Cavernous Malformation

Etiology

• A benign vascular hamartoma (J. Rootman, Marotta, & Graeb, 2003).  
• Congenital malformation with slow growth over time.
• No inheritance pattern.
• Composed of a network of vascular spaces lined by mature endothelial cells surrounded by fibrous stroma (J. Rootman et al., 2003).
• Enlargement occurs through budding of endothelium into adjacent tissue that is later ensheathed by myofibroblastic cells. (Osaki, Fay, & Waner, 2016)

Epidemiology

• Most common orbital mass in adults
• 5-9% of all orbital masses (Bonavolontà et al., 2013; J. Rootman et al., 2003).
• Most common mass of the inferior-outer quadrant of the orbit (Bonavolontà et al., 2013)
• Female>male; women account for ~60% of cases. (Calandriello et al., 2017)
• Presents most commonly in the 4th-5th decade of life  
• Commonly solitary lesions but have been associated with blue rubber bleb nevus syndrome and Maffucci’s syndrome (Chang & Rubin, 2002; Sullivan, Aylward, Wright, Moseley, & Garner, 1992).
• Rare reports of cavernous venous malformation associated with other vascular lesions (Strianese et al., 2014)

Patient History  

• Most commonly presents as painless proptosis.
• Symptoms due to mass effect
• Pain in ~40%, majority described as retrobulbar or periorbital pain, with a few reporting diffuse headache (D. B. Rootman et al., 2014)
• Decreased vision found in ~1/3, may be due to optic neuropathy or less commonly hyperopic shift.
• Diplopia
• Symptoms are usually gradual in onset, very rarely may have acute symptoms related to intralesional hemorrhage (Arora, Prat, & Kazim, 2011).

Clinical features

• Gradual proptosis
• Hyperopic shift
• Decreased visual acuity
• Acuity may be decreased in approximately 50% of patients, though usually no worse than 20/40 (Harris & Jakobiec, 1979; Yan & Wu, 2004).
• Relative afferent pupillary defect in cases with optic neuropathy
• Retinal striae and/or choroidal folds
• Optic nerve pallor in cases with long-standing compressive optic neuropathy
• Extraocular motility restriction
• No increase in mass size with Valsalva, in contrast to distensible low-flow venous malformation (Harris, 1999; Jack Rootman, Heran, & Graeb, 2014).

Testing

Establishing the diagnosis of cavernous malformation of the orbit typically occurs through combination of clinical exam and imaging.

