Typical Orbital Pathologies: Hemangioma

Abstract

Orbital hemangiomas are the most common primary neoplasm of the orbit and manifest as two distinct pathologic entities: infantile hemangiomas and cavernous hemangiomas. In this article, both infantile and cavernous hemangiomas are reviewed, with special attention paid to the natural history, clinical presentation, and management teams and approaches involved. An example case of each type of hemangioma is presented along with pearls and tips a reader can take away after reading this article.

Introduction

The orbit is a complex anatomical space that houses the eye. It is located lateral and superior to the paranasal sinuses and inferior to the anterior cranial fossa. The differential diagnosis for primary pathology of the orbit is broad due to the wide array of anatomical structures contained within this space. Different categories of potential tumors include vasculogenic neoplasms, neurogenic tumors, osseous and fibro-osseous neoplasms, lymphocytic lesions, and mesenchymal tumors.

Orbital hemangiomas are the most common primary lesions of the orbit. Two distinct pathologic entities fall under the category of hemangiomas of the orbit. The first is infantile hemangioma, which is a true benign vascular neoplasm that presents in the newborn population, is self-limiting, and is predominantly treated with medical management. The second is cavernous hemangioma, which may be more accurately called a cavernous malformation. It typically presents in the second to sixth decade of life and is predominantly a surgical disease in patients for whom the lesion is causing symptoms. When considering these etiologies, imaging is critical to narrow down the differential diagnosis. ¹ Signs and symptoms of these tumors and tumorlike lesions stem from effects that it has on form and function of the eye. Both entities will be reviewed herein with special attention paid to pathogenesis, clinical presentation, typical imaging findings, and treatment including goals, indications, and specialties involved.

Capillary/Infantile Hemangiomas

Infantile hemangiomas, also called capillary hemangiomas, are congenital lesions that are the most common childhood tumor. Roughly 7% of infantile hemangiomas involve the orbit or eyelids. ² In the orbit, they are the most common benign pediatric tumor. ³

Tumor Pathology

On histologic examination, an infantile hemangioma will have an architecture of capillaries ⁴ varying between areas of ectatic vascular channels and other areas with more compact proliferation. ⁴ On immunohistochemistry, the vessel walls will stain positively for traditional markers of vessel endothelium (CD31 and CD34) and negatively for a marker for lymphatic endothelial marker (D2–40). ⁴ In contrast to cavernous hemangioma, GLUT-1 and K _i -67 immunostaining is strongly positive.

Clinical Presentation

Infantile hemangiomas will typically present before 1 year of age and undergo an initial proliferative phase where the lesion will grow rapidly. Then between 1 and 5 years of age, the involutional phase will occur with most patients experiencing an uncomplicated and self-limited course.

Superficial infantile hemangiomas can be immediately identified as reddish, elevated skin lesions. By contrast, deeper infantile hemangiomas may be blush or violaceous. The most common location in the orbit is the upper eyelid or the superior orbit. Though infantile hemangiomas are benign, they can potentially cause significant morbidity. Residual scarring from involuted lesions may affect cosmesis. In retro-orbital hemangiomas, there may be anterior displacement of the globe, proptosis, and associated sequelae including exposure keratopathy or astigmatic amblyopia. ⁵ If there is mass effect on the optic nerve within the orbital apex, a patient may experience compressive optic neuropathy. Up to 60% of patients with hemangiomas of the eyelid may develop amblyopia. Strabismic amblyopia may occur with involvement of extraocular muscles, whereas deprivation amblyopia may develop secondary to a ptotic involved eyelid. ⁶

In a patient who presents with a large infantile hemangioma, or hemangiomas of multiple locations, the medical team may consider workup for PHACE syndrome. This syndrome includes posterior fossa malformations, facial hemangiomas, arterial lesions, cardiac anomalies, and eye abnormalities.

Imaging

Further evaluation of infantile hemangiomas occurs through diagnostic imaging and is undertaken with ultrasound and/or magnetic resonance imaging (MRI). These studies further characterize the extent of disease, involvement or proximity to critical neurovascular structures, and aid in treatment planning. Computed tomography (CT) is not recommended in this age group and should be avoided because of the risks of radiation exposure including the risk of malignancy. On MRI, the hemangiomas will have heterogenous intensity on T1- and T2-weighted imaging. These lesions will be contrast enhancing, and may appear in multiple anatomical spaces including the lids and orbits.

