of kaposiform hemangioendothelioma, tufted angioma, and Kasabach-Merritt phenomenon. Pediatr Blood Cancer 61 (8): 1518-9, 2014. [PubMed: 24482015]
38. Schaefer BA, Wang D, Merrow AC, et al.: Long-term outcome for kaposiform hemangioendothelioma: A report of two cases. Pediatr Blood Cancer 64 (2): 284-286, 2017. [PubMed: 27701822]

Pseudomyogenic Hemangioendothelioma

Retiform Hemangioendothelioma

Papillary Intralymphatic Angioendothelioma

Composite Hemangioendothelioma

Kaposi Sarcoma

References

1. Hornick JL, Fletcher CD: Pseudomyogenic hemangioendothelioma: a distinctive, often multicentric tumor with indolent behavior. Am J Surg Pathol 35 (2): 190-201, 2011. [PubMed: 21263239]
2. Billings SD, Folpe AL, Weiss SW: Epithelioid sarcoma-like hemangioendothelioma. Am J Surg Pathol 27 (1): 48-57, 2003. [PubMed: 12502927]
3. Mirra JM, Kessler S, Bhuta S, et al.: The fibroma-like variant of epithelioid sarcoma. A fibrohistiocytic/myoid cell lesion often confused with benign and malignant spindle cell tumors. Cancer 69 (6): 1382-95, 1992. [PubMed: 1371711]
4. Walther C, Tayebwa J, Lilljebjörn H, et al.: A novel SERPINE1-FOSB fusion gene results in transcriptional up-regulation of FOSB in pseudomyogenic haemangioendothelioma. J Pathol 232 (5): 534-40, 2014. [PubMed: 24374978]
5. Amary MF, O'Donnell P, Berisha F, et al.: Pseudomyogenic (epithelioid sarcoma-like) hemangioendothelioma: characterization of five cases. Skeletal Radiol 42 (7): 947-57, 2013. [PubMed: 23381465]
6. Pranteda G, Magri F, Muscianese M, et al.: The management of pseudomyogenic hemangioendothelioma of the foot: A case report and review of the literature. Dermatol Ther 31 (6): e12725, 2018. [PubMed: 30239066]
7. Joseph J, Wang WL, Patnana M, et al.: Cytotoxic and targeted therapy for treatment of pseudomyogenic hemangioendothelioma. Clin Sarcoma Res 5: 22, 2015. [PMC free article: PMC4615364] [PubMed: 26500758]
8. Ozeki M, Nozawa A, Kanda K, et al.: Everolimus for Treatment of Pseudomyogenic Hemangioendothelioma. J Pediatr Hematol Oncol 39 (6): e328-e331, 2017. [PubMed: 28121744]
9. Danforth OM, Tamulonis K, Vavra K, et al.: Effective Use of Sirolimus and Zoledronic Acid for Multiosteotic Pseudomyogenic Hemangioendothelioma of the Bone in a Child: Case Report and Review of Literature. J Pediatr Hematol Oncol 41 (5): 382-387, 2019. [PubMed: 31094908]
10. El Darouti M, Marzouk SA, Sobhi RM, et al.: Retiform hemangioendothelioma. Int J Dermatol 39 (5): 365-8, 2000. [PubMed: 10849129]
11. Colmenero I, Hoeger PH: Vascular tumours in infants. Part II: vascular tumours of intermediate malignancy [corrected] and malignant tumours. Br J Dermatol 171 (3): 474-84, 2014. [PubMed: 24965196]
12. Keiler SA, Honda K, Bordeaux JS: Retiform hemangioendothelioma treated with Mohs micrographic surgery. J Am Acad Dermatol 65 (1): 233-5, 2011. [PubMed: 21679834]
13. Hirsh AZ, Yan W, Wei L, et al.: Unresectable retiform hemangioendothelioma treated with external beam radiation therapy and chemotherapy: a case report and review of the literature. Sarcoma 2010: , 2010. [PMC free article: PMC2948930] [PubMed: 20936126]
14. Enjolras O, Mulliken JB, Kozakewich HPW: Vascular tumors and tumor-like lesions. In: Mulliken JB, Burrows PE, Fishman SJ, eds.: Mulliken & Young's Vascular Anomalies: Hemangiomas and Malformations. 2nd ed. Oxford University Press, 2013, pp 259-324.
15. Tamhankar AS, Vaidya A, Pai P: Retiform hemangioendothelioma over forehead: A rare tumor treated with chemoradiation and a review of literature. J Cancer Res Ther 11 (3): 657, 2015 Jul-Sep. [PubMed: 26458658]
