Hemangiomas are tumors identified by rapid endothelial cell proliferation in early infancy, followed by involution over time; all other abnormalities are malformations resulting from anomalous development of vascular plexuses. The malformations have a normal endothelial cell growth cycle that affects the veins, the capillaries, or the lymphatics, and they do not involute.
Hemangiomas are lesions that are not present at birth. They manifest within the first month of life, exhibit a rapid proliferative phase, and slowly involute to near complete resolution. Hemangiomas exhibit both a proliferating phase and an involuting phase, whereas vascular malformations are more stable and fail to regress.
Hemangiomas of the oral cavity are not common pathologic entities, but, among hemangiomas, the head and the neck are common sites. Most true hemangiomas involute with time, but a certain small percentage do not, which may present with complications that require treatment (see Complications). An estimated 10-20% of true hemangiomas incompletely involute and require postadolescent ablative treatment.
Hemangiomas are associated with the following syndromes:
The term hemangioma has been commonly used to describe a large number of vasoformative tumors. Unfortunately, the nomenclature and the classification of these entities have been complex and not entirely consistent over time. The complexity and the inconsistency have led to a large number of terms and classification schemes being used, resulting in confusion in understanding the pathophysiology of these lesions and in comparing data from different periods. The nomenclature lends little insight into the natural history and the management of these lesions.
What was referred to as a hemangioma 30 years ago is not necessarily what a hemangioma would be referred to as today. The term hemangioma described many lesions that bore little relationship to each other apart from their being involved with vessels. With this concept in mind, this article discusses oral vasoformative tumors under the broad and not entirely correct term oral hemangiomas.
In 1982, Mulliken and Glowacki described the classification scheme that is most accepted today. This scheme is straightforward and essentially divides the vasoformative tumors into 2 broad groups: hemangiomas and vascular malformations (see Table 1 below). The vascular malformations can be further subdivided into arterial, venous, capillary, and lymphatic malformations.
Table 1. Classification of Vasoformative Tumors
Vascular malformations need to be understood in terms of their embryology and development. The classic sequence of events usually falls into 3 stages: (1) the undifferentiated capillary network stage, (2) the retiform developmental stage, and (3) the final developmental stage. In the undifferentiated capillary network stage, the primitive mesenchyme is nourished by an interlacing system of blood spaces without distinguishable arterial and venous channels. Separate venous and arterial stems appear on either side of the capillary network in the retiform developmental stage. The retiform developmental stage begins at about 48 days of embryonic development. The final developmental stage begins at 2 months' development and involves the gradual replacement of the immature plexiform network by the mature vascular channels.
The more common capillary hemangioma represents an arrest in the development of the mesenchyme primordia in the undifferentiated capillary network stage. As differentiation progresses, primitive vessels penetrate deeper into the subcutaneous layer, the muscle, or the bone tissue and give rise to capillary hemangiomas. Termination of development in the retiform developmental stage may produce venous, arterial, or capillary malformations because this stage is characterized by an established venous, arterial, and capillary system. In the final developmental stage, the maturation of the venous and lymphatic systems predominates. Aberrations in this mature stage of development result in venous malformations and lymphangiomas.
Proliferating hemangiomas have been shown to have estradiol-17 beta-receptors in the cytoplasm, and corticosteroid treatment has been theorized to block these receptors. Lack of estradiol receptors in stable or involuting lesions has supported this theory, and steroid treatment has become a first line of treatment for proliferating lesions.
A number of growth factors, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), transforming growth factor-beta (TGF-beta), and interleukin 6 (IL-6), have been demonstrated as regulators of angiogenesis. Takahashi et al outlined a number of cellular markers that distinguish the phases of hemangiomas; these markers include tissue metalloproteinase (TIMP-1), bFGF, proliferating cell nuclear antigen, type IV collagenase, VEGF, and urokinase.
Another theory suggests that the endothelial cells of hemangiomas are derived from a distant population of endothelial precursors carried by existing vascular pathways to a receptive environment. Potential sources include the bone marrow and the placenta. A small embolic nidus of placental endothelial cells could reach fetal tissues through the permissive right-to-left fetal shunt of fetal circulation.
This occurrence could, in part, explain the 3-fold increased risk of hemangiomas observed in infants subjected in utero to chorionic villus sampling, because local placental injury might predispose the shedding of cells into the fetal circulation. At least 5 markers of hemangiomas are uniquely co-expressed in the placenta: GLUT1, merosin, Lewis Y antigen, Fc-R11b, and type III iodothyronine deiodinase. Recently, a comparison of the transcriptomes of the human placenta and infantile hemangiomas supported a placental origin of the tumors.
Hemangiomas are the most common tumors of infancy, occurring in as many as 2.6% of neonates and 12% of children aged 1 year.[7, 8] Up to 30% of preterm infants with low birth weight (1000 g) may have hemangiomas. Fifty percent of venous malformations occur in the head and the neck.
In the oral cavity, the bones and the muscles are affected as well as the mucosa and the skin. The incidence of intraosseous hemangiomas varies from 0.5-1.0% of all intraosseous neoplasms. The bones most frequently affected are the vertebral column and the calvaria. The most commonly affected facial bones are the mandible, the maxilla, and the nasal bones. Intraosseous lesions affect the mandible more often than the maxilla, with a ratio of 2:1 reported in one study. Involvement of the zygoma is rare.
