Recent Advances in Ophthalmology—9 HV Nema, Nitin Nema
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Malignant Orbital Tumors in Adults1

Kaan Gündüz,
Rengin A Kurt,
Esra Erden,
Ömür Ö Uçakhan-Gündüz,
 
INTRODUCTION
Malignant orbital tumors in adults comprise a diverse group of tumors including primary, secondary, and metastatic tumors. The primary malignant orbital tumors include lymphoid, lacrimal gland, neurogenic, and vascular tumors. Secondary orbital tumors reach the orbit by direct extension from adjacent structures such as eyelid, conjunctiva, eyelid, globe, paranasal sinuses, or nasal cavity (Table 1.1). Orbital metastases usually reach the orbit by the hematogenous route and frequently originate from breast, lung, and prostate cancers.
TABLE 1.1   Classification of the malignant orbital tumors in adults
Ocular adnexal lymphoma
Malignant lacrimal gland tumors
  • Adenoid cystic carcinoma
  • Pleomorphic adenocarcinoma (malignant mixed tumor)
  • Adenocarcinoma
  • Mucoepidermoid carcinoma
Malignant neurogenic tumors
  • Malignant peripheral nerve sheath tumor
Malignant vascular tumors
  • Angiosarcoma
  • Hemangiopericytoma
Secondary tumors
  • Eyelid tumors
    • Basal cell carcinoma
    • Squamous cell carcinoma
    • Sebaceous carcinoma
    • Malignant melanoma
  • Conjunctival tumors
    • Squamous cell carcinoma
    • Malignant melanoma
  • Intraocular tumors
    • Uveal malignant melanoma
  • Paranasal and nasopharynx tumors
Metastatic tumors
2
A review of 1264 orbital lesions by Shields et al disclosed that malignant orbital lesions accounted for approximately 34% (at least one third) of all space-occupying orbital lesions in a combined clinical and histopathologic series.1 Table 1.2 shows the frequency of various malignant orbital tumors in adults in their series. Malignant orbital tumors accounted for 27% of the orbital lesions in young adults and middle aged patients (age range 19-59 years) and 58% of the orbital lesions in older patients (age range 60-92 years).1 Lymphomas and secondary orbital tumors were the most frequent malignancies, each accounting for approximately 10% of all the space-occupying orbital lesions in adults followed by metastatic tumors (7%) and lacrimal gland tumors (6%).1
 
OCULAR ADNEXAL LYMPHOMA (OAL)
 
Clinical Features
Ocular adnexal lymphoma represents the malignant end of the spectrum of ocular adnexal lymphoproliferative disease and has reactive lymphoid hyperplasia (RLH) and RLH with atypia as its benign and intermediate forms respectively. The overall incidence of systemic lymphoma is increasing but no corresponding information exists for OAL.
Ocular adnexal lymphomas are the most common primary orbital malignancy.2 The majority of orbital lymphomas are seen primarily in adults in the 50-70 years age group. Ocular adnexal lymphomas can affect the orbit, lacrimal gland, eyelids, or the conjunctiva (Fig. 1.1). It most often presents as a non-tender, firm, subcutaneous mass in the anterior orbit; as a conjunctival salmon-patch infiltrate (Fig. 1.2); or as an eyelid infiltration.3,4
TABLE 1.2   The frequency of malignant orbital tumors in adults among all biopsy proven orbital lesions1
Malignant orbital tumors
Frequency orbital lesions (%)
Ocular adnexal lymphomas
10
Malignant lacrimal gland tumors
6
Malignant neurogenic tumors
< 1
Malignant vascular tumors
1
Secondary tumors
10
Eyelid tumors
2
Conjunctival tumors
2
Intraocular tumors
4
Paranasal tumors
1
Nasopharynx tumors
1
Metastatic tumors
7
3
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Fig. 1.1: A 72 year-old woman with lymphoma in the right superior orbit producing proptosis and bulging in the upper eyelid
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Fig. 1.2: Conjunctival lymphoma with typical salmon color and diffuse margins
However, in 30-40% of patients, systemic involvement is seen within 5-10 years after diagnosis of the orbital lymphoma.
Most OALs are of the non-Hodgkin's stage IE (extranodal) low-grade B-cell variety.3,4 More superficial tumors of T-cell lineage, such as mycosis fungoides, can also occur in the periocular skin and typically cause a secondary ectropion of the lower eyelid.
Ocular adnexal lymphomas may be associated with systemic lymphoma; thus, a full systemic work-up is required for staging of the lymphoma and to look for other foci of lymph node involvement. Fluorine 18 deoxyglucose positron emission tomography (FDG PET) proved to be 4useful in detecting systemic extranodal lymphomatous sites not detected in conventional imaging. Therefore, it may be used to evaluate systemic involvement in OAL patients.5
Many lymphomas are thought to develop as a result of mistakes occurring during the normal lymphocyte response to infections or inflammation. There is increasing evidence of a role of chronic infection in OAL. Both Chlamydia psittaci (C. psittaci) and Helicobacter pylori (H. pylori) have been identified to date in patients with OAL.6,7
 
