Pathogenesis of orbital lymphangioma remains controversial

Clinical features, treatment and prognosis are correlated with the location of the tumor.

Lymphangioma is a rare, diffusely infiltrating benign nonencapsulated vascular tumor most commonly diagnosed in the first or second decade of life. Despite their congenital nature and low proliferative potential, lymphangiomas often show some degree of progressive enlargement or growth.

They are distinct, however, from capillary hemangiomas in their lack of significant communication with the vascular system and lack of spontaneous regression. Lymphangiomas can arise in many of the soft tissue sites of the body, including the eyelids, conjunctiva and orbit.

Lymphangioma constituted 0.3% to 1.5% of all histopathologically diagnosed orbital tumors in five major published series. It is believed that the actual frequency may be higher because some asymptomatic and mildly symptomatic cases do not undergo a biopsy procedure. There is no significant race or sex predilection, although lymphangiomas seem to be slightly more reported in females.

Varied theories

The pathogenesis of orbital lymphangioma is controversial.

A 2-year-old female with a sudden bleed in the left eye with mild proptosis and ptosis. Images: Zielinski KM, Bardenstein DS, Levine MR

Wright and colleagues suggested that most lymphangiomas represent venous anomalies or varices because a connection of these tumors to the venous system can be demonstrated by venography.

Harris and colleagues considered lymphangioma channels to be isolated from the normal orbital vasculature. They found that, unlike a varix, a lymphangioma was not affected by postural change, except for the dependency-related diffusion that affects all tissues. They also found that neither arteriography nor venography filled lymphangiomas.

Jones suggested that the human orbit may have lymphatic channels. He demonstrated in animals that India ink injected into the extracellular space of the orbit appeared in the cervical lymph nodes. Therefore, lymphangioma may represent a hamartomatous abnormality of existing orbital lymph vessels. Those features that favor a lymphatic origin include a simple layer of endothelial cells lining the channels, lymph-like fluid and a thin septal stroma that may hold lymphocyte aggregates.

However, lymphoid follicles are frequently absent, and electron microscopy has shown features of both lymphatic channels and venous channels. Interestingly, studies using tritiated thymidine have shown that the endothelial lining has a turnover rate similar to that of normal mature cells, suggesting that lymphangiomas represent areas of maldevelopment rather than actively proliferating and growing true neoplasias.

Orbital lymphangiomas can be associated with an orbital and/or intracranial arteriovenous malformation. Katz and colleagues attempted to explain this by stating that lymphangiomas represent a spectrum of multicentric venous lymphatic vascular malformations, depending on the time of occurrence during embryonal development.

The most common initial complaint reported was progressive swelling or a mass affecting the eyelids with or without ptosis (Figure 1). Proptosis and hemorrhage were the next two most commonly reported symptoms. In a study by Wright and colleagues, 61% of patients had proptosis at rest, which increased with the Valsalva maneuver. Acute proptosis may also occur secondary to lymphoid hypertrophy within the tumor after upper respiratory tract infections (Figures 2 through 5).

A 2-year-old female with sudden proptosis status post medial orbital biopsy.	CT scan showing a left feathery retrobulbar mass, which was histopathologically consistent with a lymphangioma.
The same patient at age 4 developed extreme proptosis during an upper respiratory infection, which resolved.	The patient at age 6 with mild proptosis and 20/20 vision.

Orbital hemorrhage occurred in 55% of patients in Wright’s study. Although hemorrhage into these lesions was a major factor in their enlargement, bleeding into the surrounding tissues and cyst formation was also quite frequent. Without a tumor capsule or a substantial stroma between the adjacent channels, the expansion of blood cysts is relatively unrestrained, and proptosis can be dramatic (Figure 6). Mild anisometropic amblyopia has occurred in patients whose cysts indented the globe and went untreated.

Hemorrhage in conjunction with cyst formation has been termed “chocolate cyst.” Hemorrhages are frequently associated with pain and sudden proptosis and in children by nausea and vomiting. Additional symptoms reported include pain, reduction in vision and tearing. Signs include eyelid and brow thickening, ptosis, diplopia, tearing, recurrent epistaxis, conjunctival cysts and soft and hard palate cysts (Figure 7).

A 15-year-old female with a sudden retrobulbar bleed with proptosis, ptosis and decreased vision in the left eye.

The same patient with hard and soft palate lymphangioma.

Differential diagnosis

The differential diagnosis of unilateral proptosis and orbital inflammation includes the following:

• Orbital cellulitis
• Orbital pseudotumor
• Foreign body
• Ruptured dermoid cyst
• Lymphangioma
• Subperiosteal abscess
• Orbital myositis
• Thyroid orbitopathy
• Primary or metastatic neoplasm
• Orbital hemorrhage (eg, neuroblastoma, leukemia, rhabdomyosarcoma)

Clinical features, treatment and prognosis are correlated with the location of the lymphangioma.