Intramuscular hemangiomas in the oral region are most commonly seen in the masseter, compromising 5% of all intramuscular hemangiomas.
Hemangioma, the most common tumor of infancy, affects as many as 12% of whites, but it rarely occurs in darker-skinned individuals. Vascular malformations also more commonly occur in whites.
Hemangiomas are approximately 3-5 times more common in females than in males. The male-to-female ratio for venous malformations is reported in one study to be 1:1. Arteriovenous hemangiomas of the oral cavity have a predilection for females. Intraosseous hemangiomas are about 3 times more common in females than in males.[12, 17]
The patient's sex does not influence the speed or the completeness of involution of hemangiomas.
By their definition, hemangiomas occur in infants and children. The incidence of hemangiomas increases to 23% in premature infants with a birthweight of less than 1000 g.
Vascular malformations have a much broader range of incidence. Barrett and Speight observed 35 oral vascular malformations over a 48-year period at their institution. The mean age was 52.6 years, with a range of 12-90 years.
Intraosseous vascular malformations most commonly occur in the fourth decade of life but range from infancy to the eighth decade of life.
The peak incidence of central vascular malformations of the jaws is in the second decade of life.
Intramuscular vascular malformation of the head and the neck most commonly present in the third decade of life.
Hemangiomas and vascular malformations are diagnosed fairly easily with a careful history and a physical examination.
Capillary hemangiomas are usually not present at birth but are antedated by a pale, well-demarcated, flat area, most visible with agitation. These prodromal lesions may appear as a pale halo surrounding an area of telangiectasis or as a very fine telangiectasia similar to the port-wine stain.
Elevation occurs early during the first year of life and increases from the ages of 3-8 months, with some growth continuing into the second year of life. A stable interval of 6-12 months often follows the growth period. Then, a slow spontaneous involution, which usually begins in the center of the lesion, takes place in most cases. Involution often begins as a darkening of color followed by the appearance of numerous gray or pallid regions and fibrous septae within the lesion. Historically, most lesions have reportedly involuted by the time the patient is aged 7 years, with 86% of those lesions regressing by the time the patient is aged 5 years.[19, 20, 21, 18, 22]
The patient's sex and the size of the hemangioma do not influence the speed or the completeness of resolution. The location of the lesion does not generally influence its behavior, but lesions of the lower lip are less favorable. Patients with multiple lesions have rates of resolution similar to those with single lesions; however, separate lesions in the same individual do not necessarily grow or involute simultaneously. Lesions that have not improved after 3 years are unlikely to resolve by age 7 years. Unfortunately, early improvement does not always lead to early resolution. Involution may continue into the late teenage years.
Cavernous hemangiomas are composed of large, irregular, deep dermal and subcutaneous blood-filled channels that impart a purplish discoloration to the overlying skin. They are typically soft, poorly defined, and readily blanch with compression, giving them a characteristic "bag of worms" feel. The lesion may expand and darken with crying, when agitated, or when placed in a dependent position. Often, a capillary component overlies a cavernous component, and it may be difficult to distinguish these components histologically. Cavernous and mixed hemangiomas demonstrate the same patterns of proliferation as those of capillary lesions. However, involution is often incomplete, depending on the location and the presence of associated arteriovenous malformations.
Vascular malformations are present at birth and continue to grow with the child. The growth may become accelerated when the patient undergoes puberty or pregnancy, with the attendant hormonal changes.
On examination of the oral cavity, the vascular malformations of the mucosa and the adjacent soft tissues are usually readily apparent. The tissues have a slightly bluish hue and are soft. Venous channels become engorged when placed in a dependent position. They are readily compressible and fill slowly when released. They lack a prominent pulsation; if they represent an arteriovenous malformation, a thrill may be present.
Although the mucosal and soft tissue lesions are readily suspected by their appearance, the intrabony lesions may be difficult to distinguish on sight alone. Central jaw lesions can show hypermobility of the teeth and distortion of the arch form. Severe hemorrhage following dental extraction is not an uncommon presentation of central hemangiomas of the maxilla and the mandible. Common clinical findings in central hemangiomas of the jaws include gingival bleeding, postextraction bleeding, swelling, pain, mobility of the teeth, and bony expansion. Root resorption of the teeth has been reported in 30% of cases, but the vitality of the teeth is usually not affected.
Intramuscular vascular malformations represent a challenge on diagnosis because they exhibit few signs on clinical examination. Oftentimes, the extent of the lesion is not clinically apparent on examination, and imaging studies frequently define more extensive lesions than suspected.
The causes of vasoformative tumors are unknown. One hypothesis postulates that placental cells, such as the trophoblast, may be the cell of origin for hemangiomas. Therefore, hemangiomas may arise secondary to some event in utero. However, conflicting evidence supports this hypothesis. One study found placenta-associated vascular antigens to be expressed by hemangiomas but not by other vascular malformations or tumors. On the other hand, a separate investigation found immunohistochemical staining of certain trophoblastic markers to be negative in all infantile hemangiomas that were examined. The relationship between hemangiomas and placental tissues needs further investigation.