Treatment

Treatment of orbital infantile hemangiomas depends on if the mass is symptomatic and potentially threatening vision. In an asymptomatic patient, the lesion can be observed as it is expected to be self-limiting over the first few years of life. Indications for treatment include proptosis causing exposure keratopathy, optic neuropathy, and lesion-induced amblyopia. ⁷ Medical management is the first-line therapy and is highly individualized, whereas surgical treatment is indicated only if the lesion is refractory to medical therapy. ⁸ Pediatrics, pediatric ophthalmology, and in some surgical cases otolaryngology and/or neurosurgery are involved in the treatment of these patients.

Propranolol is the first-line medical treatment for infantile hemangiomas. Léauté-Labrèze et al first reported the use of propranolol in 11 patients with infantile hemangiomas in 2008. ⁹ Although the mechanism of action as a nonselective adrenergic β-blocker is understood, the therapeutic mechanism in hemangioma involution is still unknown. It is likely that the mechanism may involve peripheral vasoconstriction as a relatively quick reduction in lesion color, and fullness is often observed within 24 to 72 hours of treatment initiation. However, it is not known how vasoconstriction leads to sustained regression of the lesion. ² The risks of treatment with propranolol include hypoglycemia, bradycardia, hypotension, or bronchospasm. Thus, treatment must be monitored by a pediatrician sometimes in coordinated care with a pediatric cardiologist and includes anticipatory pretherapy evaluation, as well as monitoring of blood glucose and vital signs throughout treatment. ^{5 8}

Topical treatment with timolol gel can be used if there is a superficial orbital or eyelid component of the lesion. Indications include an eyelid hemangioma causing significant cosmetic deformity or potentially causing deprivation amblyopia secondary to lid ptosis. ¹⁰ Guo and Ni first reported the use of timolol to treat periocular infantile hemangiomas. ¹¹ A follow-up study by their group reports a group of seven patients who experienced a 55 to 95% reduction in hemangioma size with timolol treatment. ¹² Using topically applied β-blocker in this manner avoids the morbidity and health care utilization in monitoring for the systemic side effects of oral propranolol.

Other medical therapies that have been used for treatment of infantile hemangiomas include oral and injectable steroids. However, injectable steroids have not found wide use in this anatomical location due to close proximity to and risk of injury to the extraocular muscles and optic nerve. Cyclophosphamide, vincristine, and interferon α have all been described but have fallen out of favor due to less predictable effects and risks of significant systemic effects including neurotoxicity.

Surgery is indicated in patients who do not respond to medical therapy but continue to experience a threat to vision. ¹⁰ Orbital decompression or removal of the lesion could be considered. Delayed surgical therapy after involution of the majority of the lesion can also be undertaken to remove residual fibrofatty tissue and improve cosmesis. Pulsed-dye laser, Nd:YAG (neodymium:yttrium aluminum garnet) laser, and irradiation have all been described but are rarely used as propranolol has become more efficacious.

Case Example

A female infant born at 28 weeks was noted to have increasing right periorbital edema and proptosis starting at day of life (DOL) 40, corrected gestational age 34 3/7 weeks. No superficial skin changes were noted. Ophthalmologic examination showed bilateral iris and peripheral retinochoroidal colobomas. Orbital ultrasound was unrevealing. MRI at DOL 50 showed a right intraconal mass measuring ∼15 × 12 × 13 mm with intermediate T1 signal intensity ( Fig. 1a ), T2 hyperintensity ( Fig. 1b ), and avid enhancement ( Fig. 1c ). Subtle curvilinear zones of low intensity within the mass may suggest internal flow voids. Propranolol 0.4 mg three times a day (0.66 mg/kg/d divided three times a day) was started on DOL 51 and was increased to 2 mg/kg/d divided three times a day on day of life 53. Repeat MRI on DOL 74 showed partial interval involution of the suspected right orbital capillary hemangioma consistent with response to medical therapy ( Fig. 1d–f ). She was continued on this therapy for 11 months without rebound in the size of the hemangioma and, therefore, therapy was discontinued. She is now 3 years out from treatment without recurrent symptoms.

Fig. 1.