16. Dabska M: Malignant endovascular papillary angioendothelioma of the skin in childhood. Clinicopathologic study of 6 cases. Cancer 24 (3): 503-10, 1969. [PubMed: 5343389]
17. Fanburr-Smith JC: Papillary intralymphatic angioendothelioma. In: Fletcher CDM, Bridge JA, Hogendoorn P, et al., eds.: WHO Classification of Tumours of Soft Tissue and Bone. 4th ed. IARC Press, 2013, pp 148.
18. Neves RI, Stevenson J, Hancey MJ, et al.: Endovascular papillary angioendothelioma (Dabska tumor): underrecognized malignant tumor in childhood. J Pediatr Surg 46 (1): e25-8, 2011. [PubMed: 21238627]
19. Shang Leen SL, Fisher C, Thway K: Composite hemangioendothelioma: clinical and histologic features of an enigmatic entity. Adv Anat Pathol 22 (4): 254-9, 2015. [PubMed: 26050262]
20. Mahmoudizad R, Samrao A, Bentow JJ, et al.: Composite hemangioendothelioma: An unusual presentation of a rare vascular tumor. Am J Clin Pathol 141 (5): 732-6, 2014. [PubMed: 24713748]
21. Tateishi J, Saeki H, Ito K, et al.: Cutaneous composite hemangioendothelioma on the nose treated with electron beam. Int J Dermatol 52 (12): 1618-9, 2013. [PubMed: 22998114]
22. Soldado F, Fontecha CG, Haddad S, et al.: Composite vascularized fibular epiphyseo-osteo-periosteal transfer for hip reconstruction after proximal femoral tumoral resection in a 4-year-old child. Microsurgery 32 (6): 489-92, 2012. [PubMed: 22511340]
23. Jackson CC, Dickson MA, Sadjadi M, et al.: Kaposi Sarcoma of Childhood: Inborn or Acquired Immunodeficiency to Oncogenic HHV-8. Pediatr Blood Cancer 63 (3): 392-7, 2016. [PMC free article: PMC4984265] [PubMed: 26469702]
24. Dow DE, Cunningham CK, Buchanan AM: A Review of Human Herpesvirus 8, the Kaposi's Sarcoma-Associated Herpesvirus, in the Pediatric Population. J Pediatric Infect Dis Soc 3 (1): 66-76, 2014. [PMC free article: PMC3933043] [PubMed: 24567845]
25. El-Mallawany NK, Kamiyango W, Slone JS, et al.: Clinical Factors Associated with Long-Term Complete Remission versus Poor Response to Chemotherapy in HIV-Infected Children and Adolescents with Kaposi Sarcoma Receiving Bleomycin and Vincristine: A Retrospective Observational Study. PLoS One 11 (4): e0153335, 2016. [PMC free article: PMC4833299] [PubMed: 27082863]
26. Rees CA, Keating EM, Lukolyo H, et al.: Mapping the Epidemiology of Kaposi Sarcoma and Non-Hodgkin Lymphoma Among Children in Sub-Saharan Africa: A Review. Pediatr Blood Cancer 63 (8): 1325-31, 2016. [PMC free article: PMC7340190] [PubMed: 27082516]
27. Macken M, Dale H, Moyo D, et al.: Triple therapy of vincristine, bleomycin and etoposide for children with Kaposi sarcoma: Results of a study in Malawian children. Pediatr Blood Cancer 65 (2): , 2018. [PubMed: 28988435]
28. Régnier-Rosencher E, Guillot B, Dupin N: Treatments for classic Kaposi sarcoma: a systematic review of the literature. J Am Acad Dermatol 68 (2): 313-31, 2013. [PubMed: 22695100]
29. Tsao MN, Sinclair E, Assaad D, et al.: Radiation therapy for the treatment of skin Kaposi sarcoma. Ann Palliat Med 5 (4): 298-302, 2016. [PubMed: 27701876]
30. Singh NB, Lakier RH, Donde B: Hypofractionated radiation therapy in the treatment of epidemic Kaposi sarcoma--a prospective randomized trial. Radiother Oncol 88 (2): 211-6, 2008. [PubMed: 18439694]
31. Lebbe C, Garbe C, Stratigos AJ, et al.: Diagnosis and treatment of Kaposi's sarcoma: European consensus-based interdisciplinary guideline (EDF/EADO/EORTC). Eur J Cancer 114: 117-127, 2019. [PubMed: 31096150]