Usually, no laboratory studies are useful in the diagnosis or management of oral hemangiomas.
Workup of oral hemangiomas requires some form of imaging to determine their extent and flow characteristics. The following modalities may be helpful:
Procedures other than a clinical history or examination, including aspiration of intraosseous lesions, that are used to diagnose oral hemangiomas readily produce frank blood. Performing a biopsy of oral hemangiomas can be potentially dangerous.
Histopathologically, vasoformative tumors share many similar microscopic features, and overlap between hemangiomas and vascular malformations exists. Hemangiomas are subclassified as capillary or cavernous, depending on the size of the vascular channels. Vascular malformations, as true structural anomalies, exhibit a normal rate of endothelial cell turnover. Spaces are lined by endothelium without muscular support. An increase in normal- and abnormal appearing blood vessels occurs. The endothelial cells of early lesions may be plump, obscuring the lumen of the capillaries. Phleboliths may develop as a result of dystrophic calcification in thrombi. Intimal thickening or diverse arteriovenous connections can sometimes be seen in serial sections. Johann et al showed that histological diagnosis alone is not sufficient to correct diagnoses of oral hemangioma. Moreover, immunohistochemistry to GLUT1 is a useful and easy diagnostic method that may be used to avoid such misdiagnosis.
Salient histopathologic findings of vasoformative tumors that distinguish them are as follows:
Diagnosis and management of oral vasoformative tumors and oral hemangiomas span a wide range of options. Treatment of oral vasoformative tumors can be divided into 2 broad categories: medical treatment and surgical or invasive treatment (see Surgical Care).
Kane et al developed a management algorithm that covers most of the current thinking regarding these tumors.
At initial presentation, a history and physical examination are performed, and an MRI is obtained to determine the extent of the lesion because extensive spread may not be evident on examination. Presence of bruits, pulsatility, or deep extent would also make angiography a useful adjunct.
From this database, whether the lesion in question is a vascular malformation or a hemangioma can be ascertained. If it is a hemangioma, then whether the lesion is proliferating needs to be ascertained. For proliferating lesions, either observation or steroids are options. In lesions that are not proliferating, whether the lesion is involuting needs to be determined. Involuting lesions can be managed by observation. If the involution is incomplete and arrested, then the lesion can be managed the same as a low-flow vascular malformation.
If the lesion in question is determined to be a vascular malformation rather than a hemangioma, then its flow characteristics must be gauged. High-flow lesions require presurgical embolization followed by aggressive ablative therapy. Low-flow vascular malformations can be managed in numerous ways. For the easily collapsible lesions that are accessible, sclerotherapy, laser therapy, or cryotherapy are alternatives. For those that are not accessible, do not have compressible components, or are functionally compromising, then ablative surgery is indicated. For lesions that are insufficiently ablated or sclerosed, other modalities can be used in a complementary fashion.
Treatment of vasoformative tumors represents a challenge because the morbidity can range from minor bleeding and swelling to life-threatening hemorrhage and airway embarrassment. Because of the propensity of hemangiomas to regress spontaneously, approaches to management depend on their size, their location, their behavior, and the age of the patient. Hemangiomas are usually managed conservatively, and vascular malformations in soft tissue are managed by a number of preferred methods, with special cases such as those in bone or muscle by other methods. The advent of technologic advances in interventional radiology and use of sclerosing and medical therapy has changed the management of these lesions considerably in the past few decades.
Most true hemangiomas require no intervention, but 10-20% require treatment because of their size, their location, or their behavior. Individualized therapy depends on the age of the patient, the size and the exact location of the lesion, the stage of growth or regression, and the functional compromise. In general, the treatment of small hemangiomas that do not compromise function is observation. Conservative management consists of periodic visits, parental support, and photodocumentation. The ultimate result of involution for capillary hemangiomas is far superior to primary excisional therapy. Excision can be justified under certain conditions, especially when function is compromised.
For adults with oral vascular malformations, the treatment depends on the proliferative nature and the extent of the lesions and on the functional impairment, usually hemorrhage and airway problems. For limited lesions, treatment for cosmetic reasons may be an acceptable risk-benefit decision.
When lesions, especially those involving the oropharynx and the subglottic areas, are rapidly proliferative in children, urgent intervention is indicated. In adults, most of these lesions, if stable and not progressing, can be managed with conservative treatment. Treatment of the more extensive lesions can entail significant morbidity from the radical surgical treatment necessary to eradicate them. Many of the treatment alternatives have evolved to avoid the disfiguring and functionally debilitating standard treatments. Many of the treatments have resulted in recurrence or persistence of the lesions, and undergoing multiple procedures in an effort to eradicate disease is not unusual.
For high-flow vascular malformations, complete resection of extensive tumors can be a formidable task. Deep skull base extension and internal carotid artery or vertebral artery branch recruitment may preclude resectability. Embolization in this setting has not demonstrated significant palliative value. Kane has reported 3 deaths related to tumor extension and hemorrhage in this subset. With embolization, inadvertent passage of the agents to unwanted areas of the circulation is always a risk. Superselective catheterization and a careful choice of agents have minimized this complication.
