Ординатура / Офтальмология / Английские материалы / Orbital Tumors Diagnosis and Treatment_Karcioglu_2005

Orbital granulomatosis and vasculitis with proptosis; EOM disturbance; ON vasculitis and/or compression; conjunctivitis, scleritis;

choroidal ischemia

Localized, poorly delineated nonspecific inflammation in the orbit causing proptosis and EOM disturbance

Orbital vasculitis and soft tissue necrosis causing proptosis, EOM disturbance, scleritis and choroidal ischemia

Necrotizing granulomatosis of conjunctiva and other periocular soft tissues

KCS; occlusive retinopathy; conjunctivitis scleritis; ON and

orbital soft tissue vasculitis causing proptosis and ophthalmoplegia

Uveitis; retinochoroidal vasculitis; scleritis with or without optic neuritis; extraocular myositis with EOM disturbance and proptosis

Conjunctivitis; erythematous discoloration of eyelid and periorbital skin; ophthalmoplegia, ptosis and proptosis due to orbital polymyositis in cases associated with giant cell myocarditis (cadiopulmonary workup including EKG, cardiac echogram, chest x-ray, etc.)

Fibrosis of adnexal tissues causing atrophy of conjunctiva and eyelid skin; madarosis; ptosis and EOM disturbance; heterochromia iridis

KCS with or without Sjögren’s syndrome; scleritis (50% of cases) with or without scleromalasia perforans and orbital soft tissue inflammation and necrosis

demonstrating daughter cysts with scoleces is diagnostic (Figure 29.3).23–25

Other examples of parasitic orbital infections are cysticercosis, myiasis, and trichinosis of extraocular muscles.26–28

NONSPECIFIC INFLAMMATIONS

Orbital Pseudotumor

Orbital pseudotumor is a nonspecific chronic inflammatory condition of unknown etiology. Although an underlying immune process is suspected, no conclusive mechanism has been established for the development of this curious entity. Clinically, the orbital pseudotumor may develop with sudden onset of painful proptosis associated with motility disturbances, eyelid swelling, redness, and chemosis.29 It may develop as a diffuse or localized lesion, and its histopathology varies accordingly from case to case.

The pseudotumor may be grouped into two main categories: diffuse and localized nonspecific orbital inflammation. The localized nonspecific inflammation is further divided according to specific sites (i.e., myositis, dacryoadenitis, periscleritis, and perineuritis). Each subgroup may present as an acute, subacute, or chronic inflammatory process in a given patient.

The histopathology of the pseudotumor usually consists of a mixed polymorphonuclear and lymphocytic infiltrate during the early phases; as the disease advances, lymphoid follicle formation and fibrous tissue proliferation dominate the picture.30 Patchy aggregates of lymphocytes and/or lymphoid follicles are frequently seen. Occasionally the lymphoid infiltrates are confluent as in lymphoproliferative neoplasia. These cases may clinically simulate orbital lymphoma and, therefore, should be further evaluated with flow cytometry and genetic studies (see Chapter 12). In many instances, the biopsy diagnosis for the pseudotumor is not pathognomonic but must be correlated with clinical and radiologic findings. Occasionally, the

FIGURE 29.3. Echinoccocal cyst, which presented with unilateral proptosis (A). The unilocular cystic lesion shown in the gross photograph (B) was removed in toto. Histopathologic slide (C) reveals partially calcified cyst wall. Inset: Diagnostic scoleces recovered from the cyst fluid.

orbital pseudotumor with systemic involvement may simulate metastatic disease.31

CT and MRI findings of diffuse orbital pseudotumors include contrast enhancement owing to the high vascularity of inflammation, which infiltrates the fibroadipose tissues and extraocular muscle enlargement.32 The MRI finding of hypointensity on T2weighted images, relative to normal muscle, may be useful to differentiate pseudotumor from metastatic tumors by vascular congestion.33 If the pseudotumor is localized with compression onto adjacent struc-

tures, including the globe, or is causing bony erosion, the differential diagnosis is difficult.32

