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

tracranial pressure leads to edema of the fellow optic disk.48 Although Foster–Kennedy syndrome has been most commonly associated with meningiomas, this phenomenon is also seen with optic nerve gliomas, craniopharyngiomas, and other space-occupying lesions of the orbit and the cranium, including abscesses.49 Color vision abnormalities, afferent pupillary defect, and visual field loss are also seen with secondary meningeal tumors in the orbit. In some cases, with minimal or no proptosis, the visual field deficit and diminished vision are incorrectly attributed to glaucoma or optic neuritis.

Ultrasonography is not helpful in differential diagnosis of secondary meningiomas because most of these lesions are located deep in the posterior orbit. Approximately 50% of all cranial meningiomas appear in the sphenoid wing; another 20% are located in the sellar area. Therefore, the secondary effect of these neoplasms on the orbit, optic nerve, and other ocular structures is immense.

Because of their high cell density and tendency to develop calcification, meningiomas of the sphenoid ridge and sellar region present as hyperdense lesions on CT; diffuse hyperostosis of en plaque meningioma is particularly apparent on CT.50,51 Since en plaque lesions grow in diffuse fashion, knowledge of the anatomy of the region as revealed by MRI, including the shape of the basal cisterns, orbital foramina, and blood vessels is required to determine accurately the extent of the disease. Most meningiomas, particularly the aggressive, angioblastic type, develop intense enhance-

ment after the intravenous injection of contrast medium.52 Although MRI usually does not produce a good image contrast between the tumor and the adjacent soft tissues in the orbit, it is superior to CT in the study of sellar and juxtasellar areas.53

Sphenoid ridge meningiomas are difficult lesions to diagnose clinically because they may mimic glaucoma, optic neuritis, and other intraorbital and intracranial neoplasms, metastatic tumors, and lymphomas.54 One should also keep in mind that nonspecific neurologic findings such as headache, changes in mental status and personality, hypothalamic abnormalities, and seizures may very well be seen in meningiomas, particularly with intrasphenoidal ridge and perisellar tumors.55 Intracranial meningiomas extending into the orbit through the foramina may also mimic the clinical features of myasthenia gravis. Therefore, patients with atypical presentations of myasthenia limited to ocular and/or cranial musculature should be thoroughly evaluated to rule out an intracranial mass lesion.56

Ectopic Meningioma

Ectopic meningioma is a rare tumor that seems to appear to originate from ectopic arachnoidal tissue outside the central nervous system in skin, scalp, nasal cavity and paransal sinuses, and in other viscera.57–59 Among other sites, ectopic meningiomas also develop within the orbit.60–63 Ectopic orbital meningiomas have been described in children and adults, with a sig-

nificant male predominance. These tumors presented space-occupying lesions, primarily in the medial orbit. The histopathogenesis of the ectopic orbital meningioma is not clear. The most conceivable of many hypotheses is that these lesions originate from regressed orbital meningoceles with leftover arachnoidal tissue, trapped within orbital soft tissues.59,60

The role of trauma may also explain the pathogenesis of some cases. It is possible that penetrating trauma can dislodge meningeal tissues within the orbit that later serve as a nidus for the development of meningiomas.64 In the author’s personal experience of two patients with ectopic orbital meningioma, one had a history of trauma that resulted in the enucleation of the globe and the other did not but had a su- perior–medial eyelid/orbit mass that had been growing slowly and ultimately caused mechanical upper lid ptosis. In the patient with the history of trauma, the tumor developed 20 years later within the inferior orbit with no other evidence of dislocated meningeal tissue (Figure 23.11). Ectopic meningiomas usually present with a meningotheliomatous histology and respond well to total surgical excision.

