Infantile Hemangiomas – Causes, Symptoms, Treatment - Health

Infantile Hemangiomas/Hemangioma also knew as hemangiomas of infancy or infantile hemangiomas (IH), are the most common benign tumor of infancy[rx]. They are often called “strawberry marks” due to their clinical appearance. Endothelial cell proliferation results in hemangiomas. There are different types of hemangiomas. Congenital hemangiomas are visible at birth whereas infantile hemangiomas appear later in infancy. Infantile angiomas are characterized by early, rapid growth followed by spontaneous involution.

Hemangiomas are common benign vascular tumors that often present in childhood. While the majority are small, nonproblematic, and can be managed conservatively, some hemangiomas may be associated with underlying syndromes or concerning for visceral involvement. Symptomatic lesions may develop ulceration, bleeding, vision disturbances, functional limitations, or disfigurement.

Types of Hemangioma

Types of hemangiomas	Characteristics
Superficial hemangiomas	Localized in the papillary dermal layer [rx]
Deep hemangiomas	Localized in the reticular dermal layer or the subcutaneous tissue [rx]
Mixed hemangiomas	With both a superficial and a deep component [rx]

Multiple theories have been outlined, but there are still more to be discovered.

The clonality of endothelial cells of the hemangioma – [rx,rx]. Hypoxia and acidosis are known to create a disturbance of the equilibrium between proangiogenic and antiangiogenic factors. These situations stimulate endothelial cell proliferation and thereafter growth of the infantile hemangioma [rx].

The theory of hypoxia and the successive angiogenesis – [rx,rx,rx]. In addition to the proliferation of endothelial cells, intrauterine or perinatal hypoxia and acidosis, both stimulate angiogenesis by increasing the secretion of VEGF (vascular endothelial growth factor). HIF1- alpha (hypoxia-inducible factor 1 alpha) induces the gene-transcription of VEGF, which is the most powerful angiogenic factor.

Others Types of

Infantile hemangiomas – Infantile hemangiomas are the most common benign tumor found in children. They are made up of blood vessels, often called strawberry marks, and are more common in girls than in boys. They usually appear on the skin of infants in the days or weeks after birth. They tend to grow quickly for up to a year. Most then shrink or involute without a further problem, however, some can ulcerate and form scabs which can be painful.^[rx] Depending on their location and size, they may also be disfiguring.
Congenital hemangiomas – Congenital hemangiomas are present on the skin at birth, unlike infantile hemangiomas, which appear later. They are fully formed at birth, meaning that they do not grow after a child is born, as infantile hemangiomas do. They are less common than infantile hemangiomas. Congenital hemangiomas can be colored from pink to blue.
Cavernous liver hemangioma – A cavernous liver hemangioma or hepatic hemangioma is a benign tumor of the liver composed of hepatic endothelial cells. It is the most common liver tumor, and is usually asymptomatic and diagnosed incidentally on radiological imaging. Liver hemangiomas are thought to be congenital in origin.^[rx] Several subtypes exist, including the giant hepatic hemangioma, which can cause significant complications.
Compound hemangioma – Some hemangiomas are a mix of the capillary and cavernous types.
Lobular capillary hemangioma (pyogenic granuloma) – These small, red bumps often appear on the hands, face, and arms. Because they contain so many blood vessels, they bleed easily — often with just mild contact. This type of hemangioma is also sometimes referred to as a “pregnancy tumor” because they often appear during pregnancy, typically in the nose and mouth.
Drug-induced hemangioma – Drug-induced hemangiomas are reported side-effects for some drugs in nonclinical toxicology animal models, studying carcinogenesis. For example, hemangiomas of the mesenteric lymph node were increased significantly at 700 mg/kg/day of Empagliflozin in male rats, or approximately 42 times the exposure from a 25 mg clinical dose. ^[rx] It is inferred from nonclinical animal studies that some drugs can also produce hemangiomas in humans, and careful dosing during therapeutic drug design can ensure their safe use.
Intramuscular hemangioma – Hemangiomas in muscle tissue can develop at any age, but most often occur in young adults. Capillary hemangiomas are more common in muscle than cavernous and compound types. Any muscle can be involved. Because they are located within the muscle, these hemangiomas often show no visible signs, although some may cause swelling in the area of the tumor that increases with activity. These tumors are often painful and require treatment.
Bone hemangioma – The hemangiomas that occur in bones typically occur in the skull or spine and are most common in people who are 50 to 70 years of age. Capillary and cavernous types are the most common hemangiomas found in bone. They can grow on the surface or deeper into the center canal of a bone. Because they typically do not cause symptoms, these tumors are often found by chance when an x-ray or MRI image is taken for another purpose.
Internal organ hemangioma – Although uncommon, hemangiomas can develop in internal organs, most often the liver and intestines. Like hemangiomas found in bone, hemangiomas in internal organs are often found by chance during tests for another purpose. Unless they are causing symptoms, these hemangiomas do not require any treatment.