Right intraconal orbital infantile hemangioma. Pretreatment axial magnetic resonance imaging (MRI) showing ( a ) intermediate T1 signal intensity, ( b ) T2 hyperintensity, and ( c ) avid enhancement. Posttreatment MRI showing partial interval involution consistent with response to medical therapy on ( d ) axial T1-weighted, ( e ) axial T2-weighted fluid-attenuated inversion recovery (FLAIR), and ( f ) sagittal T1-weighed MRI.

Cavernous Hemangioma (Cavernous Venous Malformation)

Cavernous hemangiomas, also called orbital cavernous venous malformations, are the most common benign primary orbital lesion in adults. ^{13 14} Although historically classified as hemangiomas, the classification scheme of the International Society for the Study of Vascular Anomalies ¹⁵ and a consensus statement by Harris et al ¹⁶ argue that cavernous hemangiomas should be classified among low-flow nondistensible venous malformations.

Orbital cavernous hemangiomas present between 20 and 60 years of age and are more common in women. Jayaram et al ¹⁷ has postulated a role of menopause, showing that in patients who were postmenopausal and were presumed to have decreasing levels of estrogen and progesterone, lesions decreased in size or remained stable. Regarding tumor laterality, a retrospective study of 104 patients with orbital cavernous hemangiomas shows slight left-sided predominance (53.8%) ¹⁸ with rare bilateral involvement. Orbital cavernous hemangiomas are predominantly intraconal. ^{19 20} Finally, these lesions may be associated with blue rubber bleb nevus syndrome, ²¹ a rare cutaneovisceral hemangiomatosis or Maffucci's syndrome, which is associated with multiple cavernous hemangiomas.

Tumor Pathology

Histologically, orbital cavernous hemangiomas consist of numerous large vascular spaces lined by endothelial cells and stroma, separated by fibrous septa ¹⁴ and enclosed in a fibrous pseudocapsule. ⁴ They are without a prominent arterial supply. The characteristic slow vascular flow and stasis of these lesions give rise to the presence of intralesional thrombosis in many of the lumens. The most widely held view of proliferation of these lesions proposes that these variable regions of thrombosis trigger neovascular activity and hemangioma proliferation.

Clinical Presentation

Clinically, orbital cavernous hemangiomas present as months to years of slowly progressing proptosis. Patients do not typically experience pain. The lesion is identified when it reaches a large enough size to cause functional symptoms such as optic neuropathy, diplopia, or a cosmetic change usually in the form of proptosis. Alternatively, the lesion may be discovered incidentally when the orbits are being imaged for some other purpose.

A complete evaluation of the patient will involve a comprehensive ophthalmologic examination including assessment of visual fields, visual acuity, and color vision using the Ishihara plates. Proptosis is the most common sign of cavernous hemangioma and exophthalmometry can be used to evaluate the degree of proptosis. At presentation, patients generally have ∼5 mm of proptosis. After proptosis, visual disturbance is the next most common finding, present in some degree in roughly 50% of patients. Patients with optic neuropathy may show optic disc papilledema with desaturation to red color, blurring of optic disc margins, and dilation of optic head veins. Late findings include optic atrophy secondary to mass effect. The eyes should also be examined for signs of exposure keratopathy.

Imaging

Imaging ^{22 23} plays an important role in the characterization and diagnosis of cavernous orbital hemangiomas. A well-circumscribed rounded or oval lesion will be seen on both CT and MRI. Because of the small size of the lesions and adjacent neurovascular structures being studied, both CT and MRI should be obtained with thin slice thickness, typically 0.5 to 1 mm for CT and <3 mm for MRI. In a soft-tissue format on CT, the lesion will show a homogenous well-circumscribed soft-tissue density mass. ¹⁴ Adjacent bony remodeling may be seen and contrast enhancement ranges from heterogenous to diffuse depending on the phase of imaging. ¹⁴ They occasionally contain microcalcifications. On MRI, T1-weighted imaging will show a lesion isointense to muscle and gray matter, and hypointense to fat, whereas T2-weighted imaging will show a lesion hyperintense to fat and brain. ¹⁴ A low-intensity pseudocapsule and septations in some cases can also be seen. Like CT, contrast enhancement in MRI depends on the phase and is typically progressive with the lesion being more patchy and heterogeneously enhancing early on and diffusely enhancing later. This is accomplished by multiphase dynamic contrast MRI and confirms the diagnosis of orbital cavernous hemangioma over related vascular lesions. High-flow vascular lesions such as arteriovenous malformations and aneurysms can be differentiated from cavernous hemangiomas on imaging by the presence of tortuous flow voids indicating feeding arteries or draining veins. Other vascular tumors including infantile hemangiomas, hemangiopericytomas, and hemangioendotheliomas are less well defined and more irregular than cavernous hemangiomas.