Craniopharyngioma

Craniopharyngiomas are benign, epithelial tumors of the sellar area that present as partially cystic, partially solid masses in children and adolescents. These tumors originate from the Rathke pouch epithelium and account for approximately 2 to 5% of all intracranial tumors. Craniopharyngiomas do not present a gender preference but do have a bimodal age distribution with one peak for children and adolescents and another one for adults.65

Craniopharyngiomas are divided into two basic clinical pathologic types: adamantinomatous and capillary. Capillary craniopharyngiomas present as solid tumors, are found more often in adults, and cause occlusive hydrocephalus, which produces frequent symptoms of headaches, nausea, vomiting, and papilledema. Endocrine deficiencies, including diabetes insipidus and dwarfism, are also seen in a great majority of the patients, primarily in children with the adamantinomatous type. However, the visual disturbances secondary to compression of optic structures and invasion of the orbit are more frequently seen in adults (Figure 23.12).66,67 The adamantinomatous type of craniopharyngioma is primarily seen in children and often presents with partially calcified cystic lesions. CT and MRI are indicated to diagnose and define the extent of these tumors; MRI enables a better delineation of the tumor extent, especially on coronal and sagittal views. Differential diagnosis of these masses should include cystic pituitary adenomas, suprasellar meningiomas, dermoid cysts, gliomas of

FIGURE 23.12. MR images of an 11-year-old boy who presented with headache and visual deficit bilaterally. The coronal MRI (top) is a T1-weighted, contrast-enhanced view in which the cyst wall and the inferior solid portion of the tumor reveal strong signal enhancement. The midsagittal, T1-weighted view (bottom) shows the marked enlargement of the sella by the tumor; optic chiasm cannot be identified.

the optic chiasm, and granulomatous inflammatory lesions such as sarcoidosis.

Pituitary Adenoma

Pituitary adenomas rarely involve the orbit secondarily. The prolactin-secreting type (prolactinoma) is known to extend into the posterior orbit occasionally (Figure 23.13).46 These lesions are histopathologically benign but invasive tumors that typically present with amenorrhea and galactorrhea in women and hypogonadism and space-occupying lesions in men. “Giant” prolactinomas are invasive; these tumors are defined as lesions larger than 4 cm at the greatest diameter that produce serum prolactin in excess of 1000 ng/mL. Some become very large and invade perisellar structures and beyond; superior extension is most common, but these lesions are also known to extend laterally,

posteriorly, inferiorly, and, less often, anteriorly into adjacent anatomic structures such as cavernous sinus and orbit.68,69

When the orbit is involved, the tumor causes proptosis, extraocular motility disturbances, orbital congestion, and increased intraocular pressure. If the orbit has been extensively invaded by the pituitary adenoma, the prognosis is poor. However, if the orbital invasion can be detected early, prior to compressive optic neuropathy, potentially disastrous visual damage can be reversed with a combination of surgery and medical treatment with bromocriptine, which is known to reduce the size of the tumor effectively and lower the levels of serum prolactin.70

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Compared with orbital diseases and other conditions in patients who seek consultation in ophthalmic practice, metastases to the orbit are rare. Nevertheless, the ophthalmologists con-

fronted with presumed orbital metastases play an important role in the diagnosis and management of these patients. Up to 35% of patients with orbital metastasis present with no known history of primary tumor at the time of ophthalmologic examination.1,2 The ophthalmologist should be able to identify symptoms and signs more commonly associated with metastatic orbital disease, recognize the results of imaging studies, know the most frequent primary sites that disseminate to the eye and orbit, and implement appropriate management according with the original tumor and stage of the disease.

INCIDENCE AND EPIDEMIOLOGY

In biopsy-proven series, the frequency of metastatic tumors among orbital mass lesions ranges from 2.5 to 10%.3–5 The ratio between orbital metastases and ocular metastases varied from 1:8 in histopathologic series to 1:1.4 in more recent clinical series.6–9