• Ultrasound
• Tumors can be compressible on ultrasound with slow refilling (J. Rootman et al., 2003).
• B-Scan
• Demonstrates spherical shape, typically intraconal, with well defined posterior surfaces.
• Can show accentuation of adjacent extraocular muscles (J. Rootman et al., 2003)
• Can be helpful in differentiation from infiltrating lesions.
• A-scan
• Demonstrates well defined borders with high reflectivity posterior due to the capsule. Moderate to high internal reflectivity within the mass (Osaki et al., 2016).
• Ultrasound limited in evaluating lesion relationship to surrounding tissues, particularly in the orbital apex.
• Conventional angiography
• Classically shows small pools of contrast within the mass that appear in the late arterial phase and persist late into the venous phase. Consistent with a low flow venous malformation.
• Majority of the tumor mass does not opacify.
• With modern imaging capabilities angiography is rarely necessary. Lower risk imaging modalities are preferred.
• Risk of cerebral infarction or ophthalmic artery occlusion.
• Computed tomography (CT)
• Typically shows a well delineated round to ovoid mass located in the muscle cone.
• When located at the orbital apex lesions may have a typical pear shape (Kloos, Mourits, Saeed, & Mourits, 2013).
• Most frequently located in the middle third of the orbit, more commonly in the intraconal space laterally (McNab, Selva, Hardy, & O’Donnell, 2014)
• Majority are located laterally within the cone.
• Approximately half demonstrate slight outward displacement of the lateral orbital wall (J. Rootman et al., 2003).
• Enhancement with contrast, often delayed and patchy initially, reflecting the lack of feeding vessels (Osaki et al., 2016).
• Calcification, which can be seen in venous-lymphatic malformations, is not typically found in cavernous malformation (Selva, Strianese, Bonavolonta, & Rootman, 2001).
• Structures adjacent to the mass are typically displaced, rather than surrounded by the tumor.
• Exception to this rule is in the orbital apex where there is little room for displacement, so critical vessels and nerves may become incorporated into the capsule (Harris, 2010).
• Orbital fibrous tumors (Warner, Burkat, & Gentry, 2013)  and lymphatic malformations (Selva et al., 2001) may mimic cavernous malformation on imaging.
• Magnetic Resonance Imaging (MRI)
• Well circumscribed mass isointense or slightly hypointense compared to extraocular muscles on T1-weighted images and hyperintense on T2-weighted images (Ansari & Mafee, 2005).
• Melanoma may have similar signal characteristics on non-contrast imaging (Lorenzano, Miszkiel, & Rose, 2017)
• With gadolinium contrast, cavernous malformations show early patchy enhancement that slowly fills the entire lesion. Enhancement appears homogenous by 20 to 60 minutes (J. Rootman et al., 2003)
• Significantly slower enhancement compared to other enhancing orbital lesions such as varices or hemangiopericytoma (Ramey, Lucarelli, Gentry, & Burkat, 2012)
• Time-Resolved Imaging of Contrast KineticS (TRICKS)
• TRICKS MRA allows rapid acquisition of images to show 3D dynamic information about intravascular flow (Swan et al., 2002).
• Cavernous malformations typically show delayed enhancement and limited flow (Kahana et al., 2007).
• Characteristic sinusoidal spaces fill progressively over ~30 seconds. There is slow washout of contrast (Ramey et al., 2012)
• Advantages of TRICKS MRI/MRA
• No radiation
• Combines high tissue detail of MRI with dynamic flow assessment without the risks associated with conventional angiography.
• Histopathology
• Classically features large ectatic channels lined by mature endothelial cells surrounded by multiple layers of smooth muscle with a well circumscribed outer fibrous capsule.
• Desmin negativity indicates myofibroblastic differentiation, rather than true smooth muscle differentiation (Osaki, Jakobiec, Mendoza, Lee, & Fay, 2013).
• Intraluminal thrombosis may be present.
• Dysplasia and hypercellularity tend not to be present. Cellular components are mature.
• Immunohistochemistry (Osaki et al., 2013)
• Negative for most markers of cellular proliferation.
• Lack glucose transporter protein type 1 (GLUT-1), similar to lymphatic malformations, which is expressed in all infantile hemangiomas
• Near absence of nuclear protein Ki-67 (marker of cellular proliferation) indicates vascular malformation rather than a benign neoplasm (Osaki et al., 2013).   

• Congenital anomaly with no known inheritance pattern.

• Schwannoma
• Hemangiopericytoma / Solitary fibrous tumor
• Lymphatic malformation
• Melanoma
• Neurofibroma

Natural History

• Small and asymptomatic lesions can be managed conservatively
• Lesions that are observed should be followed with serial ophthalmic exams, visual field testing and imaging.
• Radiologic growth rate varies between studies. In one case study a rate of 10-15% growth was seen in a year (D. B. Rootman et al., 2014)
• Progression of proptosis is also variable, in one study the rate was approximately 2 mm per year, with an average of 5 mm of proptosis at presentation (Harris & Jakobiec, 1979).
  • In another study, 5 patients had no clinical or radiographic growth over 3 or more years (Scheuerle, Steiner, Kolling, Kunze, & Aschoff, 2004).
• Enlargement may accelerate during puberty and pregnancy.
  • Circulating estrogen and progesterone may have an effect on progression. (Osaki et al., 2016)
  • In post-menopausal women with theoretically decreasing hormone levels there may be a halt in progression or even a decrease in size (Jayaram, Lissner, Cohen, & Karagianis, 2015).
• Extremely rare for sudden changes or intralesional hemorrhages to occur. (Jack Rootman et al., 2014).