Radiologic Features
On orbital CT and MRI, lymphoid lesions typically mold to structures such as the globe and bony orbit. There is usually no bone destruction. Lymphoid lesions are hypo to isointense with respect to the orbital fat and extraocular muscles on T1-weighted images (Fig. 1.3) and usually isointense on T2-weighted images (Figs 1.4 and 1.5).8 In the clinical and radiologic differential diagnosis of OALs, dacryoadenitis, inflammation, metastasis and benign and malignant tumors must be considered. Dacryoadenitis is usually hypointense on T2-weighted images and benign and malignant epithelial tumors are hyperintense.
 
Histologic Features
Accurate histopathologic evaluation is the most critical step in the management of orbital lymphomas. At least part of the tissue obtained after surgery should arrive at the pathology laboratory fresh (without fixatives).
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Fig. 1.3: Bilateral lacrimal gland lymphoma in a 63 year-old woman. T1-weighted orbital MRI shows that the lacrimal gland masses have a molded appearance and are isointense to the extraocular muscles and cerebral gray matter (arrow)
5
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Fig. 1.4: T2-weighted coronal orbital MRI showing the superiorly located orbital lymphoma isointense to the extraocular muscles and cerebral gray matter
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Fig. 1.5: T2-weighted orbital MRI shows that the lacrimal gland lymphoma is isointense to the extraocular muscles and cerebral gray matter (arrow)
The histopathologic spectrum for lymphoid tumors of the orbit ranges from a benign reactive lymphoid hyperplasia to lymphoma. The histologic classification of lymphoma is beyond the scope of this review, but the REAL (Revised European American Classification of Lymphoma) classification applies to tumors of the orbit.9 Most orbital lymphomas are of non-Hodgkin's B-cell type (Fig. 1.6).
6
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Fig. 1.6: Lymphoid infiltration composed of small lymphoid cells (Hematoxylin-Eosin, x20)
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Fig. 1.7: Neoplastic B lymphocytes demonstrate strong and diffuse positivity with CD-20 (CD, x40)
Ocular adnexal lymphoma consists of five types of lymphoma, the most common of which is extranodal marginal zone (EMZT) or MALT type followed by the follicular lymphoma. The other types including mantle cell lymphoma, diffuse large B-cell lymphoma, and lymphoplasmacytic lymphoma are occasionally seen in the orbit. T-cell lymphoma is rare in the orbit and usually of the natural killer cell variety.
Immunohistochemistry is a sensitive technique to identify antigenic expression of lymphoma cells. CD 20 is the target antigen for mature B lymphocytes and is commonly used in the immunohistochemical evaluation of lesions that are suspected to be lymphomas (Fig. 1.7).7
 
Treatment and Prognosis
As for other extranodal forms of lymphoma, the treatment of ocular adnexal lymphoma depends on the stage and histologic classification. For isolated ocular adnexal lymphoma (stage IE) of low grade, external-beam radiation therapy (EBRT) is considered the standard treatment.1013 The median total dose of radiation used in EBRT for NHL of the orbit is 30-40 Gy (Fig. 1.8). Low-grade lesions are usually treated with a 30 Gy dose; intermediate and high-grade lymphomas are treated with higher doses. For more widespread disease or for higher-grade lymphomas, systemic chemotherapy or a combination of chemotherapy and EBRT may be more appropriate.14 Combination chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or cyclophosphamide, vincristine, doxorubicin, and dexamethasone (CVAD) have been used in the treatment of OAL with systemic involvement.
Another alternative for stage IE low-grade lymphoma of the ocular adnexa, particularly low-grade B-cell follicular lymphoma or MALT lymphoma may be monoclonal antibody therapy or radioimmunotherapy.15 The most commonly used antibody is CD20, rituximab (Rituxan), which leads to the destruction of B-cells using mechanisms of complement and antibody-mediated destruction as well as induction of apoptosis. Radioimmunotherapy refers to the administration of a monoclonal antibody in combination with a radioactive ligand. Ibritumomab tiuxetan (Zevalin) is usually given as a single dose following an infusion of rituximab. Radioimmunotherapy with zevalin in combination with rituximab has shown greater efficacy for treatment of low-grade lymphoma than rituximab alone.
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Fig. 1.8: Regression of proptosis and orbital mass after incisional biopsy and external beam radiotherapy (40 Gy) to the right orbit
8
These antibodies are most commonly used in combination with other agents, so their solitary effect is hard to assess. They seem to reduce but not eliminate lymphoma. However, some centers reported good results in treating low-grade orbital lymphoma with rituximab or rituximab in combination with ibritumomab. Systemic monoclonal-antibody therapy with rituximab (Rituxan) or ibritumomab tiuxetan (Zevalin) potentially decrease the likelihood of systemic recurrence during the follow-up period.4,15 Monoclonal antibody therapy may also be less toxic than systemic chemotherapy and may be associated with fewer ocular complications than radiation therapy.
Another treatment option is the use of oral antibiotics. Using a 3 weeks course of doxycycline, there was a therapeutic effect in half of patients presumably to eradicate the infection that underlies lymphomagenesis. Another study has shown effect in a few patients using the typical anti-H. pylori triple therapy.16 Controversy does exist as to how antibiotic elimination of underlying infection could eradicate a genetic dysregulation.
 