The localized presentations of orbital pseudotumor, such as Tolosa–Hunt syndrome and lacrimal pseudotumor, may mimic neoplasia. Tolosa–Hunt syndrome, otherwise known as painful external ophthalmoplegia, is another orbital inflammatory process of the orbit with unknown etiology.34,35 It is conceivable that it represents a localized form of idiopathic orbital inflammation. The clinical symptoms include a severe, deep orbital pain associated with functional deficiencies of third, fourth, fifth, and sixth cranial nerves. It is typical that the orbital pain, which presents abruptly, also responds to systemic corticosteroid treatment with the same suddenness.36 Other symptoms of the disease, including third, fourth, and sixth cranial nerves palsies and the hypoesthesia of the periorbital skin, also respond well to corticosteroid treatment. Although bilateral cases do occur, the great majority of patients with Tolosa–Hunt syndrome present unilaterally and, therefore, their lesions should be differentiated from tumors that can involve the orbital apex area (e.g., meningioma, pituitary adenoma, neurofibroma, paraganglioma, secondary nasopharyngeal squamous cell carcinoma, metastatic tumors). Tumors of the apex, however, usually cause a gradual development of extraocular muscle dysfunction, depending on the location of the lesion, which may be accompanied by dull pain but usually not with abrupt onset of panophthalmolplegia and explosive pain.37,38 Although the imaging studies are not specific for Tolosa–Hunt syndrome, they are helpful to rule out neoplasia. Burkitt’s lymphoma has also been reported to simulate Tolosa–Hunt syndrome.39

Localized lacrimal fossa pseudotumor may present as an isolated mass lesion. Imaging is not very helpful to differentiate lacrimal gland masses and other anteriorly localized pseudotumors (Figure 29.4). Burkitt’s lymphoma may also mimic acute-onset localized pseudotumor in the lacrimal gland fossa.40–42 These lesions should be differentiated from lymphoma, other lacrimal gland tumors, and inflammation such as Sjögren syndrome (SS) and sarcoidosis by means of histopathologic examination (Figure 29.5).

Hematic Cyst and Cholesteatoma

Although orbital hemorrhage terminology is not very strict, hematoma usually refers to a localized collection of blood within soft tissues that develops secondary to trauma. Hemorrhage may occur spontaneously without any physical exertion in otherwise healthy individuals.43 When blood collection within the orbit becomes organized and is surrounded by a thin pseudocapsule, the entity is commonly known as a hematic cyst (Figure 29.6).44,45 Hematic cysts usually develop within 1 to 2 weeks of orbital trauma,

but some cases are reported to occur up to 20 years after orbital injury.46 These cysts may become large enough to cause proptosis, extraocular motility disturbance, or compression on the globe and optic nerve. Hematic cysts, which can be easily demonstrated with ultrasonography, CT, or MRI, are lined by fibrovascular tissue at the periphery and contain degenerated erythrocytes, protein debris, and cholesterol crystals.47 In many instances, the thin nonepithelial lining is attached to adjacent structures by fibrous adhesions. The adhesions may be self-resolving or easily

detached surgically in early cases; if the lesion persists, however, they may turn into firm fibrous bands. Hematic cysts may develop within the muscle cone or subperiosteal orbital locations.44 If the hemorrhage develops within an existing lymphatic or vascular tumor, these lesions are known as blood cysts or chocolate cysts.

Cholesteatoma is another cystic lesion that is confined by a thicker pseudocyst wall without epithelial lining. It is conceivable that some chronic hematic cysts develop into cholesteatomas. Like chronic

hematic cysts, these lesions contain cholesterol crystals and other blood breakdown products that act as foreign material and trigger a fulminant granulomatous reaction.48,49 Cholesteatomas are usually located in the superior lateral orbit within the lacrimal gland fossa. Histopathologically, the lesion is composed of cholesterol clefts, hemosiderin and hematoidin granules, other blood breakdown products, and fibrin, surrounded by a mixed lymphohistiocytic infiltrate and multinucleated foreign body giant cells (Figure 29.7). Imaging studies may show a cystic, semicystic, or

FIGURE 29.6. The patient presented with spontaneous bleeding into the orbit with minimal proptosis of the left eye and diplopia at extreme left gaze

(A). MR image shows a large cystic lesion with marked enhancement in the lateral orbit (B). When the orbit was explored through a lateral orbitotomy, a dark red, spherical lesion was identified and removed with blunt dissection (C). The lesion was a totally encapsulated blood clot, which microscopically showed different degrees of organization (D).

solid lesion within the diploë of the bone or within the orbital soft tissues with erosion of the adjacent bone (Figure 29.8).