Causes of Infantile Hemangiomas

The etiology of infantile hemangiomas is poorly understood, but there are several hypotheses. The most likely hypothesis suggests that hypoxic stress upregulates expression of GLUT 1 and VEGF leading to the mobilization of endothelial progenitor cells. The progenitor cells are positive for CD133 and CD31[rx]. Another hypothesis suggests that placental trophoblasts serve as the origin of stem cells for hemangiomas[rx]. A third hypothesis suggests that IH development involves vasculogenesis from progenitor cells (de novo formation) as well as the formation of new vessels from existing ones (angiogenesis)[rx]. Angiogenic factors have been suggested to act on endothelial cells and pericytes to initiate the formation of a capillary network[rx].

Symptoms of Infantile Hemangiomas

Symptoms of a hemangioma are:

A red to reddish-purple, raised sore (lesion) on the skin
A massive, raised, tumor with blood vessels

Most hemangiomas are on the face and neck.

Capillary hemangiomas usually appear in the first six months. They can be red to reddish-purple, raised lesions on the skin. They can also be large, raised lesions with visible blood vessels. Typically, parents notice a spot on a baby’s skin that grows in size and color.

Hemangiomas that involve the eye can cause serious eye problems. If large and unchecked, they can lead to poor vision development from amblyopia or “lazy eye.” If the hemangioma involves the eye itself, it can cause glaucoma. Hemangiomas in the eye socket can press on the optic nerve. This can cause optic nerve atrophy and lead to vision loss.

Diagnosis of Infantile Hemangiomas

Histopathology

Upon histopathological examination of infantile hemangioma, a multinodular pattern fed by a single arteriole can be seen[rx]. The nodules are composed of hyperplastic endothelial cells, pericytes with and without lumens and prominent basement membranes. The involution stage of the hemangioma is marked by dilated vascular lumens and flattened endothelial cells (which give the IH its lobular architecture). Fibrosis becomes pronounced as involution progresses[rx]. During involution, IH expresses a tissue inhibitor of metalloproteinase, which also inhibits angiogenesis[rx]. Placenta-associated vascular antigens staining, including FcRII, Lewis Y antigen (LeY) and merosin, is also observed during involution. Upon immunohistochemical evaluation of the endothelial cells, they express CD31, von Willebrand factor, and urokinase in all phases. Infantile hemangiomas express glucose transporter protein-1 (GLUT 1) during all phases of their development. Thus, immunohistochemical studies can be used to distinguish the development stages of IH.

