Oral Hemangiomas

Etiology

The cause of OHs is poorly understood, although genetic mutations, embolic phenomenon, and hormones may play a prominent role in development. One hypothesis suggests that OHs are due to embolic placental endothelial cells, which enter the fetal circulation following trauma or some other cellular stressor and serve as stem cells. This explanation is consistent with studies that demonstrate that chorionic villus sampling increases the risk of hemangiomas. Another theory is that spontaneous, or inherited, loss-of-function mutations on chromosome 5q lead to the constitutive activation of angiogenesis, resulting in hemangioma formation. A third hypothesis is that hemangiomas develop due to the upregulation of vascular endothelial growth factor (VEGF) and glucose transporter 1 (GLUT1) production by nearby cells in response to hypoxic stressors. However, none of these hypotheses address the female predominance of hemangiomas or the predilection of these vascular tumors for the head and neck.[4]

Epidemiology

Oral hemangiomas affect up to 6.4% of infants, with limited data available to estimate prevalence in older age groups. These tumors are more common on the ventral surface of the tongue, as opposed to oral vascular malformations, which are more prevalent on the lips. OHs have a 3:1 female-to-male predominance and are more common in Whites. Infants who are premature, twins or triplets, have low birth weight (less than 1 kilogram), or who are born to older mothers are more likely to develop OHs.[5]

Pathophysiology

Hemangiomas are speculated to develop through a combination of angiogenesis (the growth of new vessels from established vessels) and vasculogenesis (the novel formation of vessels from stem, or progenitor, cells). Three characteristic stages of growth have been noted: (1) endothelial cell proliferation, (2) rapid growth, and (3) spontaneous involution. Growth begins after progenitor cells, possibly originating from the placenta, move through the circulation and implant on distant regions of the body.

During the proliferative phase, endothelial cells rapidly multiply, stimulated by factors such as VEGF, basic fibroblast growth factor (bFGF), and transforming growth factor-beta (TGF-beta). Estradiol-17 beta-receptors are also uniquely present in the cytoplasm of endothelial cells during this first phase, although their role in proliferation is not completely understood. During the rapid growth phase, the number of endothelial cells stabilizes, and the cells themselves will enlarge, leading to an overall increase in structure size.

Lastly, spontaneous involution occurs when the vessels decline in number, and endothelial cells are replaced by fat, fibroblasts, and connective tissue. The inciting event for involution is unclear but may involve the Notch pathway, which includes transmembrane Notch receptors and its ligands (delta and jagged).[6][7]

Histopathology

During the proliferative phase of OH development, the vessels are small, disorganized, and contain tiny lumens, which can be difficult to visualize on microscopic examination. In contrast, the endothelial cells are wide and contain prominent basement membranes composed of alpha-smooth muscle actin.

In the rapid growth stage, the endothelial cells enlarge, their basement membranes become less prominent, and the number of cells stabilizes. As the vessels mature and enter the spontaneous involution phase, the endothelial cells lose their contents and become flattened, with certain cells undergoing apoptosis to be replaced by fat, fibroblasts, and connective tissue.

While endothelial cells during any phase of OH growth will demonstrate CD31, von Willebrand factor, and urokinase, cells during the involution phase uniquely demonstrate Fc gamma receptors (FcII), Lewis Y antigen (LeY), and merosin. Immunohistochemistry can be used to distinguish not only the growth phase but the type of lesion, as infantile hemangiomas will exhibit positivity for glucose transporter 1 (GLUT-1), which is not present in congenital hemangiomas or vascular malformations.[8][9]

History and Physical

While hemangiomas of the head and neck are relatively common, the presence of these lesions in the oral cavity is rare and can thus lead to clinical uncertainty. OHs will most often involve the lips, tongue, buccal mucosa, and palate. Patients, or their parents, may note changes in these structures over time as they proliferate, stabilize, and (possibly) regress. During the first three to nine months of life, OHs can demonstrate rapid growth, followed by a period of stabilization at about one year-of-age. Most OHs will then enter into a phase of spontaneous involution, with 85% to 90% of lesions resolving within the next four years.

Hemangiomas of the lower lip have been noted to show lower rates of involution than lesions located elsewhere. Also, if patients have more than one OH, the behavior of one structure is not predictive of the rates of progression or involution of another. Most OHs are painless and asymptomatic and are diagnosed on routine physical examination. However, patients with central (intraosseous) or intramuscular hemangiomas may present with gingival bleeding (spontaneous or post-traumatic), excessive bleeding after dental procedures, or increased mobility of the teeth.