The superficial lymphangioma typically presents as a small multilobulated cystic mass of bulbar conjunctiva and/or the lid that neither affects vision nor displaces the globe. When cosmetically unacceptable, they can be removed with good results (Figures 8 through 12).

A 6-year-old male with a lymphangioma infiltrating the eyelid and eyebrow, giving the patient severe ptosis and mild amblyopia.	The same patient with lymphangioma with hemorrhage of the soft and hard palate.
The patient status post levator resection in the right eye.	The patient 3 years later with a periorbital re-bleed with ptosis in the right eye.

The orbital lymphangioma is located behind the orbital septum and involves the intraconal and/or extraconal space. Usually it presents with sudden proptosis and occasionally with pain due to spontaneous intralesional hemorrhage or to lymphoid proliferation in the connective tissue of the tumor during an upper respiratory infection. Other signs can include ptosis, eye movement restriction and compressive optic neuropathy with papilledema and secondary glaucoma.

The combined lymphangioma consists of both the superficial and deep form and involves the intraconal, extraconal preseptal and postseptal spaces. It has as anterior component with multiple conjunctival or lid cysts. Similar cystic lesions of mucous membranes of the mouth and palate are often observed in this group. Spontaneous intratumoral hemorrhage may result in periorbital ecchymosis, ptosis and amblyopia. Optic nerve dysfunction may occur as the result of an acutely expanding tumor. The patient may require surgery either on an urgent basis in cases of acute retrobulbar hemorrhage with optic nerve compression or on an elective basis for cosmetic problems.

An isolated intracranial vascular venous anomaly associated with a cavernous hemangioma has been reported previously in patients with combined lymphangioma and related cerebral hemorrhage.

To establish diagnosis, CT scan and MRI of the orbit are obligatory. CT scan usually shows a multilobulated cystic mass within the orbit, and intralesional calcifications may be demonstrated. MRI is the modality of choice to identify the hemorrhagic cyst as well as the lymphatic cystic component. Hemorrhagic cyst (acute and subacute) shows increased signal on both T1- and T2-weighted MRI images, whereas lymphatic cysts are hypointense on T1-weighted images and hyperintense on T2-weighted images. MRI study is most helpful in documenting fluid level within the multicystic lesion.

Pathologic examination of a lymphangioma reveals a nonencapsulated lesion with variably sized cystic spaces lined by flattened endothelial cells. Pericytes and smooth muscles are absent from the vessel wall. This feature, the progression by recurrent intralesional hemorrhages and absence of clinical response to interferon and corticotherapy help to distinguish lymphangioma from cavernous hemangioma.

As previously mentioned, the lesions consist of nonencapsulated networks of endothelial-lined channels, which are separated by thin septa and filled with pale-staining fluid. Lymphatic aggregates are frequently present. Harris and colleagues postulated that the basic lesion is a network of small caliber, malformed vascular channels that arborize irregularly throughout portions of the orbit.

Although the lumens are not continuous with the orbital circulation, there are small nutrient vessels within the fragile walls, which may be the source of hemorrhage. Bleeding into these channels or microcysts may cause hemorrhage and expansion into macrocystic lesions and massive blood cysts. This may be precipitated by a viral illness or a trauma.

Clinical course, treatment

Right eye with a subconjunctival bleed.

The clinical course of lymphangioma is slightly variable. There may be small hemorrhages with proptosis, which then may return to normal, while the patient’s normal vision is maintained. In other instances the proptosis remains after the bleeding subsides. In other case reports, bleeds from days to weeks occur, resulting in visual compromise from optic nerve compression or from extreme proptosis.

Treatment of these intertwining cystic lesions can be problematic. The mainstay of treatment is a conservative approach in hopes of spontaneous resolution. Several treatment modalities have been described, including observation, systemic steroids, needle decompression of cysts with imaging guidance, surgical resection, staged laser treatments, cryotherapy and sclerotherapy. Any local intervention must be undertaken cautiously because of possible damage to functionally important orbital structures.

Conservative management has reportedly been followed by spontaneous resolution and normalization of vision in selected cases. Wilson and colleagues described conservative management as limitation of the patient’s activity or bed rest in an outpatient or inpatient setting, cold compresses and monitoring of visual acuity, pupillary light reaction and appetite.

The use of systemic steroids has generally been described as helpful; however, some authors have found it to be of minimal help. Sires and colleagues have recommended corticosteroid for symptomatic relief, loss of vision and motility dysfunction, as well as peri- and postoperative administration to decrease inflammation and swelling in surgical cases.

Theoretically, the beneficial effect of steroids in lymphangioma is a reduction of lymphoid hypertrophy and stabilization of the vasculature. It may have a better effect in children because of their lack of pseudoencapsulation that slowly develops over time.

Surgical indications

Surgical management is indicated when there are major macrocysts that raise the orbital pressure, compress the optic nerve and cause extreme proptosis. Imaging studies can help determine the best surgical approach. Surgery should consist of limited intraorbital dissection and decapitation of the offending blood cysts. An aggressive approach may result in the destabilization of multiple macrocysts and significant recurrent bleeding.