Almost any primary tumor originating elsewhere in the body has been reported to metastasize to the orbit.10,11 The most frequent primary sites are those most common in the adult and older populations, including breast, lung, prostate, and malignant melanoma.12–15 Metastases from the liver and gastrointestinal tract are seen more frequently in Japan than in the United States and Europe, reflecting geographical, environmental, or genetic susceptibilities.16 From clinical ophthalmologic practice, tumors with more aggressive behavior, like metastatic carcinoma from the lungs, tend to be underrepresented. At the time of presentation of orbital metastasis, patients with lung carcinoma are usually in poor clinical condition. Metastatic cancer from an unknown primary site is a clinical challenge for all physicians. In a recent series, the primary tumors remained undetected in 10% of patients without history of primary tumor at the time of ophthalmologic examination.15

In developed countries, because of the trend toward early diagnosis of cancer and the use of more sophis-

ticated imaging studies, most patients with metastatic orbital lesions present with a known history of primary tumors. In approximately one out of four patients with presumed orbital metastases, the orbital specialist may be the first physician to demonstrate the dissemination of the tumor.15 The time lag between the diagnosis of the primary tumor and orbital manifestation varies according to the biologic behavior of the tumors. Carcinomas from the breast, thyroid, and kidney have relatively long delays between diagnosis of the primary and the manifestation of metastasis, but this time lapse is very difficult to determine accurately.

Contrary to what one might expect from metastatic disease, most orbital metastases present as unilateral, solitary masses. Only 10% of orbital metastases are bilateral.13,17 Bilateral disease is more frequent in breast carcinoma (19%) than other tumors (2–5%). In a combined case series,10 47% have demonstrated concurrent involvement of other sites, including the eye. Combined ocular and orbital metastases have been observed in 21% of cases from an ophthalmologic practice.15 Concurrent involvement of the central nervous system is less than 5%.18

CLINICAL FINDINGS

Two recent series reported average ages of 44.8 and 62 years, but age may vary depending on the primary tumor.15,16 In other published cases, the average age was 59 years for breast, 58 years for lung, 70 years for prostate, and 45 years for malignant melanoma.5,10,11,19 The sex predominance is also dependent on the origin of the metastatic tumors. Amemiya et al. reported 74 males and 52 females, but the most frequent primary site was the lung.16 In contrast, Shields and coworkers found 60 females and 40 males in a series with predominant breast carcinomas.15

The most frequent complaints of patients with presumed metastatic disease to the orbit are proptosis, ocular motility disturbances and diplopia, pain, palpable mass, ptosis, and lid swelling. Visual acuity may not be affected during the early phases of the disease. The duration of symptoms varies from one to a few months in lung primaries to more than a year in slow-

growing carcinoid tumors, depending on the growth rate of the tumor. A distinguishing feature of orbital metastasis is the progressive course associated with motor and sensory deficits. These deficits may be significant, even with small metastatic orbital masses because of their rapid development. Slow-growing lesions (e.g., pleomorphic adenomas), would not cause as much orbital dysfunction, even when they reach much larger sizes.

Individual symptoms reflect particular tissue involvement within the orbit. Tumors that infiltrate fat and extraocular muscles produce proptosis.20–25 When muscle involvement is early, the presenting complaint is diplopia. Pain is usually associated with periosteal and bone involvement. Pulsation may be the result of either bone destruction or highly vascular tumors like unusual cases of renal carcinoma. A rare sign is enophthalmos, observed in approximately 10% of cases in some series.10 It is generally related to the fibroblastic response associated with breast carcinoma and other tumors with a schirrous stromal component (Figure 24.1). Enophthalmos may also result from fat atrophy.20

Information obtained from clinical, imaging, and surgical studies indicates that the lateral orbit is the most common location of orbital metastasis (39%), followed by the superior (32%), medial (20%), and inferior (12%) quadrants.10 Goldberg and coworkers summarize the clinical presentation of metastatic orbital disease in five generalized types.10

1.Mass formation. More than 65% of the patients present with mass formation (Figure 24.2). Primary mass effect presents with axial or nonaxial

proptosis because of displacement of the globe. The mass may be palpable in anteriorly located tumors. Posterior lesions may present with papilledema and pressure on the posterior globe.