Although bone destruction in general may suggest malignancy, the sclerosing character of the bony destruction, which is best seen in bone window images, suggests a benign lesion. Multiple cuts of the frontal bone should be examined to rule out the possibility of intracranial extension. A recent report suggests that a preexisting bone abnormality may lead to the development of cholesteatomas at least in some cases.50

Bone destruction makes one think along the lines of metastatic tumors, but benign lesions such as brown tumor, aneurysmal bone cyst, and ruptured or leaking dermoid50 should also be considered.51

Because of the extensive foreign body reaction around the lesion, cholesteatomas usually establish many firm adhesions to the surrounding soft tissues and bone, causing destruction of these tissues. The extensive adherences make the surgical excision of these lesions difficult. Lack of capsule forces one to do sharp dissection around the lesion, which may damage vital structures such as entrapped and atrophied extraocular muscles, nerves, and blood vessels. In particular, the superior and lateral rectus muscles and the levator muscle are likely to be entrapped within the cholesteatoma and may lose their structure and function.

Osteomyelitis of the orbital bones, primarily evolving as a complication of paranasal sinusitis, is another entity that should be considered in the differential diagnosis of cholesteatoma. In osteomyelitis the bone infection extends into the soft periosteal space and beyond. Precise delineation of the lesion can be done with CT and MRI, particularly in combination with bone SPECT (single photon emission CT), a sensitive technique used to detect osteomyelitis within cranial and orbital bones.52

Mucocele

Although a commonly encountered space-occupying lesion in the orbit, the mucocele is technically not a neoplasm but a cyst developing as a result of inflammation or trauma. Its cavity is lined by pseudostratified respiratory epithelium prolapsing into the orbit from a paranasal sinus, most commonly the frontal sinus; ethmoid and maxillary sinuses are the other sites

of mucoceles.53 The primary mucocele develops as a result of an inflammatory obstruction of the ostium of a paranasal sinus. The histopathologic appearance of the mucocele wall, consisting of respiratory epithelium and thinned bony elements with nonspecific chronic inflammation, reflects its evolution from a chronic inflammatory process.

Secondary mucoceles, on the other hand, are most commonly seen after orbital trauma and surgery; they may also develop secondary to neoplasms of paranasal sinuses and nasal pharynx. If there is a superimposed infection, the lesions are referred to as pyocele on CT and MRI; the mucocele presents as a well-delineated cystic structure originating from a paranasal sinus. Depending on their location, secondary mucoceles may compress onto orbital structures including extraocular muscles, optic nerve, and the globe.54

On CT, mucoceles present as hypointense, expanding masses originating from the paranasal sinuses. Early in their development these lesions are small, mucus-containing cysts. Later in their development, they are characterized by crescent-shaped and thinned remodeling of the bony walls of the orbit and sinuses.55 On MRI, mucocele presents with different appearances depending on the amount of free water in its luminal contents. When the intraluminal mucus becomes inspissated, the signal intensity in both T1and T2-weighted images decreases, moving closer to that of normal air content of the sinus.56

Clinically, the mucocele usually presents with displacements and proptosis, extraocular motility, particularly in the direction of the sinus extension into the orbit, and other compressive symptoms.57 The crepitant or calcified hard wall of the mucocele may be palpated underneath the superior or medial orbital rim. Mucoceles in general are rare in children; how-

ever, a unique variant, ethmoidal mucopyocele, is known to occur as a secondary space-occupying lesion in the medial canthal area, with lateral displacement of the globe.