OHs are soft, compressible masses that can present with significant variation depending on location and depth. Superficial lesions may demonstrate a prominent red hue and be described as lobulated, sessile, or pedunculated. Deeper lesions are often more difficult to visualize and may appear as a soft blue or violent discoloration distinct from surrounding mucosa. Diascopy, the blanching of an oral lesion following compression with a finger or glass slide, is a physical examination maneuver that can be used to distinguish vascular lesions (blanching) from purpura (non-blanching). OHs are also noted to become more prominent and darken when lowering the head and/or compressing the abdomen.[10][11]

Evaluation

Hemangiomas within the oral mucosa can be diagnosed clinically, without the need for lab work or additional imaging. If treatment is desired, a color-doppler ultrasound is often the first-line imaging modality as it can readily provide morphological and vascular information while being cost-effective, non-invasive, and without the risk of radiation. If an intraosseous or intramuscular hemangioma is suspected, a contrast-enhanced MRI would be the imaging modality of choice and is considered superior to CT scan. Generally, a biopsy of OHs is avoided due to a high risk of bleeding. However, a biopsy would be recommended if a malignant process is suspected.[12]

Treatment / Management

Most oral hemangiomas will not require treatment due to their benign presentation and a high rate of complete involution over time. However, for OHs that present with impairment in speech, swallowing, or airway compromise, and for the 10% to 20% of lesions that persist into adolescence or adulthood, treatment is recommended. Current treatment options are divided into two categories: medical and surgical (or interventional).

Beta-blockers, such as propranolol, are the mainstay of medical treatment for OHs. The mechanism is unclear but has been suggested to include local vasoconstriction and triggering of apoptosis in endothelial cells. Patients are typically initiated on a regimen of propranolol 2-3 milligrams per kilogram per day divided into three doses, with improvement in OH appearance noted within 1-2 days after therapy begins. Throughout the duration of beta-blocker therapy, which may be up to 6 months, patients should be monitored for side effects, including bradycardia, hypotension, hypoglycemia, and bronchospasm.

Oral steroids are another option in the treatment of OHs but are not preferred to beta-blockers due to their unfavorable side effect profile. Prednisone has been most frequently studied for OH treatment and can be continued for up to four months. Varying dosing regimens are mentioned in the literature, with 2 milligrams per kilogram per day used in some studies and 20 to 30 milligrams per day used in others. It is generally agreed that if no change in the OH is noted within 2 weeks, prednisone therapy should be discontinued.

Patients, especially children, should be monitored while on steroid therapy for the development of hypertension, persistent hyperglycemia, changes in mood, and growth retardation. For patients with OHs resistant to beta-blockers and steroids, interferon-alpha has been studied with some success but is generally not preferred due to the risk of spastic diplegia, neutropenia, thrombocytopenia, and hepatic toxicity. For patients who do not respond to medical therapy, or present with compromise in function, interventional or surgical options can be offered.

Surgical resection offers definitive treatment for OH and may be preferred for smaller lesions located on the lips and buccal mucosa. Resection would not be preferred for large lesions on the tongue as significant removal of tissue can result in chronic impairment of speech and swallowing. Sclerotherapy, in which a foreign agent (such as 3% sodium tetradecyl sulfate or ethanolamine oleate) is injected into one of the major vessels of an OH, leading to endothelial damage and obliteration of the lumen, is an evolving treatment modality for these lesions. Thus far, studies have demonstrated favorable results with minor adverse reactions following sclerotherapy treatment, but the risk of thrombosis with embolization does remain.[13][14][15][16](A1)

Differential Diagnosis

When diagnosing oral hemangiomas, the following conditions should also be considered:

• Vascular malformation
• Vascular ectasia
• Pyogenic granuloma
• Granular cell myoblastoma
• Angiomyolipoma
• Angiosarcoma
• Hemangiosarcoma
• Kaposi’s sarcoma
• Lymphangioma

Prognosis

Oral hemangiomas have an overall favorable prognosis, as these lesions are benign, and only a minority (10% to 20%) will require treatment. Intraosseous, especially mandibular, hemangiomas are associated with higher morbidity due to increased risk of spontaneous and post-procedural hemorrhage.

Complications

Complications associated with OHs depend on the size and location of the lesion and may include:

• Ulceration (the most common complication)
• Hemorrhage
• Dysphagia and failure to thrive
• Speech impairment
• Airway compromise