The 2 primary medical treatments are steroids and beta-blocker therapy.[27, 28, 29] Interferon is rarely used because of the risk of spastic diplegia. Vincristine has been reported to decrease the size of a large segmental mandibular hemangioma in the setting of PHACES syndrome.
Steroids have become a mainstay in the treatment of proliferating hemangiomas in infants and children. High doses of systemic or intralesional steroids are the first-line treatment, and a dramatic response is observed in 30% of patients.
Fost and Esterly first reported the use of systemic steroids in the treatment of hemangiomas. Prednisone at a dose of 20-30 mg/d was given for 2 weeks to 4 months. Both of the patients with capillary hemangiomas had a definite response, and 3 of the 4 patients with mixed hemangiomas had a definite response. Fost proposed that therapy be discontinued if no response occurred after 2 weeks because of the multiple adverse effects of systemic steroids in infants. Edgerton also proposed the use of systemic steroids in the treatment of hemangiomas. He followed 7 patients receiving 20-40 mg/d of prednisone for 30-90 days, with a definite response occurring in all of the patients.
Sasaki et al used a tapering dose of steroids, starting with prednisone 3 mg/kg/d for 3 days, followed by 5 weeks of every other day dosing of prednisone at 1.5 mg/kg/d, and then by 1 week of every other day dosing of prednisone at 0.75 mg/kg/d. A response did not occur in any of the 13 patients with cavernous hemangiomas, and only 60% of the patients with capillary hemangiomas had a definite or probable response. Pope et al demonstrated in a randomized controlled trial that oral corticosteroids offered more clinical and biological benefit than pulse steroids, with a higher risk of adverse effects noted in 20 patients with problematic hemangiomas.
Bartoshesky et al had conflicting results with steroids, showing a definite response in only 2 of 17 patients with mixed hemangiomas. Hawkins et al reported the use of steroids to control hemangiomas of the airway, and 8 of 9 patients showed improvement and avoided tracheotomy. Use of intralesional triamcinolone acetonide (4 mg/mL) led to a 4-fold increase in mast cells; a regression of the hemangioma; and a decrease of the cytokines platelet-derived growth factor-alpha (PDGF-alpha), platelet-derived growth factor beta (PDGF-beta), IL-6, TGF-beta1, and TGF-beta3 in one study. bFGF and VEGF levels were unaltered by steroid therapy. Also, enhanced expression of the mitochondrial cytochrome b (CYTB) gene was noted following steroid therapy.
Of note, frequent monitoring of blood pressure should be performed using the appropriately sized blood pressure cuff during the administration of systemic corticosteroid therapy.
Although the effectiveness of interferon alfa in the treatment of hemangiomas has been documented in many reports, the risk of spastic diplegia generally favors an alternative agent. Blei et al reported the use of interferon alfa-2a in parotid hemangiomas (13 females, 1 male) in which the response was poor. Greinwald et al described a prospective randomized trial of interferon alfa-2a involving 24 patients with massive or life-threatening hemangiomas of the head and the neck. They were given daily subcutaneous injections for 4 months. Of those patients, 58% had a greater than 50% reduction in the size of the tumor and 42% had a complete response. Response rates were greater than those for corticosteroids (58% vs 30%). Another investigation found that interferon alfa-2b was effective in reducing the size of the tumor in more than two thirds of patients.
However, some concern exists regarding the toxicity of interferon alfa, especially in children. The most serious adverse effects include neurologic effects (eg, spastic paresis, seizures, coma), hematologic effects (eg, neutropenia, thrombocytopenia), and hepatic toxicity.
Spastic diplegia generally improves after discontinuation of the drug.
Beta-blockers, most specifically propranolol, have been in use since mid 2008 for infants with severe or disfiguring hemangiomas. Beta-blockers can cause rapid involution of hemangiomas, but may be contraindicated in patients with malformations of the great vessels. Hypotension and bradycardia may occur.[27, 40] Most infants reported have been treated with propranolol at a dose of 2-3 mg/kg/d in 2-3 divided doses. Duration of therapy varies from 2-10 months. As early as 24 hours after the initiation of therapy, many infantile hemangiomas have begun to change from intense red to purple, with evidence of softening. Most continue to improve until nearly flat and with significantly diminished color.
Leaute-Labreze et al conducted a randomized control trial to assess the safety and efficacy of oral propranolol. Of 460 infants who underwent randomization, 456 received treatment. On the basis of an interim analysis of the first 188 patients who completed 24 weeks of trial treatment, the regimen of 3 mg of propranolol per kilogram per day for 6 months was selected for the final efficacy analysis. The frequency of successful treatment was higher with this regimen than with placebo (60% vs 4%, P <.001). A total of 88% of patients who received the selected propranolol regimen showed improvement by week 5, versus 5% of patients who received placebo. A total of 10% of patients in whom treatment with propranolol was successful required systemic retreatment during follow-up. Known adverse events associated with propranolol (hypoglycemia, hypotension, bradycardia, and bronchospasm) occurred infrequently, with no significant difference in frequency between the placebo group and the groups receiving propranolol.
The mechanism of action is unknown; however, some hypothesize that local vasoconstriction may be a factor, which is based on the early color change and softening of the lesion. One study has demonstrated that nonspecific and beta2-selective blockers (eg, propranolol) triggered apoptosis of capillary endothelial cells in adult rat lung tissue, suggesting a similar mechanism may be plausible for hemangioma endothelial cells.