History and Physical

Infantile hemangioma is usually absent at birth but can present with several types of precursor lesions. These include a pale area of vasoconstriction, an erythematous macule, a telangiectatic red macule or blue bruise-like patches. Infantile hemangiomas become clinically apparent within 1 to 4 weeks. The localization is ubiquitous, and they may occur on the skin and mucosal surfaces. The majority present as a single localized cutaneous hemangioma but infantile hemangioma may be multifocal or segmental. Hemangiomas occur most commonly on the head and the neck and are seen in 60 % of cases. This is followed by lesions on the trunk in 25% of cases, and least commonly, on the extremities, seen in 15% of cases[rx]. Hemangiomas can be superficial, deep or mixed with components of both superficial and deep layers. Superficial lesions involve the superficial dermis and are raised, lobulated and bright red. Deep hemangiomas, also called subcutaneous hemangiomas, arise from the reticular dermis and/or the subcutis layer, and appear as a bluish-hued nodule, plaque or tumor. Mixed hemangiomas have features of both locations.

The natural history of infantile hemangioma has a triphasic evolution:

Blood tests. If there are multiple tumors or if your symptoms are concerning for a specific disease pattern, your doctor may recommend blood tests for genetic analysis.
Early proliferative or growth phase – Usually, there is rapid growth during the first three months and gradual growth in months five to eight of life. Deep infantile hemangiomas tend to proliferate for a longer period and can be seen doing so until the ninth or twelfth month of life[rx].
Plateau phase – The lesion remains stable and quiescent for a period of months (between 6 and 12 months of life).
Involution phase – This may occur within the first year of life and can continue for several years. The regressive infantile hemangiomas become softer and more compressible, and the color changes from bright red to purple or gray. The skin may return to normal, but often there are residual changes (excessive fibrofatty tissue, telangiectasia, skin laxity)[rx][rx].

Evaluation

Most Infantile hemangiomas are diagnosed clinically. A skin biopsy can be performed if there is any doubt. Infantile hemangiomas stain positive for GLUT 1. Imaging studies like ultrasonography, computed tomography (CT) are indicated to confirm the diagnosis and the extent of deep IH without superficial changes. This is done to rule out associated anomalies and to differentiate proliferating IH from other tumors.

Imaging features.[rx]

Ultrasound – Capillary hemangiomas appear as irregular lesions in the orbit demonstrating high internal reflectivity with irregular acoustic structures. A scan shows low to medium reflectivity with high spikes produced by the septae. Increased flow within a lesion can be demonstrated by Doppler echography.
Computed Tomography (CT) scan – Capillary hemangiomas appear as well-defined to irregular pre-septal or post-septal, intraconal or extraconal-heterogenous soft tissue masses which enhance with contrast. There is no evidence of calcification or bony erosion. They may appear well-defined or ill-defined.
Magnetic resonance imaging (MRI) – they appear as well-defined or ill-defined lesions which are hypointense on T1 weighted images and hyperintense on T2 weighted images. The characteristic feature is the presence of flow voids within the lesion. They demonstrate diffuse enhancement with Gadolinium contrast which is best appreciated in fat-suppressed images.
Angiogram – In this test, dye is injected into the surrounding bloodstream making the hemangioma show up in an x-ray image.
Biopsy – At times, it may be difficult to distinguish hemangiomas from other tumors, and a biopsy is sometimes necessary to confirm a diagnosis of hemangioma. In a biopsy, a tissue sample of the tumor is taken and examined under a microscope. Looking at the tissue under a microscope may be the best way to tell if the tumor is indeed a hemangioma and what subtype it is. During the biopsy, your doctor may give you a local anesthetic to numb the area and take a sample using a needle. Biopsies can also be performed as a small operation.