Mucoceles of the lacrimal drainage system should not be confused with sinus lesions. Lacrimal sac mucoceles, at times, particularly in adults, may simulate lymphomas.58

SPECIFIC INFLAMMATIONS

Sarcoidosis

Sarcoidosis is an idiopathic multisystem disease that commonly involves the orbit and the eye. Systemically it involves the lungs and the upper respiratory tract, liver, spleen, lymphatic, and hematopoietic tissues, central nervous system, and the skin. Although there is considerable evidence that sarcoidosis is infectious, its etiopathogenesis is still unknown.59 The typical noncaseating granulomas are made of T lymphocytes of helper and suppressor types and dendritic Langerhans cells with deoxyribose human leukocyte antigen (HLA) expression. Perivascular inflammation is characteristic of a delayed type of hypersensitivity reaction. Patients with sarcoidosis usually demonstrate the systemically deficient T-cell responses associated with T- cell lymphopenia. Although the exact significance of granuloma formation in sarcoidosis is not known, it appears that this tissue reaction is a secondary event as a result of exaggerated cellular immune response to a class of unknown antigens. The initial step in granuloma formation of sarcoidosis is considered to be triggered by the cytokine interleukin 1, which increases the proliferation of helper T lymphocytes and activates

those cells. Activated helper T cells in turn secrete interleukin 2, which is a mitogen that stimulates the proliferation of helper T cells even further.60 As a consequence, these cells aggregrate at the site of the causative insult and secrete monocyte chemotactic factors that lead to the gathering of epithelioid macrophages and multinucleated giant cells to form granulomas. Sarcoidosis is also associated with abnormalities of humoral immunity manifested by polyclonal hyperglobulinemia.61,62 Granulomas are made of epithelioid cells and multinucleated giant cells, surrounded by lymphocytes and occasional plasma cells. Many inclusion bodies have been described in the giant cells of sarcoidosis, but none of these are pathognomonic. The granulomatous response of sarcoidosis is rather typical but not unique for this entity; fungal diseases, tuberculosis, Crohn’s disease, and leprosy may produce similar granulomas.63

Approximately one fourth of sarcoidosis patients develop ocular and orbital manifestations including anterior and posterior uveitis, chorioretinitis, conjunctival and eyelid granulomas, and orbital mass lesions (Figure 29.9). The lacrimal gland is a common site of involvement. But although autopsy studies show a high percentage of microscopic disease, only 15 to 20% of the patients present clinical symptoms. Although virtually any part of the orbit may be involved, the most common site of sarcoidosis is the lacrimal fossa. The disease in this location may be confused with chronic dacryoadenitis, Sjögren’s syndrome, or spaceoccupying lesion (Figure 29.10).64 Sarcoid granulomas may also extend into the orbit from adjacent sinus mucosa.65 If other manifestations of the disease are absent, these cases may mimic secondary orbital tumors; they can be differentiated only by biopsy.

Patients with distinctive systemic manifestations

FIGURE 29.10. A large orbital mass extending to the apex and into the cavernous sinus through the optic canal in a known sarcoidosis patient. The patient was treated with oral corticosteroids and methotraxate, and the size of the orbital lesion was considerably reduced in size but persisted after 2 years of treatment.

with bilateral hilar lympadenopathy, skin lesions, uveitis, and so on, usually show increased levels of angiotensin-converting enzymes (ACEs). Serum lysozyme and calcium levels may also be increased in sarcoidosis, but neither test is specific for the disease. The ultimate diagnosis is by biopsy. Some advocate preforming biopsies only on sarcoid-suspect lesions, such as skin and conjunctival nodules in which the yield is usually rewarding. Others support random (blind) biopsy of the conjunctiva in sarcoid suspects (Figure 29.11). The yield of the random biopsy without a distinct lesion is rather low (around 25% positive). Since the conjunctival biopsy is simple to perform, has low morbidity, and can be inexpensively and quickly done in the clinic, as opposed to more invasive biopsies of transbroncheal lymph nodes, liver, and orbit, it is practical to do biopsies of the conjunctiva randomly early in the workup of a patient suspected of having sarcoidosis.66 If the biopsy reveals granulomatous inflammation, more invasive procedures with high morbidity can be avoided.