MALIGNANT LACRIMAL GLAND TUMORS
Malignant epithelial lacrimal gland tumors account for 15-25% of all lacrimal gland tumors.17 Malignant tumors of the lacrimal gland include adenoid cystic carcinoma, pleomorphic adenocarcinoma, mucinous adenocarcinoma, and mucoepidermoid carcinoma.
 
Adenoid Cystic Carcinoma
 
Clinical Features
Adenoid cystic carcinoma is the most common epithelial lacrimal gland malignancy.18 Although adenoid cystic carcinoma is more common in adults, it can also occur in children. The age range is from 6.5-79 years with a mean of 45 years. Because this tumor may present in children, a high clinical suspicion is indicated for any unilateral mass in the upper temporal quadrant, even in teenagers and children where these tumors are mistaken for dermoids.
Patients with adenoid cystic carcinoma usually present a mass lesion having a more rapid temporal sequence, usually less than 1 year (Figs 1.9 and 1.10). The presenting symptoms are pain, globe displacement, mass or swelling, numbness, diplopia, visual change, lacrimation, and ptosis. Because this tumor invades perineurally and into adjacent bone, there may be pain and more rarely numbness.9
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Fig. 1.9: A 50 year-old man with right proptosis due to adenoid cystic carcinoma of the lacrimal gland
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Fig. 1.10: A 17 year-old adolescent with right proptosis from adenoid cystic carcinoma of the lacrimal gland
 
Radiologic Features
Neuroimaging studies reveal a round to oval mass with irregular margins and bony destruction (Fig. 1.11).8,19,20 Soft tissue calcification can also be seen. MRI with contrast enhancement is best for assessing the invasion of the tumor into the surrounding structures such as the cavernous sinus, brain, and bone marrow. The tumor is isointense with respect to the extraocular muscle and cerebral gray matter on T1-weighted images (Fig. 1.12) and homogeneously hyperintense on T2-weighted images (Fig. 1.13).810
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Fig. 1.11: Orbital axial CT demonstrating lateral orbital wall destruction adjacent to the lacrimal gland adenoid cystic carcinoma (arrow)
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Fig. 1.12: T1-weighted coronal orbital MRI demonstrating adenoid cystic carcinoma isointense to the extraocular muscles and cerebral gray matter (arrow)
11
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Fig. 1.13: T2-weighted axial orbital MRI showing ACC homogeneously hyperintense to the extraocular muscles and cerebral gray matter. The tumor has irregular margins (arrow)
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Fig. 1.14: Histopathologic examination shows adenoid cystic carcinoma consisting of adenoid and cribriform patterns (Hematoxylin-eosin, x100)
 
Histologic Features
Adenoid cystic carcinoma presents most commonly with a cribriform (swiss cheese) pattern; the basaloid (solid), sclerosing, tubular, and comedocarcinoma patterns are seen in Figure 1.14.21 The basaloid variety has the worst prognosis and is usually seen in patients older than 40 years of age.22 Perineural invasion is commonly seen with adenoid cystic carcinoma.12
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Fig. 1.15: Gross photograph of the completely excised ACC showing a well-circumscribed mass with irregular margins
 