Indications for treatment

• Vision loss/optic neuropathy
• Diplopia
• Disfiguring proptosis
• Pain  
• Headache
• Progression of size

Medical and non-surgical

• Observation: often optimal in incidentally identified cases.
• Radiotherapy
  • Useful for apical cases where the capsule may involve critical structures that are more likely to be injured during surgical excision.
  • Stereotactic fractionated radiotherapy (SFRT) (D. B. Rootman, Rootman, Gregory, Feldman, & Ma, 2012)
    • Involves delivery of radiation fractionated over a number of days.
    • Greater dose of radiation overall than gamma knife radiosurgery but may be less damaging to surrounding structures.
    • One small series described an average 60% decrease in lesion volume after treatment with resolution of symptoms in all 5 patients (D. B. Rootman et al., 2012).
    • Exact mechanism for the success of radiotherapy remains unclear.
      • May induce thrombosis and fibrosis in the lesion that closes off the vascular spaces decreasing lesion size.
  • Multisession Gamma Knife Radiosurgery (Goh, Kim, Woo, & Lee, 2013)
    • Focuses high-energy gamma rays to a specific point through stereotactic guidance.
    • Accurate focus of radiation reduces risk to the nerve and adjacent structures.
    • In a series of 5 patients, tumor shrinkage was seen in all patients with a reduction in volume of 70-87%. All patients had improvement in visual acuity.
• Sclerotherapy
  • May be considered for patient not unable or unwilling to undergo surgical intervention.
  • Intralesional injection of pingyangmycin (bleomycin A5) into low-flow vascular lesions in the orbit, including cavernous malformations, induces endothelial apoptosis leading to decreased lesion size (Yue et al., 2013).

Surgical

• Surgical approach dependent on lesion location, size, and relationship to orbital structures.
  • Anterior transconjunctival, transcaruncular or transcutaneous orbitotomy can be used for smaller, more anterior lesions
  • Orbital apex lesions may require lateral orbitotomy with or without osteotomy, or rarely a transcranial approach.
  • Endoscopic endonasal techniques may be useful for masses in the posterior medial orbit.
    • Endoscopic transethmoidal approach can be done alone or in combination with medial rectus detachment for small lesions in the medial apex (Wu et al., 2013)  
  • A cryoprobe can used to facilitate extraction (Rosen, Priel, Simon, & Rosner, 2010).  
• Larger lesions, particularly lesions in the apex, recruit adjacent structures into the capsule, which can include vessels that supply the optic nerve (Harris, 2010)
  • Traction during surgery can produce vasospasm or rupture leading to nerve or retinal ischemia.
• For masses that cannot be completely excised safely, modifications may include subtotal resection, shrinkage with bipolar cautery or local decompression (Harris, 2010).
  • Clinical course for subtotal resection is variable, some may continue to enlarge.
• Some surgeons advocate exsanguination of the mass to facilitate removal (J. Rootman et al., 2003).  
• Recurrence after surgical excision is rare.

Complications of surgery

• Vision loss
• Diplopia/motility disturbance
• Enophthalmos
• Ptosis
• Corneal anesthesia
• Pupillary abnormalities
• Loss of accommodation
• Risks specific to the chosen surgical pathway

Complications of radiotherapy (D. B. Rootman et al., 2012)

• Non-optic cranial neuropathies
• Radiation retinopathy
• Pituitary dysfunction
• Secondary tumors
• Risk of these complications is quite low, <3%, in doses under 4500 cGy.

• Vision loss: decreased acuity and visual field deficits
• May persist even after treatment if optic neuropathy present
• Proptosis and restriction of extraocular movements typically resolve after excision.

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