No protocol for initiating propranolol therapy in infants with hemangiomas is universally accepted. Therapy should be approached with extreme caution in neonates and infants who generally do not have preexisting venous hypertension or any other hemodynamic disorder. Of particular note, infants with hemangiomas associated with PHACES syndrome are at higher risk for cerebral vascular accidents secondary to cerebral vascular anomalies, and these infants should not receive beta-blockers.
Ran et al reported six cases of infantile hemangiomas successfully treated with oral itraconazole at approximately 5 mg/kg/day. Since itraconazole has been shown to inhibit angiogenesis and tumor growth in vitro and in vivo associated with some cancers, they propose itraconazole may have a similar effect on infantile hemangiomas.
Exclude infants with evidence of the following:
Baseline laboratory tests and evaluation include the following:
Initially in the hospital, especially if the patient is in a high-risk category (whether in or out of intensive care unit, cardiac care unit, or monitored bed), monitor for 24-72 hours; practices vary considerably.
Monitoring 1 hour after administration (dosing) includes the following:
At home, parents should observe for signs of lethargy, poor feeding, and/or bronchospasm.
Blood pressure and heart rate should be evaluated intermittently at the pediatrician's office.
Surgical or invasive treatment of oral hemangiomas has evolved. Complete surgical excision of these lesions offers the best chance of cure, but, often, because of the extent of these benign lesions, significant sacrifice of tissue is necessary. For example, lesions of the tongue may require near-total glossectomy, which is followed by severe functional impairment to vital functions, such as swallowing, speech, and airway maintenance. As a result, multiple adjunctive procedures have been introduced to eradicate the disease, leaving less of a functional impairment. These adjunctive procedures have also been used to reduce both the blood loss and the morbidity of surgical procedures.
Embolotherapy is one of the more commonly used adjunctive procedures in the treatment of vascular tumors. Embolization literally means the occlusion of a vessel by the introduction of a foreign body. In a broader definition, it also means any other occlusion that is obtained with a proliferating reaction of the vessel wall. As technical expertise with interventional radiology advances, the options for treatment of vascular malformations and hemangiomas become broader. Vessels can be treated not only via superselective catheterization but also through permucosal and percutaneous techniques.
Although embolotherapy has attracted much interest in the last decade and a half, the principle of vascular embolization for head and neck tumors is not new. In 1904, Dawbain, Lussenhop, and Spence described the preoperative injection of melted paraffin-petrolatum into the external carotid arteries of patients with head and neck tumors. In 1930, Brooks introduced particulate embolization when he described the occlusion of a traumatic carotid-cavernous fistula by injecting a fragment of muscle attached to a silver clip into the internal carotid artery. The tremendous upsurge in interest in embolization came with the advent of advances in catheter technology to allow highly selective delivery of agents.
Agents for embolotherapy can be broadly divided into 2 groups: absorbable materials and nonabsorbable materials (see the List below). The nonabsorbable materials can be further subdivided into particulate, liquid, sclerosing, and nonparticulate agents. The Food and Drug Administration (FDA) status of the discussed materials should be investigated prior to their use; many are not FDA approved. A full discussion of the procedure for each use and the associated costs and complications is beyond this review. For a full discussion, individual references on each therapy should be consulted.
Absorbable materials are as follows:
Nonabsorbable materials are as follows:
In the treatment of vasoformative tumors, the resorbable materials are not particularly useful in the long term, except when they precede a surgical treatment and only short-term occlusion is required. They resorb over time, and the occluded vessel recanalizes, restoring flow to the occluded segment. Autologous clots produce a duration of vessel occlusion of only 48 hours, and, by 2 weeks, approximately one half of the vessels are recanalized. Gelfoam occlusion has a duration of 3-4 months, but recanalization usually follows. Gelfoam is occasionally used in combination with coils or other nonabsorbable substances (eg, tissue adhesive) for permanent occlusion.
Nonresorbable materials comprise the mainstay of embolotherapy for vasoformative tumors. Polyvinyl alcohol sponges (Ivalon) are obtained by reticulation of polyvinyl alcohol with formaldehyde. The sponge has the property of being compressible when wet and reexpanding to its original shape and size when a dried piece is placed in an aqueous solution, such as blood. These properties make Ivalon particularly well suited for large vessels, in which it produces a permanent occlusion. Histologically, Ivalon is initially invaded by fibroblasts, with subsequent dense, fibrous connective tissue around the sponge and a moderate inflammatory reaction around the area of thrombus that involves the artery wall. Then, organization of the thrombus occurs, with fibrosis of the arterial wall and disappearance of the inflammatory infiltrate.
Recanalization of the thrombus does not occur, and partial occlusion of the vessel wall by an organized thrombus is commonly found beyond the initial occlusion. Ivalon can be used in combination with stainless steel coils and other devices. Greene et al described 2 cases of embolization of maxillary hemangiomas with Ivalon followed by sclerotherapy with sodium morrhuate. No recurrence was reported at 2-year follow-up examinations in both cases.
Microspheres of stainless or ferromagnetic steel, acrylic, methylmethacrylate, silastic, and silicone are inert and available in a variety of sizes. They are rarely used when treating oral vascular formations.