Treatment and Prognosis
Treatment consists of complete surgical resection, if possible (Fig. 1.15). Radical surgery in the form of orbital exenteration with or without removal of orbital bony walls and postoperative radiation therapy (EBRT or less commonly plaque brachytherapy) are often indicated (Figs 1.16 and 1.17).23,24 An EBRT dose of 50-60 Gy is usually recommended. Intra-arterial chemotherapy has also been advocated. Intracarotid cisplatin in conjunction with intravenous doxorubicin were used in patients with adenoid cystic carcinoma in conjunction with exenteration and EBRT with relatively good survival.24
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Fig. 1.16: 40 year-old man with right upper eyelid mass from adenoid cystic carcinoma of the lacrimal gland
13
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Fig. 1.17: The socket has nicely healed 6 months after exenteration and external beam radiotherapy (55 Gy) to the right orbit
Despite aggressive local therapy, a significant proportion of patients (more than 50% according to most series) develop metastatic disease. Patients usually die of intracranial spread as a result of perineural invasion and lung and bone metastasis.23 Adenoid cystic carcinoma can grow insidiously and exhibit recurrence and metastasis years after the initial treatment. The mortality rate for adenoid cystic carcinoma of the lacrimal gland is more than 50% at 5 years.23
 
Pleomorphic Adenocarcinoma (Malignant Mixed Tumors)
 
Clinical Features
Malignant mixed tumors usually arise from an unoperated or incompletely excised pleomorphic adenoma (Fig. 1.18).25,26 Rarely, they may develop de novo. The age range is from 30-79 years, with a mean of 57 years. Patients with malignant mixed tumors tend to be older than those with pleomorphic adenoma.
 
Radiological Features
On imaging with CT, the tumor demonstrates lacrimal fossa destruction. It is not possible to distinguish this tumor from other malignant tumors of the lacrimal gland based on the CT appearance.25,26 The tumor is isointense to the extraocular muscle and cerebral gray matter on T1-weighted images and heterogeneously hyperintense on T2-weighted images (Figs 1.19 and 1.20).8 The heterogenous appearance on T2-weighted images is similar to the heterogenous internal structure of pleomorphic adenomas.14
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Fig. 1.18: 65 year-old woman with pleomorphic adenocarcinoma of the right orbit arising from a pleomorphic adenoma excised elsewhere in an incomplete fashion 12 years ago
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Fig. 1.19: T1-weighted axial MRI shows pleomorphic adenocarcinoma with irregular margins that is isointense to the extraocular muscles and cerebral gray matter (arrow)
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Fig. 1.20: T2-weighted coronal MRI demonstrates pleomorphic adenocarcinoma that is heterogeneously hyperintense (arrow) to the extraocular muscles and cerebral gray matter. The arrowhead shows a cyst within the lesion
15
 
Histologic Features
Malignant mixed tumors have the histologic features of a benign mixed tumor with areas of malignant change. In most cases, the malignant elements are poorly differentiated.
 
Treatment and Prognosis
The recommended treatment is complete excision of the tumor with its periorbital base, and surrounding bone. Postoperative EBRT is recommended. If metastases have occurred, treatment is limited to surgical debulking followed by postoperative EBRT.
It has been observed that tumors arising from a pre-existing pleomorphic adenoma run a better prognosis compared to tumors that arise de novo.27 The cause of death is intracranial extension and distant metastasis to chest wall, lung, and bone.
 
Adenocarcinoma
 
Clinical Features
This tumor tends to occur in older population ranging from 18-80 years, with a mean age of 50 years.27,28 Adenocarcinoma has a propensity to metastasize to regional lymph nodes and the lungs and is associated with a shorter patient survival time than adenoid cystic carcinoma. Adenocarcinoma usually presents as a rapidly developing mass with pain (Fig. 1.21).27,28 Imaging features are similar to other malignant lacrimal gland tumors discussed earlier (Figs 1.22 and 1.23).
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Fig. 1.21: 69 year-old man with adenocarcinoma of the left lacrimal gland. The patient had undergone incisional biopsy of the lesion elsewhere for a rapidly growing eyelid mass. He presented with a ptotic eyelid and limited eye motility in all directions of gaze
16
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Fig. 1.22: T1-weighted axial MRI shows the lacrimal gland adenocarcinoma demonstrating moderate contrast enhancement with gadolinium injection. The tumor blends imperceptively with the lateral rectus muscle (arrow). The hypointense area in the vicinity of the lateral rectus muscle shows the site where the prior biopsy was performed (short arrow)
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Fig. 1.23: T2-weighted axial image showing the lacrimal gland adenocarcinoma that is hyperintense to the extraocular muscles and cerebral gray matter (arrow)
 
Histologic Features
Adenocarcinoma shows pleomorphic cells with many mitotic figures arranged in sheets and cords and lumen formation with mucin production (Figs 1.24 and 1.25). The mucin content of the adenocarcinoma may be demonstrated with mucicarmine and alcian blue stains (Fig. 1.25).27,28
 