Typical Locations and Staging CHEER Staging

The location of a cavernous hemangioma within the orbit is variable but is typically intraconal in about two-thirds of patients as reported by Bleier et al (61%), ²⁰ Yan and Wu (75%), ¹⁹ and McNab et al (86.5%). ¹⁸ Bleier et al ²⁰ report that the remainder of orbital hemangiomas are in the optic canal in 22% of patients and are extraconal in 13% of patients. McNab et al ¹⁸ report that in their 104 patients, 71.2% of hemangiomas were in the middle third of the orbit, whereas 15.4 and 13.5% were located in the anterior and posterior thirds of the orbit, respectively.

El Rassi et al ²⁴ developed the Cavernous Hemangioma Exclusively Endonasal Resection (CHEER) staging system to better reference the location and stage of orbital hemangiomas that may lend itself to endonasal endoscopic surgical resection ( Table 1 ). This staging system defines seven different anatomical locations or stages for orbital hemangiomas based on whether the lesion is intraconal or extraconal as well as its relationship to the muscular trunk of the ophthalmic artery and the vertical relationship with the medial rectus muscle. This study found that as the stage of the lesions increased, survey respondents increasingly preferred a binarial and two-surgeon approach over a uninarial and one-surgeon approach.

Table 1. CHEER staging of orbital hemangiomas.

Stage	Extraconal/intraconal	Description
I	Extraconal	Orbital cavernous hemangioma
II	Intraconal	Anterior to the inferomedial muscular trunk of the ophthalmic artery and inferior to the horizontal axis of the medial rectus
III	Intraconal	Anterior to the inferomedial muscular trunk of the ophthalmic artery and superior to the horizontal axis of the medial rectus
IVA	Intraconal	Posterior to the inferomedial muscular trunk of the ophthalmic artery without extension into the optic canal
IVB	Intraconal	Isolated within the optic canal or posterior to the inferomedial muscular trunk of the ophthalmic artery with extension into the optic canal
VA	Extraconal/intraconal	Pterygopalatine and/or infratemporal fossa extension through the inferior orbital fissure
VB	Extraconal/intraconal	Intracranial extension through the superior orbital fissure

Treatment

The mainstay options for management of orbital cavernous hemangiomas include observation and surgery. In rare and unique circumstances, other modalities of treatment including stereotactic radiosurgery, sclerotherapy, or intralesional treatment with pingyangmycin ¹⁵ can be considered.

Treatment indications and goals depend on the treatment modality in question. For surgical therapy, treatment is indicated in cases of lesions causing problematic symptoms including compression of the optic nerve, extraocular gaze restriction, and disfiguring cosmesis. In these cases, the goals of surgery are to improve vision, diplopia, and cosmesis, respectively. In the absence of these symptoms, the patient and treatment team can consider a period of observation as progression is typically slow and acute bleeding and expansion is a rare complication. Surgical excision is also considered when growth is identified on interval imaging. Stereotactic radiosurgery may be indicated to improve visual function and control lesion size in patients who are poor operative candidates for anesthesia or whose lesions involve critical neurovascular structures and are thus poor candidates for gross total resection.

The choice of surgical treatment approach depends on the location of the lesion within the orbit and its relationship to critical neurovascular structures. ²⁵ In general, the principle of not crossing critical structures is observed in choosing which approach to utilize. Surgical approaches can be open and endoscopic and include anterior orbitotomy, lateral and transcranial orbitotomy, and an endoscopic transnasal approach. ^{20 26 27}

Rootman et al report five cases of the use of stereotactic radiosurgery ²⁸ for management. This is a treatment modality not typically utilized, as there appears to be anterior visual pathway sensitivity to larger single doses of radiation. ²⁹ However, in the five patients in their study, the authors determined that the location of the tumor and involvement of local structures placed the patient at such significant surgical risk that they utilized stereotactic radiosurgery. These five patients treated with 40 to 50 Gy and the authors found that they were able to improve visual function and control lesion size.