Isobutyl-2-cyanoacrylate (IBCA) is a rapidly hardening plastic adhesive similar to superglue. The liquid plastic is readily injectable, even through very small catheters, and it polymerizes almost instantly upon contact with ionic fluids, such as blood or vascular endothelium. This polymerization leaves the plastic solid. Abroad, IBCA is the most popular tissue adhesive, but it is not available in the United States. N -butyl-2-cyanoacrylate, an adhesive with similar properties, is available in the United States.
Silicone rubber (Dow-Corning) is a convenient biocompatible material for vascular occlusion. A disadvantage of silicone rubber is that it does not have tissue adhesive properties; thus, the vascular bed must be completely filled to keep the substance in place. No tissue reaction between the elastomer and the vessel wall is apparent either macroscopically or microscopically.
Microfibrillar collagen (Avitene) is a hemostatic agent derived from bovine hide. Its mechanism of action is thought to involve platelet aggregation and activation. Two weeks after embolization, a severe granulomatous arteritis occurs, which subsides by 3 months, with fibrosis replacing inflammation.
Absolute ethanol is used as a sclerosing agent. Its presumed mechanism of action is a direct toxic effect on the vascular endothelium that activates the coagulation system on the dehydrated endothelium. Thus, the vascular occlusion is not achieved instantly but rather in days to weeks. The toxic effect extends to the perivascular tissue, and the use of absolute ethanol has led to perivascular necrosis. Absolute ethanol can be delivered through the tiniest of catheters. It is naturally sterile and is quickly diluted after injection, reducing its toxic effects. It is among the most popular of agents used in oral vascular malformations today; it is delivered permucosally, percutaneously, or through catheters. Ethyl alcohol (95%), which is percutaneously injected into the lesion, is similar to absolute ethanol.
When using absolute ethanol, approximately one third of the volume of the lesion can be injected. Injection of alcohol into oral lesions is followed by marked swelling 6-8 hours later. By using small volumes and carefully avoiding direct deposition into the overlying mucosa, necrosis of the mucosa can usually be avoided. When necrosis does appear, it is usually present by 10 days and heals with local care. Sclerosing solutions produce thrombosis of the vessels and a hard mass. The surrounding soft tissue becomes edematous, and ecchymosis, which increases in severity for 8-12 hours, is frequently present.
Other agents used for sclerosis of oral vascular tumors include sodium morrhuate, sodium tetradecyl sulfate (STS), and hydroxypolyethoxydodecan (an agent that is a double hydrophilic and hydrophobic chain).
Gilbert et al described their experience with 3 patients using intralesional sodium morrhuate for oral hemangiomas. Sodium morrhuate is used as a 5% solution of the sodium salts of cod liver oil. Multiple 0.05-mL injections are given by using a tuberculin syringe circumscribing the lesion, and a final injection is given into the center of the lesion. Aspiration is performed to avoid intervascular injection. Repeat injections are performed at 4- to 7-day intervals. Morgan uses a similar scheme over a 12-year period with 5% sodium morrhuate, giving multiple 0.05-mL circumlesional injections and a final 0.5-mL injection into the center of the lesion. Repeat injections are given at 4-day intervals. Chin used 5% sodium morrhuate in a maxillary hemangioma in an adult. The lesion shrank, and a repeat injection was given 3 weeks later. Five years later, no evidence of the lesion was present.
STS (Sotradecol) is another commonly used sclerosant for oral vascular tumors. STS causes intimal inflammation, thrombus formation, and often permanent obliteration of the veins. In animal studies, STS produces long-term arterial thrombosis in large arteries and marked inflammatory reactions in small vessels, with eventual replacement by connective tissue. In an early report on the use of STS in oral hemangiomas, Baurmash and Mandel used 1% STS. Later reports and more recent reports use a 3% solution.[50, 51, 52, 25, 48]
Minkow et al used a technique of intralesionally injecting 0.1-0.5 mL of 3% STS into oral hemangiomas. Repeat injections were performed at 2-week intervals. He reported on 24 patients, ranging in age from 11-79 years and involving 15 females and 9 males. Satisfactory results were reported in all patients, with minimal adverse effects and disappearance of the lesions without scarring. O'Donovan et al recommended 3% STS, using 0.5-2 mL volumes of sclerosants and manual compression of the lesions to ensure stasis.
Kane et al recommended 3% STS used alone for oral hemangiomas but in combination with surgery for vascular malformations. Sclerotherapy was used as an adjunct, in which high-flow vascular malformations were first embolized with Ivalon sponges, Avitene, or Gelfoam. All sclerotherapy in vascular malformations was followed by surgery. Of the hemangiomas, 31% were treated by sclerotherapy alone.
Seccia and Salgarello treated 18 patients over an 8-year period with hydroxypolyethoxydodecan. It acts as a detergent, attacking the lipids of the cell membrane. Multiple 0.5-mL injections were given. He reported that 90% of the oral lesions were controlled with sclerotherapy alone.
With many of the sclerosants, some precautions need to be heeded. Allergic reactions to sodium morrhuate, tetradecyl sulfate, and oleate have been reported. Fatty acid and detergent sclerosants produce hemolysis, resulting in hemoglobinuria. Sodium morrhuate was recommended to be limited to 90 mL.