Treatment and Prognosis
The recommended treatment is exenteration and EBRT as soon as the diagnosis has been established histopathologically.27,2817
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Fig. 1.24: Atypical epithelial cells form solid nests. A few abortive adenoid structures are also seen (Hematoxylin-eosin, x100)
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Fig. 1.25: Mucin is detected in the lumen of abortive adenoid structures (Mucicarmine, x100)
 
Mucoepidermoid Carcinoma
 
Clinical features
Although mucoepidermoid carcinoma is the most common primary carcinoma of the salivary glands, it is rare in the lacrimal gland. It has been reported to occur in patients aged between 12 and 81 years old with a mean age of 50 years.27,29 In contrast to other malignant lacrimal gland tumors, mucoepidermoid carcinoma usually presents as a slowly enlarging painless mass. Proptosis and diplopia may develop later.18
 
Histologic Features
Histopathologically, these tumors comprise mucus secreting cells interspersed with epidermoid and basal cells. The malignant behavior of the tumor increases with increasing preponderance of epidermoid cells and increasing number of mitoses.
 
Treatment and Prognosis
High grade tumors require exenteration and supplemental external beam radiotherapy while low grade tumors can do well with resection with or without supplemental EBRT.27,29
 
MALIGNANT NEUROGENIC TUMORS
 
Malignant Peripheral Nerve Sheath Tumor
 
Clinical Features
Malignant peripheral nerve sheath tumor (MPNST), or malignant schwannoma, is a very rare tumor of the orbit.30,31 MPNST usually arises de novo in the orbit although it may also arise from a neurofibroma or schwannoma. The term malignant peripheral nerve sheath tumor is preferred over the previously used term malignant schwannoma because Schwann cell origin has not been demonstrated in all cases of MPNST.
Malignant peripheral nerve sheath tumor (MPNST) is usually a tumor of adults although it can rarely can also affect children.3032 MPNST presents with rapidly progressive proptosis and displacement of the globe. Pain, ptosis and signs of optic nerve compression can also be present.30,31 The tumor usually occurs in the superior orbit because of the tendency of this tumor to arise from the supraorbital and supratrochlear nerves.30,31 However, MPNST can occur in other orbital locations as well (Figs 1.26 and 1.27).31
 
Radiologic Features
On CT and MRI, malignant peripheral nerve sheath tumors generally have ill-defined irregular borders. There may be adjacent bone invasion.30,31
 
Histologic Features
Hstopathologically, there is usually no capsule31 although in rare instances the tumor appears to be encapsulated.32 The tumor is composed of spindle-shaped cells with nuclear pleomorphism, hyperchromatism and mitotic figures (Fig. 1.28). Occasionally, epithelioid cells and multinucleated giant cells are present.30,3119
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Fig. 1.26: Malignant peripheral nerve sheath tumor in a 67 year-old patient. Axial CT shows that the tumor occupies the anterior and middle orbit (arrows)
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Fig. 1.27: Coronal CT demonstrates that the malignant MPNST occupies the superior and inferior orbit (arrows)
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Fig. 1.28: MPNST is a highly cellular tumor composed of spindle cells with nuclear pleomorphism and hyperchromatism (Hematoxylin-eosin, x200)
20
The nerve of origin in MPNST is evident in about 50% of the cases.
MPNST shows positive immunoreactivity with S-100, which is less uniform and focal compared to schwannoma. Transmission electron microscopy (TEM) demonstrates prominent nucleoli suggesting a malignant tumor. The presence of long-spacing extracellular collagen (Luse bodies) in TEM suggesting a Schwann cell origin has not been convincingly demonstrated in all MPNSTs.30,31
 
Treatment and Prognosis
Treatment of MPNST consists of total excision of the soft tissue tumor. Adjacent bone should be removed if there is bone invasion. MPNST has a tendency to develop perineural spread resulting in orbital recurrence and intracranial invasion. The risk of metastasis increases if the patient develops orbital recurrence. Therefore, it is important to obtain clear margins at the time of initial surgery to reduce the risk of metastasis. If this is not possible or documentable, some authors have suggested an aggressive approach consisting of exenteration and radiotherapy (50-60 Gy).30,31 Others recommend continued observation with serial neuroimaging studies after complete excision of the orbital tumor.32 Chemotherapy has been used in patients with distant metastasis but there is no substantial evidence to prove that it is effective.30,31
The prognosis for survival in patients with MPNST of the orbit appears to be poor. Metastasis from orbital MPNST usually occurs to the regional lymph nodes and the lung.30, 31 Metastasis usually develops within the first 2 years after diagnosis.30 In one series, 9 of 13 patients with orbital MPNST were deceased within 5 years after diagnosis.31
 