Treatment of Infantile Hemangiomas

Non-Pharmacological

Compression – Intermittent pneumatic compression is a treatment that uses inflatable sleeves or leggings to apply pressure to the tumor. It can be helping in decreasing the swelling associated with a hemangioma. It will not, however, make the hemangioma go away.
Embolization – In this procedure, the blood supply to the tumor is closed off. This is a minimally invasive procedure where small particles are injected into the blood vessels to block them off. Sclerotherapy is a similar procedure where chemical agents are used to closing off the vessels. These procedures can be very helpful in shrinking the tumor and decreasing pain. Often, however, the tumor will regrow its blood supply overtime after these procedures. Embolization is also sometimes used prior to surgery to reduce the risk of heavy blood loss.
Beta-blockers – such as oral propranolol (2mg/kg/day) have been shown to be effective as first-line therapy. However, the side effect profile of propanolol includes bradycardia, hypotension, bronchospasm, and hypoglycemia. Oral prednisone (2-4mg/kg/day) is an alternative therapy that can be used. The high dose of prednisone would have to be slowly tapered over weeks to months. Prednisone’s adverse reactions would include irritability, sleep disturbance, hypertension, bone demineralization, cardiomyopathy, and growth retardation. The topical beta-blocker, timolol, is used for smaller, superficial, and uncomplicated, infantile hemangiomas.
Anti-inflammatory medication – If a hemangioma is growing near vital structures, such as the nose, lips, or eyelids, your doctor may recommend steroid medication. Steroids are often used to slow down the growth of the tumor. The drugs may be injected directly into the hemangioma or given orally.
Topical antiseptics – Eosin, which also has antiangiogenic properties, has been reported to be of benefit.
Interferon-alpha – may be useful but is rarely recommended, as it has been associated with the development of cerebral palsy in a few infants.
Vincristine – was reported effective in the past but is rarely used today
Intralesional – can be used to treat small focal lesions[rx]. Otherwise, surgical excision may be considered to prevent complications. Surgical excision involves removing the residual fibrofatty tissue and this improves treatment outcomes.
Pulsed dye laser (PDL) – is indicated for telangiectasia, but PDL remains controversial for infantile hemangiomas that are deep[rx].
Corticosteroid therapy – is an alternative option for patients who have contraindications or inadequate response to propranolol ^[rx]. Typical dosing is prednisone at 2–3 mg/kg daily and monitoring for side effects including adrenal axis suppression, cushingoid facies, irritability, and stomach irritation is recommended. For localized IH, an intralesional steroid injection can be considered and can be used in conjunction with the favorable responses obtained with propranolol. Sirolimus may be a last-resort treatment in refractory cases.
Laser therapy – is a treatment option typically used for persistent telangiectasia or residual lesions during or after hemangioma involution. The pulse dye laser is commonly used owing to its preferential absorption by hemoglobin; Nd: YAG is sometimes also used in lesions with significant venous drainage. Laser treatments during the growth phase of IH are controversial and generally not pursued because of the possibility of blistering, ulceration, and long-term pigmentation changes ^[rx].
Radiotherapy – It embolization are used in hepatic hemangiomas [rx,rx]. Each type of therapy has its indications, contraindications, side effects, and risks; therefore, the treatment of hemangiomas remains a challenge. Because the exact mechanisms of action of several therapies remain unknown, the subject is of great interest for researchers. Therefore a high number of studies are performed and more are need to be conducted in order to achieve target-therapies.