2.Infiltration. Approximately 25% of the patients present diffuse or localized infiltration of orbital tissues characterized by diplopia, increased resistance to retrodisplacement of the globe, and, rarely, enophthalmos.

3.Functional. Predominant decrease in cranial nerve function not related to the size of the mass or degree of infiltration.

4.Inflammation. Acute or subacute orbital and periocular inflammatory signs.

5.Silent. No orbital signs or symptoms.

Metastatic disease may present as focal nodular muscle enlargement without compromise of other orbital tissues.21–25 One or more muscles may be affected, and even bilateral involvement has been reported. The horizontal rectus muscles are more commonly affected than the vertical recti and oblique muscles. In some cases diffuse muscle enlargement may resemble an inflammatory pseudotumor or thyroid orbitopathy.23 The differential diagnoses of muscle enlargement include Graves ophthalmopathy, orbital myositis, lymphoma, vascular malformations, amyloidosis, and specific inflammatory diseases.25 A transient response to steroid treatment may be misleading because it can occur in metastatic lesions of the orbit. The two most frequent metastatic tumors associated with extraocular muscle involvement are breast carcinoma (55%) and melanoma (21%).25

FIGURE 24.2. Mass formation of a metastatic tumor (squamous cell carcinoma), presenting as a large space-occupying lesion, superior medial to the globe in the right orbit. The axial CT image reveals the necrotic nature of the tumor core, indicating a rapid growth. The mass was causing inferior lateral proptosis and extraocular motility problems. The primary of this lesion was unknown despite extensive workup, including thorough consultations with ear, nose, and throat specialists.

DIAGNOSTIC PROCEDURES

Orbital Imaging

Computed tomography (CT) and magnetic resonance imaging (MRI) provide information regarding tissues involved with tumor. Growth pattern is either a welldelineated mass or a diffuse lesion with irregular margins. Multifocal nodularity of the muscles, which may

be demonstrated by CT scan or MRI, is more consistent with the diagnosis of a metastatic process (Table 24.1).24,25 The relative frequency of each presentation is as follows: orbital mass 58%, bone 25%, muscle 9%, and/or diffuse involvement 8%. Although classic presentations have been described, carcinomas from the same primary site may disclose a discrete mass in some patients and a diffuse pattern in others.

On CT scan, metastatic lesions are very similar in density to extraocular muscles.26 Muscle involvement usually discloses a solitary mass with irregular borders; other findings include bone destruction with or without intracranial or sinus extension. Evidence of direct intracranial extension has been demonstrated in 46% of patients with orbital metastasis.26

CT scans are particularly useful in suspected cases of prostate carcinoma and other metastatic tumors with bone involvement. The bone lesions may be either hyperostotic (osteoblastic) or hypostotic (oseolytic). In general, prostate carcinoma causes a hyperostotic (osteoblastic) response (Figure 24.3).

T1-weighted MR images provide excellent resolution to differentiate muscle involvement from the hyperreflective orbital fat.27,28 T1-weighted images with fat suppression allow better visualization and resolution of soft tissue growth pattern and location. T2weighted images are less specific; metastatic tumors are hyperreflective with these studies, particularly after gadolinium injection (see Chapters 9 and 10).

Echography of the orbit is useful to measure enlarged muscles and may occasionally show cystic degeneration of necrotic tumors but is not very helpful in most instances.

The most important point in the evaluation of patients with presumed metastatic disease is guided history taking. Elderly patients who had primary tumors in other body sites treated several years prior to orbital manifestations may forget or intentionally deny any history of cancer.

A systemic workup should be done by a medical oncologist in confirmed cases for the evaluation of other metastatic sites and staging. The ophthalmolo-

TABLE 24.1. Diagnosis of Metastatic Disease of the Orbit.

FIGURE 24.3. Hyperostosis of the superior orbital rim in a patient with metastatic prostate carcinoma. Inset: Groups of malignant epithelial cells consistent with prostate carcinoma obtained with FNAB.

gist should clearly state the presumed diagnosis as metastatic orbital tumor.