MALIGNANT VASCULAR TUMORS
 
Angiosarcoma
 
Clinical Features
Angiosarcoma, or malignant hemangioendothelioma, is an extremely rare tumor of the eyelids and orbit. It most often develops in the skin and other soft tissues.33,34 The pathogenesis of angiosarcoma is obscure. It develops de novo in most cases although it has also been reported to arise after irradiation of some vascular tumors35 or from persistent chronic lymphedema in the extremities (Stewart-Treves syndrome).36 The tumor may originate from the vascular or lymphatic system or both.
Angiosarcomas have a predilection for skin and superficial soft tissue. The majority of tumors in the facial region arise in the upper part of the face or scalp.3321
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Fig. 1.29: An 82 year-old man with cutaneous angiosarcoma characterized by multiple bruise-like maculopapular lesions, subcutaneous nodules, and diffuse edema over his scalp, face, and eyelids(Courtesy: Drs Jerry and Carol Shields)
The central part of the face, including the eyelids and orbit is involved less often (Fig. 1.29).37 The lower face, including the mandibular region, is seldom affected. Angiosarcoma presents with multiple bruise-like lesions with indurated borders. Large advanced lesions are elevated, nodular and occasionally ulcerated.33
Angiosarcoma can occur as a primary tumor in the orbit. The patient with orbital angiosarcoma usually develops rapidly progressive proptosis and displacement of the globe. It is more frequent in the anterior and/or superior orbit and is associated with swelling of the upper eyelid.38 There is no sex predilection. The tumor seems to have a worse prognosis in adults compared to children.38
Orbital involvement by angiosarcoma is rare. Sometimes, angiosarcoma may secondarily invade the orbit from the sphenoid bone.39,40 Other manifestations include painful ophthalmoplegia, resulting in Tolosa-Hunt syndrome.41 Angiosarcoma is a very aggressive tumor that has the capacity to invade locally to central nervous system and to metastasize to lymph nodes and hematogenously to distant organs such as the liver.42
 
Radiologic Features
CT scan reveals a well-circumscribed or ill-defined mass in the orbit. The tumor may be located anteriorly or posteriorly.38,41 It is not possible to differentiate orbital angiosarcoma from other tumors by neuroimaging methods.22
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Fig. 1.30: The tumor is composed of cords of pleomorphic atypical endothelial cells lining bizarrely shaped vascular spaces (Hematoxylin-eosin, x150)(Courtesy: Drs Jerry and Carol Shields)
 
Histologic Features
Grossly, the angiosarcoma is usually an ill-defined reddish-blue mass. Histopathologically, the tumor is composed of cords of pleomorphic atypical endothelial cells lining bizarrely shaped vascular spaces (Fig. 1.30). The vascular spaces intertwine with dense fibrous connective tissue.33 CD31 is relatively sensitive and specific marker in the diagnosis of angiosarcoma. CD34 and factor VIII-related antigen are less specific.
 
Treatment and Prognosis
Orbital angiosarcoma is probably best managed with wide surgical excision including orbital exenteration if necessary. If there is a question of residual tumor, supplemental radiotherapy should be considered. If there is diffuse involvement of the eyelids, wide-field external beam radiation therapy (radiation dose in the order of 50 Gy) is the best treatment.37 The prognosis for angiosarcoma of the scalp and face seems to be poor. The 5 years survival rate of face and scalp angiosarcomas is around 12%.33 However, long-lasting remissions have been reported after total excision and external beam radiotherapy of orbital and sphenoorbital angiosarcomas.3840
 
Hemangiopericytoma
 
Clinical Features
Hemangiopericytoma is a rare vascular tumor in the orbit. It is thought to arise from the fully differentiated pericytes of the orbital blood vessels.23
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Fig. 1.31: A 64 year-old woman with hemangiopericytoma located superomedially in the left orbit
The great majority of the cases become clinically apparent in adulthood between the ages of 20 and 70 years.4245 However, hemangiopericytoma can also occur in patients outside this age range.
The patient with orbital hemangiopericytoma develops a slowly progressive unilateral proptosis with or without pain and decrease in visual acuity (Fig. 1.31).42,44 Pain was present in 21-29% of the patients in 2 series.43,45 The majority of these tumors occur in the superior orbit and produce downward displacement of the globe.42,43 However, rarely the tumor can occupy the inferior orbit.46 There may be intermittent upper eyelid swelling resembling angioneurotic edema.42 Sometimes, there is a bluish hue to the skin overlying the tumor.4244
Hemangiopericytoma can manifest a malignant clinical course with rapid growth spanning a few months. Malignant hemangiopericytomas have a tendency to undergo local recurrence, invasion into the central nervous system and metastasis to distant organs particularly the lungs, bone, and liver.43
 