The involvement of the optic nerve with sarcoidosis is usually an anterior process associated with typical retinal vasculitis; rarely, however, the optic nerve involvement may extend posteriorly and form a mass lesion.67

The treatment of sarcoidosis is directed to the systemic disease. Surgery may be necessary for purposes of biopsy or debulking orbital lesions if there is a need for histopathologic evaluation in patients with no other easily accessible biopsy sites. In a few instances, the mass-forming orbital disease presents with no his-

tory or detectable symptoms of systemic sarcoidosis (Figure 29.9). The surgical removal of the orbital sarcoid lesions is usually difficult; these mass lesions do not form capsules and, therefore, need to be excised with sharp dissection, which may damage the adjacent tissues (i.e., lacrimal gland) and cause excessive bleeding. In these patients, sarcoidosis is usually a surprising diagnosis obtained from an “orbital tumor.”64 The accepted systemic treatment is the use of oral corticosteroids and antimetabolites such as methotrexate.

Crohn’s Disease

Crohn’s disease is a granulomatous inflammation of the bowel associated with systemic manifestations. The ocular manifestations are primarily related to uveitis, episcleritis, and scleritis; however, orbital pseudotumorlike presentations, secondary to granulomatous inflammation in the orbit has been described.68,69 Optic neuritis has also been described in Crohn’s disease.70

Sjögren’s Syndrome

Sjögren’s syndrome (SS) consists of a triad of symptoms including dry eyes (keratoconjunctivitis sicca), dry mouth (xerostomia), and “dry joints” (arthritis).71 The primary SS is not associated with other connective tissue diseases; however, secondary SS symptoms overlap with the manifestations of systemic lupus erythematosus, polymyositis, polyarthritis nodosa, scleroderma, and rheumatoid arthritis.72 Like many other autoimmune diseases, SS does not have a clear-cut etiology; however, it is considered to be a mononuclear inflammatory vasculopathy.73 Many viruses, including Epstein–Barr, cytomegalovirus, hepatitis C, and HIV have been reported to have an etiologic role in SS. Immune complex formation and deposition are considered to be the physiopathology of cutaneous and ocular vasculitis.74,75

The histopathology of the conjunctiva as well as the lacrimal gland is nonspecific, consisting of the regular infiltrates of lymphocytic and plasma cells surrounded by eosinophilic basement membrane–like material. These units are called epimyoepithelial islands and are considered to be diagnostic of SS.76,77 The lacrimal gland also reveals acinar atrophy and increased fibrosis surrounding the ductules (Figure 29.5D). The diagnosis of SS is based on minor salivary gland biopsy rather than the biopsy of the lacrimal gland, since the latter procedure is more involved surgically and carries a higher morbidity.78

Keratoconjunctivitis sicca is the most common presentation of SS in the eye, occurring in about 90% of patients. Diminished tear meniscus and decreased tear breakup time (BUT) with diminished tear production documented with Schirmer strips are common

findings. Less commonly patients develop episcleritis/ scleritis in the primary type of SS.79 Because of peripheral and central nervous system involvement, optic neuritis and internuclear ophthalmoplegia may be seen in these patients. The asymmetrical orbital presentation of the disease may be confused with orbital lymphoma or sarcoidosis. In most cases, however, the disease presents with bilateral enlargement of the lacrimal glands and other symptomatology. Although SS is easy to diagnose, it should be kept in mind that SS patients have an increased risk of developing B-cell lymphomas in the salivary glands and cervical lymph nodes. This association has not been found to be true for the lacrimal gland. However, the orbital lymphoma that can mimic the presentation of SS should always be considered in differential diagnosis (see Chapter 13).