If this happens, under the best circumstances, repeat orbital decompression and exploration with very aggressive dissection and bipolar cauterization is to be considered with a Jackson-Pratt drainage system in place. This is a controversial approach, but it may be needed, as these macrocysts can re-bleed. One argument against the use of the Jackson-Pratt system is that the suction may destabilize more cysts. On the other hand, recurrent bleeding may also occur without its use.

A less frequently employed option that may be useful for some patients, especially if no surgery preceded, is injection of sclerosing agents (sodium tetradecyl sulfate). Intralesional injection of OK-432, an immunopotentiator, has also been successful in shrinking lymphangiomas.

Growth factor receptors, specifically platelet-derived growth factor receptor-alpha, are expressed by the endothelial cells lining orbital lymphangiomas. The specific role of platelet-derived growth factor receptor inhibitors, such as imatinib mesylate, is under investigation. One proposed surgical technique describes combining partial controlled decompression of the lesion with intralesional injection of Tisseel fibrin glue (Baxter AG).

Conjunctival lymphangiomas have been treated best with a CO² laser, but cryotherapy and surgical removal are also options. Infiltration of the lid and levator is best treated with a combination of surgical dissection with cautery and/or CO² laser. The CO² laser nicely removes the lymphangioma with simultaneous hemostasis (Figures 13 through 16).

A 9-month-old male with a lymphangioma infiltrating the right upper and lower lid and right eyebrow.	The patient at age 3 after some surgical debulking, still with significant ptosis.
Intraoperative view of a levator resection with lymphangioma infiltration. Preaponeurotic fat is superior to the levator muscle.	The patient at age 16 status post levator resection in the right eye. Note lymphangioma still present in right brow and right medial canthus.

Conclusion

Orbital lymphangioma should be considered in any case of proptosis in childhood. Associated extraorbital localizations, particularly intracranial vascular venous anomaly, must be ruled out. A multidisciplinary approach is needed, and the treatment has to be as conservative as possible if vision is not at risk and cosmesis is acceptable.

For more information:

• Mark R. Levine, MD, FACS, is a clinical professor of ophthalmology in the department of ophthalmology at Case Western Reserve University. He can be reached at University Suburban Health Center, 1611 South Green Road, Suite 306A, South Euclid, OH 44121; 216-291-9770; fax: 216-291-0550.
• Kathleen M. Zielinski, MD, can be reached at 1611 South Green Road, South Euclid, OH 44121; e-mail: szielinski@adelphia.net.
• David S. Bardenstein, MD, can be reached at University Hospitals of Cleveland, 11100 Euclid Ave., Cleveland, OH 44106; e-mail: david.bardenstein@uhhospitals.org.

Case study: Lymphangioma H.B. is a 2-year-old white female who presented with sudden ptosis, mild proptosis and extreme pain in the left eye (Figure CS1). A CT scan showed a retrobulbar mass suggestive of cystic changes consistent with lymphangioma (Figure CS2). The patient underwent a lateral orbitotomy, biopsy and decompression of two hemorrhagic cysts. Postoperatively, the bleed, ptosis, proptosis and pain resolved (Figure CS3). Over the years the patient had a few lesser bleeds that were treated conservatively with bed rest, cold compresses and analgesics. At age 15, the patient presented with ptosis, proptosis, decreased vision and pain (Figure CS4). A T1-weighted MRI showed multiple hemorrhagic macrocysts (Figure CS5). The patient underwent a transconjunctival inferior decompression with simple cyst decapitation, release of 30 cc of blood and bipolar cautery for hemorrhagic control. Over the next 10 days the patient had four re-bleeds with a decrease in vision to 20/400, a positive afferent pupillary defect and proptosis that required inferior decompressions, bipolar cautery of the cysts and a Jackson-Pratt drain (Figure CS6). Postoperatively, the bleeding stopped, the proptosis receded 90%, and the vision returned to 20/20 with a mild APD and some disc pallor. The patient has not had a re-bleed for 1 year (Figure CS7). A 2-year-old female with a sudden bleed in the left eye with mild proptosis and ptosis. A CT scan at another time showing cystic lesions behind the left globe. The patient after resolution of the retrobulbar hemorrhage by a conservative lateral orbitotomy and cyst drainage. The patient 13 years later with a retrobulbar bleed in the left eye with proptosis and ptosis, decreased visual acuity to 20/50 and an afferent pupillary defect. A T1-weighted MRI showing multiple hemorrhagic macrocysts in the left eye. The patient 72 hours later after one of four re-bleeds. Vision was reduced to 20/400 in the left eye. The patient 3 months later after aggressive macrocystic removal, bipolar cautery and Jackson-Pratt drainage. Patient had 20/20 vision in the left eye with slight afferent pupillary defect and optic atrophy.