Radiologic Features
Orbital CT and MRI demonstrate a well-circumscribed lesion usually located superiorly in the orbit. On CT, orbital hemangiopericytoma can demonstrate calcification in the lesion.47 Other vascular tumors such as hemangioma, lymphangioma, and varix can also demonstrate calcification in the lesion. Sometimes, the hemangiopericytoma can be extensive involving the sinuses as well as the cranial cavity.43
MRI shows that the tumor is isointense with respect to the extraocular muscles on T1-weighted images (Fig. 1.32) and hyperintense on T2-weighted images (Fig. 1.33).43 The tumor demonstrates moderate enhancement after contrast injection. As such, the tumor is indistinguishable from other well-circumscribed orbital lesions by MRI.24
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Fig. 1.32: T1-weighted coronal orbital MRI showing the superonasally located hemangiopericytoma (arrows) that is isointense to the extraocular muscles and cerebral gray matter (left) and showing marked contrast enhancement after gadolinium injection (right)
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Fig. 1.33: T2-weighted axial orbital MRI showing the hemangiopericytoma that is hyperintense to the extraocular muscles and cerebral gray matter on T2-weighted images (arrow)
Hemangiopericytoma can develop cavitation and, therefore, simulate a cystic lesion on neuroimaging studies.43
 
Histologic Features
Histopathologically, hemangiopericytoma is a well-circumscribed tumor (Fig. 1.34) composed of pericytes with ill-defined borders, large cytoplasm, and round to oval nuclei.25
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Fig. 1.34: Gross photograph of the excised orbital hemangiopericytoma showing a pink-red color tumor
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Fig. 1.35: Spindle tumor cells surround staghorn-shaped vascular channels (Hematoxylin-eosin, x200)
These cells surround the sinusoidal or staghorn-shaped blood channels lined by a single row of flattened endothelial cells (Fig. 1.35). The pericytes are surrounded by a reticulin framework. The reticulin deposits surround individual cells in hemangiopericytoma.
Some tumors possess malignant histopathologic features such as nuclear pleomorphism and numerous mitoses.43,45 Other tumors are borderline. In general, the biologic behavior of hemangiopericytoma cannot be reliably predicted from the histopathologic appearance of the tumor. Hemangiopericytomas that are capable of recurrence and metastasis usually have more than 4 mitotic figures per 10 high power fields.26
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Fig. 1.36: Tumor cells stain positive for CD34 (CD34, x200)
However, hemangiopericytomas with less than 4 mitotic figures per 10 high power fields can also rarely demonstrate malignant potential.45 Hemangiopericytomas usually stain positive for vimentin and CD34 and negative for other markers (Fig. 1.36).43
 
Treatment and Prognosis
The recommended treatment for orbital hemangiopericytoma is total excision of the tumor. Those tumors that invade the cranial cavity require a transcranial approach for removal of the tumor. External beam radiotherapy48 and brachytherapy49 have been used for incompletely excised hemangiopericytomas. A total radiation dose of at least 50 Gy should be delivered to prevent recurrence.48 Incomplete excision of the tumor is associated with a higher risk of local recurrence and distant metastasis. Distant metastasis develops in 15% of patients with orbital hemangiopericytoma. Karcioðlu et al reported that 3 of 7 (43%) patients with orbital hemangiopericytoma eventually died from central nervous system metastasis attesting to the potentially malignant nature of the tumor.43 When the tumor is found to be histopathologically malignant, some authors prefer to use orbital exenteration and supplemental external beam radiotherapy even if the tumor has been excised completely.
When the tumor shows secondary invasion into the adjacent bones, sinuses, and the cranial cavity or metastasizes to distant organs, palliative radiotherapy and chemotherapy should be administered. Chemotherapy consisting of doxorubicin hydrochloride, cyclophosphamide and methotrexate has been reported to be effective.4527
 
SECONDARY ORBITAL TUMORS
Secondary orbital tumors reach the orbit by direct extension from adjacent structures such as paranasal sinuses, nasal cavity, conjunctiva, eyelid, or globe. Among the tumors that extend to the orbit are eyelid tumors, including basal cell carcinoma, squamous cell carcinoma, sebaceous carcinoma, and malignant melanoma of the eyelid; conjunctival squamous cell carcinoma and conjunctival melanoma, and intraocular tumors including uveal melanoma. Paranasal sinus carcinomas, nasopharyngeal carcinoma and angiofibroma, and sphenoid wing meningiomas can also invade the orbit. Some of the more commonly encountered malignant tumors will be discussed below.
 