Use of laser therapy for the treatment of hemangiomas has gained popularity. Lasers have evolved to where more selective photothermolysis can be attained rather than nonselective tissue destruction.
The yellow light lasers (578-585 nm) are selectively absorbed by hemoglobin. The only other competing chromophore with these lasers is melanin. Oral mucosa may be amenable to these lasers because little melanin is present in the mucosa. Little to no damage to the mucosa or the epithelium has been reported. In the macular stage of development, a 585-nm pulsed dye laser has been used to treat a capillary hemangioma. The tunable dye laser can ablate superficial ecstatic blood vessels without significant epidermal damage or scarring. However, the 585-nm pulsed dye laser has limited penetration (1-2 mm). Waner described the use of pulsed dye lasers in the yellow light range on 11 cases of hemangioma, with 3 of them being in the oral cavity, with a successful outcome. Unfortunately, because of the minimal depth of penetration, in all but the thinnest lesions in the oral cavity, the usefulness of this laser is limited.
Apfelberg reported using a neodymium:yttrium-aluminum-garnet (Nd:YAG) laser to treat massive hemangiomas and vascular malformations in the head and the neck via intralesional laser photocoagulation. A 600-µm bare fiber with 1-2 mm of the protective cladding removed was inserted several centimeters into the lesion. The laser is theorized to institute an initial thrombogenesis in many areas of the hemangioma or the vascular malformation, and this event initiates involution by normal body processes. The Nd:YAG laser emits beams in the near infrared region of the spectrum (1064 nm). This laser has deep penetration (1 cm) and an excellent hemostatic capability that makes it more suitable for thicker, larger, more developed hemangiomas.
Dixon believed that the Nd:YAG laser was the instrument of choice for debulking vascular malformations of the tongue. This laser has less selectivity for any particular chromophore, and use on nonmucosal surfaces is reported to result in more scarring. Suen and Waner reported satisfactory results with the use of the Nd:YAG laser for oral vascular malformations in 6 patients; however, 4 of the 6 patients required repeat treatments after the initial therapy.
Argon lasers emit beams in the blue-green part of the spectrum (488-514 nm), and the wavelengths are well absorbed by melanin and hemoglobin. Its depth of penetration is limited (about 1 mm). Reportedly, because of the strong absorption of the argon laser by melanin, a large proportion of patients have experienced scarring when it is used on the skin. For laser photocoagulation of vascular malformations of the tongue, Dixon et al believed that the argon laser was the instrument of choice for superficial bleeding.
The carbon dioxide laser emits light in the far infrared region, with a wavelength of 10,600 nm. This light is primarily absorbed by water molecules. Apfelberg reported minimal-to-acceptable scarring in 17 of 21 patients with oral hemangiomas; 4 of the patients had fair results (poor scarring or minimal improvement in hemangioma deformity).
Cryosurgery for cutaneous lesions has been associated with scarring, but it may have a role in the treatment of oral mucosal lesions. Several authors have used cryosurgery for treating oral vascular tumors,[58, 59, 60, 61] although this technique has fallen into disfavor in recent years. Hartmann reported minimal scar contracture, good hemostasis, and little discomfort with the use of cryosurgery to remove a large oral hemangioma.
Complete surgical excision is a mainstay of treatment of vascular malformations if they are small and amenable to such therapy. However, for oral vascular tumors confined to the soft tissues, a combination of surgical therapies is often needed.
For central hemangiomas of the jaws, surgery is believed to offer the best chance of cure. Yih reported on 15 cases, where ligation of feeder vessels (and sometimes ipsilateral external carotid ligation) and resection or curettage were performed with no recurrences. Ligation alone of a single feeder vessel has been associated with recurrence of even larger arteriovenous malformations.
Surgery of intrabony lesions of the jaws is usually completed in combination with other procedures (eg, embolization, sclerotherapy) to reduce blood loss, but sclerotherapy alone for these lesions has been reported.[12, 62] No consensus exists on the best time interval between the embolization and the surgical treatment when embolization or sclerotherapy is used before surgery. Some clinicians advocate immediate surgery, while others suggest a delay of several days to a week. The decision on the timing needs to be individualized, depending on the goal of the embolotherapy. As the time between surgery and embolization progresses beyond 2-3 weeks, the embolization may prove to be of little development because of the development of collateral supply and recanalization of the vessels.
Treatment of these complex lesions often requires consultations with multiple specialties. In addition to surgeons, diagnostic and interventional radiologists, dermatologists, pediatricians, and internists are useful in treating these patients.
No medications, other than those used for initial treatment, are needed. For patients with an asymptomatic oral vascular malformation that is stable, nonprogressive, and that has no functional impairment or bleeding, observation is indicated. Painful perioral hemangiomas may manifest as difficult feeding and failure to thrive. Topical lidocaine-containing preparations, acetaminophen, and codeine have all been used for pain control. Smidt and Strand reported a painful hemangioma controlled with over-the-counter Orabase. Orabase contains 20% benzocaine, and possible adverse effects include allergic contact dermatitis and methemoglobinemia.