Epithelioid Hemangioendothelioma

Angiosarcoma of the Soft Tissue

References

1. Mehrabi A, Kashfi A, Fonouni H, et al.: Primary malignant hepatic epithelioid hemangioendothelioma: a comprehensive review of the literature with emphasis on the surgical therapy. Cancer 107 (9): 2108-21, 2006. [PubMed: 17019735]
2. Haro A, Saitoh G, Tamiya S, et al.: Four-year natural clinical course of pulmonary epithelioid hemangioendothelioma without therapy. Thorac Cancer 6 (4): 544-7, 2015. [PMC free article: PMC4511336] [PubMed: 26273413]
3. Sardaro A, Bardoscia L, Petruzzelli MF, et al.: Epithelioid hemangioendothelioma: an overview and update on a rare vascular tumor. Oncol Rev 8 (2): 259, 2014. [PMC free article: PMC4419652] [PubMed: 25992243]
4. Dong K, Wang XX, Feng JL, et al.: Pathological characteristics of liver biopsies in eight patients with hepatic epithelioid hemangioendothelioma. Int J Clin Exp Pathol 8 (9): 11015-23, 2015. [PMC free article: PMC4637634] [PubMed: 26617819]
5. Adams DM, Hammill A: Other vascular tumors. Semin Pediatr Surg 23 (4): 173-7, 2014. [PubMed: 25241094]
6. Xiao Y, Wang C, Song Y, et al.: Primary epithelioid hemangioendothelioma of the kidney: the first case report in a child and literature review. Urology 82 (4): 925-7, 2013. [PubMed: 23726166]
7. Reich S, Ringe H, Uhlenberg B, et al.: Epithelioid hemangioendothelioma of the lung presenting with pneumonia and heart rhythm disturbances in a teenage girl. J Pediatr Hematol Oncol 32 (4): 274-6, 2010. [PubMed: 20445417]
8. Cournoyer E, Al-Ibraheemi A, Engel E, et al.: Clinical characterization and long-term outcomes in pediatric epithelioid hemangioendothelioma. Pediatr Blood Cancer 67 (2): e28045, 2020. [PubMed: 31724797]
9. Daller JA, Bueno J, Gutierrez J, et al.: Hepatic hemangioendothelioma: clinical experience and management strategy. J Pediatr Surg 34 (1): 98-105; discussion 105-6, 1999. [PubMed: 10022152]
10. Ackermann O, Fabre M, Franchi S, et al.: Widening spectrum of liver angiosarcoma in children. J Pediatr Gastroenterol Nutr 53 (6): 615-9, 2011. [PubMed: 21832953]
11. Stacchiotti S, Provenzano S, Dagrada G, et al.: Sirolimus in Advanced Epithelioid Hemangioendothelioma: A Retrospective Case-Series Analysis from the Italian Rare Cancer Network Database. Ann Surg Oncol 23 (9): 2735-44, 2016. [PubMed: 27334221]
12. Semenisty V, Naroditsky I, Keidar Z, et al.: Pazopanib for metastatic pulmonary epithelioid hemangioendothelioma-a suitable treatment option: case report and review of anti-angiogenic treatment options. BMC Cancer 15: 402, 2015. [PMC free article: PMC4437555] [PubMed: 25967676]
13. Raheja A, Suri A, Singh S, et al.: Multimodality management of a giant skull base hemangioendothelioma of the sphenopetroclival region. J Clin Neurosci 22 (9): 1495-8, 2015. [PubMed: 25986183]
14. Ahmad N, Adams DM, Wang J, et al.: Hepatic epithelioid hemangioendothelioma in a patient with hemochromatosis. J Natl Compr Canc Netw 12 (9): 1203-7, 2014. [PubMed: 25190690]
15. Otte JB, Zimmerman A: The role of liver transplantation for pediatric epithelioid hemangioendothelioma. Pediatr Transplant 14 (3): 295-7, 2010. [PubMed: 20331517]
16. Cioffi A, Reichert S, Antonescu CR, et al.: Angiosarcomas and other sarcomas of endothelial origin. Hematol Oncol Clin North Am 27 (5): 975-88, 2013. [PubMed: 24093171]
17. Jeng MR, Fuh B, Blatt J, et al.: Malignant transformation of infantile hemangioma to angiosarcoma: response to chemotherapy with bevacizumab. Pediatr Blood Cancer 61 (11): 2115-7, 2014. [PubMed: 24740626]
18. Dehner LP, Ishak KG: Vascular tumors of the liver in infants and children. A study of 30 cases and review of the literature. Arch Pathol 92 (2): 101-11, 1971. [PubMed: 5559952]
19. Ferrari A, Casanova M, Bisogno G, et al.: Malignant vascular tumors in children and adolescents: a report from the Italian and German Soft Tissue Sarcoma Cooperative Group. Med Pediatr Oncol 39 (2): 109-14, 2002. [PubMed: 12116058]
20. Deyrup AT, Miettinen M, North PE, et al.: Pediatric cutaneous angiosarcomas: a clinicopathologic study of 10 cases. Am J Surg Pathol 35 (1): 70-5, 2011. [PubMed: 21164289]
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References

1. Smith MA, Altekruse SF, Adamson PC, et al.: Declining childhood and adolescent cancer mortality. Cancer 120 (16): 2497-506, 2014. [PMC free article: PMC4136455] [PubMed: 24853691]
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Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood vascular tumors. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

• be discussed at a meeting,
• be cited with text, or
• replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Childhood Vascular Tumors Treatment are:

• Denise Adams, MD (Children's Hospital Boston)
• Julie Blatt, MD (University of North Carolina)
• Louis S. Constine, MD (James P. Wilmot Cancer Center at University of Rochester Medical Center)
• Holcombe Edwin Grier, MD
• Paul A. Meyers, MD (Memorial Sloan-Kettering Cancer Center)
• Thomas A. Olson, MD (Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta - Egleston Campus)
• Alberto S. Pappo, MD (St. Jude Children's Research Hospital)
• Stephen J. Shochat, MD (St. Jude Children's Research Hospital)

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

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The preferred citation for this PDQ summary is:

PDQ® Pediatric Treatment Editorial Board. PDQ Childhood Vascular Tumors Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/soft-tissue-sarcoma/hp/child-vascular-tumors-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26844334]

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Disclaimer

Based on the strength of the available evidence, treatment options may be described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

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