In summary, the management of patients with orbital cavernous hemangiomas involves a multidisciplinary collaboration between ophthalmology, otorhinolaryngology, and neurologic surgery. ²⁰ Diagnostic radiology provides assistance in imaging, whereas in rare cases, radiation oncology can help with the management of symptomatic tumors not amenable to surgical resection.

Case Example

An otherwise healthy 68-year-old woman presented with 1 year of left orbital fullness. She had 9 months of blurry vision that had acutely worsened over the past 3 months. Subsequent imaging revealed a left orbital apex lesion. Axial and coronal CT soft-tissue window imaging ( Fig. 2a, d ) showed a well-circumscribed extraconal mass with homogenous soft-tissue density at the orbital apex. T1-weighted axial MRI ( Fig. 2b ) showed an orbital apex mass isointense to muscle and gray matter and hypointense to fat. T2-weighted axial MRI ( Fig. 2c ) showed the lesion as hyperintense to brain, whereas T1-weighted postcontrast MRI ( Fig. 2e ) showed a heterogenous pattern of enhancement in the brain.

Fig. 2.

Orbital apex cavernous hemangioma. ( a ) Axial and ( d ) coronal computed tomography (CT) axial soft-tissue window showing a well-circumscribed mass with homogenous soft-tissue density. ( b ) T1-weighted axial magnetic resonance imaging (MRI) showing an orbital apex mass that is isointense to muscle and gray matter and hypointense to fat. T2-weighted axial MRI showing the lesion hyperintense to brain. ( e ) T1 postcontrast MRI showing a heterogenous pattern of enhancement in the brain. ( f ) Endoscopic view of the left sinonasal cavity and orbital apex showing the lesion ( arrow ), lamina papyracea ( asterisk ), and posterior wall of the maxillary sinus ( triangle ).

Comprehensive ophthalmologic examination revealed a visual acuity of 20/20 in the right eye and 20/300 in the left eye. Color vision assessment confirmed loss in the left eye with 6/13 Ishihara color plates. Intraocular pressures were normal at 14 bilaterally. The patient had some mild optic disc atrophy.

The patient proceeded to the operating room in a combined procedure with otorhinolaryngology, ophthalmology, and neurologic surgery for left endoscopic maxillary antrostomy, ethmoidectomy, sphenoidotomy, and orbital apex decompression with resection of the orbital apex lesion. Intraoperatively, a plane was established between the lesion and the intraorbital fat with blunt and sharp dissection. The tumor was safely dissected from the medial rectus muscle and the lesion was extracted en bloc without complication.

At her 1-month follow-up, the patient had 20/20 vision in the left eye and improved color vision. Comprehensive ophthalmologic examination at 3 months showed stable improvement and minimal generalized depression of visual fields on the left eye.

Conclusion

Orbital hemangiomas can be infantile hemangiomas or cavernous hemangiomas. Both pathologic entities require the expertise of multispecialty teams to arrive at a correct diagnosis and to plan appropriate management. Ophthalmology and pediatrics utilize physical examination and MRI to evaluate newborn patients with infantile hemangiomas. Propranolol or topical β-blockers can be administered in symptomatic patients. Cavernous hemangiomas are predominantly intraconal and are typically diagnosed incidentally or after a patient experiences proptosis, diplopia, or vision loss. Ophthalmology, otolaryngology, and neurologic surgery collaborate to plan the optimal surgical approach for removal of these lesions when they are growing or causing symptoms.

Pearls and Tips.

• A high index of suspicion in patients younger than 1 year with proptosis will help diagnose infantile hemangioma.

• Lesions are contrast enhancing and have heterogenous intensity on both T1- and T2-weighted MRI.

• Treatment is limited to symptomatic lesions or lesions causing significant cosmetic deformity.

• Propranolol is the treatment of choice.

• Surgery is considered when vision is threatened and there is an inadequate response to medical therapy or for restoration of cosmesis after involution of the lesion.

• Orbital cavernous hemangioma is the most common orbital apex lesion in adults.

• It presents with painless proptosis.

• Imaging can be diagnostic and nonsymptomatic lesions can be monitored.

• Well-circumscribed contrast-enhancing rounded or oval lesion that is isointense to muscle on T1-weighted MRI and hyperintense to fat on T2-weighted MRI.

• Surgical resection is performed to treat symptomatic lesions and lesions that show growth on interval imaging.