Clinical Context: Prednisone is an immunosuppressant for the treatment of autoimmune disorders; it may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. Prednisone stabilizes lysosomal membranes and suppresses lymphocyte and antibody production.
Steroids have become a mainstay in the treatment of proliferating hemangiomas in infants and children. These agents have anti-inflammatory properties and cause profound and varied metabolic effects. They modify the body's immune response to diverse stimuli.
Clinical Context: Interferon alfa-2b is a protein product manufactured by recombinant DNA technology. Its mechanism of antitumor activity is not clearly understood; however, direct antiproliferative effects against malignant cells and modulation of host immune response may play important roles.
These agents are naturally produced proteins with antiviral, antitumor, and immunomodulatory actions. Alpha, beta, and gamma interferons may be given topically, systemically, and intralesionally.
Clinical Context: Propranolol hydrochloride is a synthetic nonselective beta-adrenergic receptor blocking agent. A generic form is available as 10-, 20-, 40-, 60-, and 80-mg tablets and as 60-, 80-, 120-, and 180-mg extended-release tablets. Inderal is available as 10-, 20-, 40-, 60-, and 80-mg tablets for oral administration. InnoPran XL is available as 80- and 120-mg extended-release tablets. No commercially available liquid formulation is available for use in children and must be formulated by a qualified pharmacist. It is indicated for hypertension and a variety of other cardiac conditions (angina) and migraine headache prophylaxis.
Clinical Context: Benzocaine is a PABA derivative ester-type local anesthetic that is minimally absorbed. It inhibits neuronal membrane depolarization, blocking nerve impulses. It is used to control pain.
Many patients who undergo treatment of oral hemangiomas often require multiple follow-up therapies. The additional treatments may include further treatments of the same type as the initial treatment or combinations of other modalities.
Complications of oral vasoformative tumors can be divided into 2 general types: complications related to the disease process and complications from treatment.
Complications from the disease process include hemorrhage, high-output states, infection, function problems (eg, airway, vision, hearing), thrombocytopenia, and ulceration. Ulceration is the most common complication of capillary hemangiomas and typically occurs centrally in large lesions. It may result in scarring and does not hasten resolution of the lesion. Ulceration may become secondarily infected and is readily treated with local wound care. Bleeding is one of the most common reasons that patients with oral hemangiomas and vascular malformations seek care.
Complications from treatment of hemangiomas are many, and, because of this, many lesions are left untreated. Treatment of the nonproliferating lesion with minimal functional impairment becomes a risk-to-benefit decision. With all treatments, a common complication is persistence or recurrence of disease.
With the 2 medical treatments, steroids and interferons, the complications are the well-known adverse effects of the drugs. No special complications are related to the treatment of vasoformative tumors, other than nonresponse to treatment.
With embolotherapy, complications can range from minor to life threatening. Complications are often related to specific kinds of embolizing devices and techniques. For embolization in general, the commonly reported complications include the risks of superselective catheterization, which include pain, infections, fever, organ infarction, and abscesses related to the introduction of external agents; exclusion of a vital segment of the blood supply; release of pyrogenic materials into the circulation; migration of emboli into other parts of the body; and general effects of drugs, such as thrombin and ethanol. Complication rates for ethanol embolization are 7.5-23%, including nerve palsies and at least 2 reported fatalities. When used permucosally for the treatment of oral hemangiomas, the only reported complication was a mucosal slough that spontaneously healed.
O'Donovan et al reported that 3 of 21 patients had minor skin ulceration following sclerosis with STS. Others have reported no complications with the use of STS injected intralesionally.[50, 51, 52]
Complications related to sclerotherapy include the following: skin necrosis (4%), temporary myoglobinuria (2%), and airway compromise (1%).
As lesions become larger and, more importantly, as the flow in the lesions becomes greater, the complications increase.
Kane et al categorized the complications from ablative surgery following embolotherapy or sclerotherapy for hemangiomas and vascular malformations into immediate and late complications (see Table 2 below).
Table 2. Complications From Ablative Surgery Following Embolotherapy or Sclerotherapy for Hemangiomas and Vascular Malformations
The morbidity of oral hemangiomas ranges from surface discoloration to life-threatening functional compromise of the airway or hemorrhage. Fatal spontaneous hemorrhage from jaw hemangiomas has been documented in 25 cases. Significant morbidity can also occur from many of the treatments of hemangiomas, and biopsy of these lesions is also fraught with danger.
Vasoformative Tumor New Nomenclature Old Nomenclature Hemangiomas Capillary hemangioma Strawberry hemangioma Juvenile hemangioma Cavernous hemangioma Mixed hemangioma Parotid hemangioma Vascular malformations Venous malformation Cavernous hemangioma Hemangiomatosis Intramuscular venous malformation Intramuscular hemangioma Capillary malformation Capillary hemangioma Port-wine stain Arteriovenous malformation Arteriovenous hemangioma
Lymphatic malformation Capillary lymphangioma
Complications Hemangiomas, % Vascular Malformations, % Immediate Complications Hemorrhage 27 60 Airway compromise 2 10 Hematoma 14 14-30 Skin necrosis 12 10-30 Coagulopathy 7 14-20 Late Complications Restricted oral opening 8 27-40 Malocclusion 8 20-40 Drooling 23 40-47 Dysphagia 23 20-27