Tropical

Timolol – Timolol is a non-selective β blocker that is used for increased intraocular pressure. In 2010, Guo and Ni first reported the clinical response to timolol 0.5% solution in a 4-month-old infant who had a thin haemangioma plaque on the upper eyelid.[rx] Subsequently, several pilot studies and case series have shown its clinical efficacy.[rx,rx,rx,rx] It has been mostly used for localized, non-ulcerated superficial IHs. Chan et al. found timolol to be more effective for lesions with a mean diameter of <11.3 mm (i.e. 100 mm³ in volume) as compared to larger lesions.[rx] It is to be applied two times a day. One drop of timolol maleate (0.5%) contains 0.25 mg of the drug.[rx] It is recommended to apply 1 drop of the gel two times a day. Some authors recommend 3-4 times application.[rx] Timolol does not penetrate deeply and hence it is not useful in deep haemangiomas.[rx] Treatment is more effective in the proliferative phase than in the involution phase, and also, plaques respond better than nodules.[rx]
Propranolol – Topical propranolol 1% ointment has been used successfully in the treatment of superficial IHs, especially as an adjuvant therapy during the wait-and-watch period. Kunzi-Rapp et al. in their series of 45 cases of superficial haemangiomas, used propranolol 1% ointment locally twice daily.[rx] Of the 65 haemangiomas treated, 59% showed regression and 26% had cessation of growth. In 15% of the cases, no response was seen. Concomitant use of propranolol ointment with pulsed dye laser (PDL) in two of their cases of ulcerated haemangioma led to the healing of ulcers in 3 and 6 weeks, respectively. In a retrospective chart review by Xu et al., 16 (57%) out of 28 haemangiomas demonstrated good response, 9 (33%) showed partial response and 3 (10%) had no response.[rx] No side-effects have been reported so far.
Imiquimod – Imiquimod, an immune response modifier with anti-angiogenic and pro-apoptotic properties, has been used in the treatment of superficial IH. Imiquimod 5% cream is applied on alternate days at bedtime and left for 8 hours. It is washed with mild soap the next morning. The duration of therapy is about 4 months. Severe inflammatory reactions may occur with the application of imiquimod. Qiu et al. studied the efficacy and safety of imiquimod in their retrospective comparative study of imiquimod versus timolol in superficial proliferative IH. They found that the efficacy of imiquimod was comparable with timolol. However, inflammatory changes were seen in 13 of 20 (65%) cases in the imiquimod group while none of the cases in the timolol group had side effects.[rx]

Surgery

Surgical excision is reserved for ulcerative, bleeding, and significantly protruding hemangiomas. This can be performed alone or in combination with other treatments, especially when the response to other treatments is limited or ineffective ^[rx]. Scarring from ulcerative hemangiomas often requires revision in combination with resection of residual disease. Delaying surgery until after involution allows for the excision of smaller and less vascular lesions. Hemangiomas with a significant vertical growth pattern are at higher risk of leaving undesirable fibrofatty residuum after involution, which can be addressed with surgical excision ^‘[rx]. This is particularly common in scalp IHs, which may develop alopecia during the involution phase and are easily excised with primary closure ^[rx].

Differential Diagnosis

When considering hemangiomas, there are various differentials that fall into this category. It is important to consider each of them to obtain the accurate diagnosis.

Congenital hemangioma
Pyogenic granuloma
Kaposiform hemangioendothelioma
Tufted hemangioma
Venous malformation
Capillary malformation: port-wine stain
Macrocytic lymphatic malformation
Malignant tumors: sarcoma, a cutaneous location of neuroblastoma or lymphoma

Complications

The complications depend on the patient’s age and on the hemangioma’s size and location. The complications of IH are listed below.

Ulceration is the most common complication and occurs in up to 10% of cases. Locations with higher risk of ulceration include the anogenital area, lower lip, axilla, and neck.
Ophthalmologic complications include amblyopia, astigmatism, myopia, retrobulbar involvement and tear duct obstruction.
Airway obstruction can be seen in nasal, subglottic and laryngeal passages.
Difficulties feeding can be seen with perioral or lip hemangiomas.
Visceral hemangiomatosis, especially multifocal hemangiomas (greater than or equal to 5 skin lesions), may be associated with liver or gastrointestinal involvement.
Cosmetic disfigurement can be seen with large facial area involvement or involvement of the nasal tip (called Cyrano nose), ears, and perioral area.
PHASES syndrome manifests with a large segmental facial hemangioma (greater than or equal to 5 cm). The PHASES syndrome acronym stands for posterior fossa malformations, hemangioma of the cervicofacial region, arterial anomalies, cardiac anomalies, eye anomalies, and Sternal or abdominal clefting[rx].
The LUMBAR syndrome manifests with lumbosacral hemangiomas and may be associated with underlying developmental anomalies. The LUMBAR syndrome acronym represents lumbosacral hemangioma, urogenital anomalies, myelopathy, bony deformities, anorectal or arterial, and renal anomalies[rx]

References

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