Rarely, the orbital specialist may request other laboratory tests and radiographic studies as part of the initial workup in a patient suspected to have an orbital metastasis. Specific tests are particularly useful in tumors that elaborate or are associated with an elevation of measurable substances in serum or urine, such as prostate carcinoma and carcinoid tumors. Carcinoid tumors have an affinity for uptake of the radiopharmaceutical [131I]metaiodobenzylguanidine (MIBG). Hanson et al. reported a patient with a known carcinoid tumor who developed a left orbital mass that demonstrated abnormal uptake of [131I]MIBG indicative of metastatic carcinoid tumor of the orbit.29

Tissue Diagnosis

Fine-needle aspiration biopsy (FNAB) (see Chapter 12) of the orbit is a simple but effective method for confirmation of the orbital metastasis (Figure 24.3).30–32 FNAB may be performed as an ambulatory procedure or in the operating room after superficial exposure of the tumor. In both situations the procedure is rapid and cost-effective. An adequate specimen usually provides material for routine studies and in some cases for special stains. The optimal setting of FNAB is guidance of the procedure by means of CT and preparation and evaluation of the specimens by an experienced cytopathologist with knowledge of orbital disease. Negative results or the presence of inflammatory cells may be misleading. Metastatic tumors with a prominent stromal component may result in nonrepresentative samples.33 The observation of a few lymphocytes as the only cells present should not rule out a metastatic disease because infiltrative orbital lesion may show

a chronic inflammatory response. Bloody samples in a patient suspected of harboring orbital metastasis should be carefully examined to detect individual, atypical cells or isolated clusters of tumor cells. Melanoma and renal carcinoma are commonly associated with hemorrhage.34 False negative results vary according to the location of the lesion within the orbit and the type of lesion, but no false positive results have been reported in FNABs for the diagnosis of orbital metastasis.1,33,34

An incisional biopsy is indicated either when FNAB results in nonrepresentative samples or when FNAB cannot be performed because of location or because ample tissue is required for special studies. Currently, most differential diagnoses are resolved by immunohistochemical staining techniques using tissue-specific antibodies. Electron microscopy is rarely used for the diagnosis of specific tumor cell types. Special studies include hormonal receptors, proliferative factors, major chemotherapy resistance gene expression, and fusion gene expression. In these instances, the orbital surgeon should communicate with the pathologist in advance regarding the required size and handling of tissue samples.

MANAGEMENT AND PROGNOSIS

The behavior and management of orbital metastases is largely dependent on the primary tumor. Although the prognosis of the patient with orbital metastasis is poor, long survival after treatment of certain neoplasms may occur. Nevertheless, even in hopeless situations, treatment to restore or maintain visual function may provide a better quality of life.

Management of orbital metastatic disease includes palliative irradiation, hormone therapy, chemotherapy, surgical excision, and observation, depending on clinical circumstances (Table 24.2). Radiotherapy is one of the more useful choices for improvement of orbital signs and symptoms and recovery of vision.35,36 Irradiation doses are divided over periods of two to four weeks for a total dose of 30 to 50 Gy (see Chap-

TABLE 24.2. Management of Patients with Metastasis to the Orbit.

ter 33). The success rate in published series is 70 to 90%. The use of adequate doses, delivery through the lateral orbital wall, and eye protection may reduce complications. In one large series, 12 patients experienced acute, transient keratoconjunctivitis; as late side effects, two cases of cataract were observed during a period of observation of 37 and 117 months.37 In advanced cases of orbital metastases, which may also involve adjacent structures, high-dose radiation (HDR) brachytherapy may be used for palliative purposes.38

Hormonal therapy is an alternative to more aggressive methods of treatment in tumors that show estrogen and progesterone surface receptors. Breast carcinoma and prostate carcinoma have been treated solely with hormonal therapy with good results. Prostate carcinoma may be responsive to orchiectomy or diethylstilbestrol.