Wegener’s Granulomatosis

Wegener’s granulomatosis (WG) is an idiopathic systemic vasculitis that also causes necrotizing granulomatous inflammation.80,81 The classic triad of the disease comprises necrotizing granulomatous vasculitis of upper and lower respiratory tracts and necrotizing glomerulonephritis. Small-vessel disease also affects the eye and orbit, leading to conjunctivitis, scleritis, uveitis, and thromboembolic phenomenon of the choroidal vessels and central retinal artery.82–84

Orbital involvement also results from necrotizing vasculitis (with or without granulomatous inflammation), leading to painful proptosis, eyelid and conjunctival edema, and extraocular motility disturbance. Optic nerve disease may result from the combination of vasculitis of the optic nerve and meningeal vessels and/or the compression caused by the orbital spaceoccupying lesion (Figure 29.12).83 This on occasion can lead to occlusion of the central retinal artery.85

Although the specific idiopathogenesis of WG is unknown, there is a consensus that the disease results from an autoimmune mechanism. Unlike other forms of vasculitis, however, it does not appear to be caused by immune complex deposition.86 It has been speculated that the vasculitis of WG is triggered by an infectious process.87,88 As a rule, respiratory tract involvement in WG precedes renal or systemic disease; however, many atypical cases with lack of involvement of one organ system or another are well recognized.89

It is well known that anti-neutrophil cytoplasmic antibodies (ANCA) function to contain the inflammatory responses by proteolysis, primarily by collagenases and elastases.90 Cytoplasmic ANCA (C- ANCA) is a very sensitive and specific serologic marker for WG, with a sensitivity increasing up to 96% for active disease.91,92 Others hypothesize that C-ANCA is not merely a marker for the disease but in itself is pathogenic.93 High and low C-ANCA titers

FIGURE 29.12. Recurrent Wegener’s granulomatosis with minimal left proptosis but atrophy of left disk as a sequela from previous episodes of activity. The orbit biopsy material shows granulomatous

(G) vasculitis.

are known to correlate well with disease activity and remission, respectively.94 Biopsy-proven head and neck orbit WG lesions particularly are known to occur without elevated titers of C-ANCA.95,96

The classic histopathologic picture includes extensive necrotizing vasculitis with necrosis and granulomatous inflammation. However, considerable variability is observed in the biopsy samples obtained from

different organs, and the classic appearance is not always demonstrable.97,98 Upper respiratory tract and orbit biopsies usually show vasculitis and necrosis but rarely granulomas.99,100 Material from lung biopsies usually shows diffuse necrotizing vasculitis of small blood vessels resembling an infectious process. Polymorphonuclear cells and eosinophils may form cuffs around blood vessels, but granulomas are rare.101,102 Samples from kidney biopsies show necrotizing glomerulonephritis without well-formed granulomas.103

Samples from orbital biopsies also fail to depict the typical combination of vasculitis and granulomatous inflammation. Kalina and coworkers reported the presence of the complete triad of vasculitis, necrosis, and granulomatous inflammation in only 54% of the samples obtained from biopsies.97

Granulomas may also present some variability; in certain instances they are seen as typical hard granulomas made of aggregates of epithelioid cells, and giant cells surrounded by lymphocytes and occasional plasma cells. Granulomas that present within necrotic areas may present as palisading lesions containing numerous polymorphonuclear leukocytes and eosinophils.

Ophthalmic involvement of WG is best categorized in two types: focal disease that results from vasculitis and primarily affects the anterior and posterior segments of the eye and contiguous disease, seen primarily in the orbit as a result of WG extending from the nasal cavity and perinasal sinuses. Orbital disease that develops acutely with painful proptosis, eyelid and conjunctival edema, and ocular motility disturbance is the most common ocular manifestation in WG.104,105 This presentation of WG may mimic orbital pseudotumor

FIGURE 29.13. (A,B) Coronal and axial T1-weighted MR images showing irregular infiltrates of amyloid in the lacrimal gland fossa. (C,D) Photomicrographs showing the amorphous, acellular infiltrates of amyloid (periodic acid–Schiff and Congo red stains). Inset: Apple green birefringence of the amyloid deposit surrounding a blood vessel.