Chemotherapy with antimetabolites is indicated in tumors that are unresponsive to hormonal therapy and in premenopausal women. Dramatic reduction of signs and symptoms has been observed with systemic chemotherapy alone.

If the only site of metastasis is the orbit, or if a solitary, circumscribed orbital mass is present, surgical excision of the tumor may relieve the clinical manifestations in some patients and even provide a reasonable tumor-free period. Experience with patients who have undergone biopsy has shown that a slow-growing carcinoid may be amenable to surgical excision. Surgical debulking may be required in patients with tumors resistant to other treatment modalities.

Observation without specific treatment of the orbital tumor is a reasonable choice for patients with asymptomatic orbital metastasis but otherwise advanced systemic disease. The prognosis of patients with orbital metastases is poor. Among patients with sufficient follow-up, 95% died of metastasis, with overall mean survival of 15 months, ranging from 3 to 96 months after diagnosis.1,15

ORIGINS OF METASTASES TO ORBIT

Breast Carcinoma

Breast carcinoma is the most common primary source of orbital metastases. The ophthalmologist should be aware that incidences of breast cancer have increased approximately 30% in the past two decades.39 The frequency of breast carcinoma among orbital metastases varies from 29 to 51%. Breast primaries are almost always identified either before or simultaneously with the metastatic disease. Rarely, an orbital metastatic focus will precede the diagnosis of a nonpalpable primary breast carcinoma.40 A long delay between the diagnosis of the primary tumor and orbital manifes-

tation is not uncommon. The average time is 4.5 to 6.5 years.40 Longer delays up to 25 years have been reported, however.40,41

Patients with breast carcinoma that has metastasized to the orbit are predominantly females, although a few cases in males have been described.42 The median age at the time of presentation is in the sixth decade.43 Bilateral orbital involvement is seen in 20% of the cases, exceeding the average incidence of bilateral metastases from other primary neoplasms.

Although symptoms and signs of breast carcinoma do not basically differ from metastases from other primary tumors, certain presentations are quite characteristic. Most breast carcinomas are invasive and infiltrate the fat and muscle. Isolated extraocular muscle involvement is more common in breast carcinoma, and the eyelid may also be affected. Slowly progressive enophthalmos with reduced motility is nearly pathognomonic of metastatic scirrhous breast carcinoma (Figure 24.1).44 Nearly 54% of patients present with an infiltrative or inflammatory syndrome that should be differentiated from such other conditions as idiopathic inflammatory pseudotumor, myositis, and cellulitis.45–47

Clinical examination should include physical examination of the breasts and axillary and supraclavicular lymph nodes. Mammography may be of help in female patients without history of prior cancer. Rarely, patients may present with metastatic disease from an unknown breast primary.48

Invasive ductal carcinoma is the most frequent breast cancer histologic type; it includes mucinous, papillary, and scirrhous variants. Other cell types are lobular invasive and undifferentiated carcinomas. Lobular carcinoma has a tendency toward multicentric and bilateral mammary gland involvement. In a literature review of orbital breast metastases, the histopathologic subtypes of 54 carcinomas were as follows: 9 invasive ductal, 5 invasive lobular, 5 scirrhous, and 35 undifferentiated.46 Scirrhous and lobular carcinoma of the breast may pose a challenge for histopathologic diagnosis because the yield of FNAB is low. The dominance of fibrous tissue in these tumors may lead to nondiagnostic results. Some authors favor the use of an incisional biopsy in suspected cases with enophthalmos or inflammatory presentations. At the time the tumor tissue is surgically removed, estrogenreceptor (ER) and progesteron-receptor (PR) status should be determined, and it is good practice to save fresh tissue for further analysis, including expression of HER2-neu.

Patients with breast cancer and orbital metastases are classified in stage IV of the system of the American Joint Committee on Cancer, which includes patients with any status of the primary tumor and lymph nodes, and distant metastases (see Chapter 30).49 Goals of treatment include improving quality of life