Secondary Orbital Involvement from Eyelid Tumors
Delays in diagnosis and treatment and incomplete excision resulting in recurrent tumors may play an important role in the orbital spread of many eyelid tumors. Diplopia, ophthalmoplegia, proptosis, limitation of eye movements are some of the clinical features suggestive of orbital invasion.
 
Basal Cell Carcinoma
Basal cell carcinoma (BCC) usually invades the orbit through direct extension from the eyelids (Figs 1.37 to 1.40). Orbital invasion in BCC depends on a number of factors including histopathologic subtype and location.5052 Orbital involvement is more common with the diffuse morpheaform and the basosquamous subtypes of BCC although it can also occur with the nodular-ulcerative subtype as well.50
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Fig. 1.37: Extensive basal cell carcinoma of the right eyelids that has invaded the orbit and produced destruction of the orbital contents in a 70 year-old woman
28
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Fig. 1.38: Axial orbital CT showing the BCC with orbital invasion
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Fig. 1.39: Tumor islands consist of atypical basaloid cells with peripheral pallisading (Hematoxylin-eosin, x100)
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Fig. 1.40: One year after orbital exenteration with bone removal, orbital reconstruction, and external beam radiotherapy, there is no clinical evidence of residual or recurrent tumor
29
The morphea form subtype is characterized by clinically indistinct margins. Incompletely excised morpheaform BCCs invade the dermis or deeper tissues leading to orbital invasion.52 The basosquamous subtype behaves in a more aggressive biologic manner with perineural invasion and orbital/intracranial invasion potential.50 Medial and lateral canthal BCCs and recurrent tumors are more prone to the development of orbital invasion.50 BCCs rarely metastasize to regional lymph nodes.
 
Squamous Cell Carcinoma
Squamous cell carcinoma (SCC) with delayed diagnosis, inadequate initial treatment, and recurrences are prone to invade the orbit (Figs 1.41 to 1.44). SCC can directly invade the orbit by contiguous spread from the eyelids.
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Fig. 1.41: Upper eyelid squamous cell carcinoma with orbital invasion in a 63 year-old woman with 2 previous tumor excisions performed elsewhere
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Fig. 1.42: Coronal orbital CT shows orbital invasion of the eyelid squamous cell carcinoma
30
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Fig. 1.43: Solid tumor islands consist of atypical pleomorphic keratotic epithelial cells. Some of the tumor islands contain keratin pearls (Hematoxylin-eosin, x100)
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Fig. 1.44: Three months after eyelid-sacrificing exenteration, the socket has nicely epithelialized
It can demonstrate perineural invasion and is associated with pain, ptosis, and ophthalmoplegia resulting in orbital apex syndrome under these circumstances.53,54 SCC is also capable of metastasis to regional preauricular and submandibular lymph nodes. The risk of regional lymph node metastasis in recurrent and extensive tumors may be as high as 20%.5531
 
Sebaceous Carcinoma
Sebaceous carcinoma (SC) tends to invade the orbit, lymphatic and vascular channels (Figs 1.45 to 1.47). Risk factors for orbital involvement in sebaceous carcinoma include multicentric origin, extensive involvement of both the eyelids, poor seborrheic differentiation, an infiltrative histopathological pattern, and intraepithelial carcinomatous (pagetoid) changes.50,56 The rates of regional lymph node and distant metastasis are also estimated to be around 20% in high-risk cases.50,56,57 The tumor has a propensity to metastasize to the lung, liver, brain, and skull.56
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Fig. 1.45: Eighty-nine year-old woman with extensive sebaceous carcinoma of the left upper eyelid
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Fig. 1.46: Axial orbital CT showing orbital invasion of the sebaceous carcinoma
32
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Fig. 1.47: The patient refused orbital exenteration and returned with a fungating mass 6 months later
 
Malignant Melanoma
Vertical growth pattern and tumor thickness are regarded as the most important negative prognostic factor in the behavior of melanomas. A Breslow thickness greater than 1.5 mm indicates a poor prognosis for eyelid melanomas.58,59 Eyelid melanomas can invade the orbit and demonstrate regional lymph node involvement. Eyelid melanomas are also associated with a risk of distant organ metastasis which can occur many years after initial diagnosis.
 
Secondary Orbital Involvement from Conjunctival Tumors
 
Squamous Cell Carcinoma
When squamous cell carcinoma (Figs 1.48 to 1.50), also known as ocular surface squamous neoplasia (OSSN), invades the subepithelial tissues and episclera, it behaves in a locally aggressive fashion. SCC lesions present as a localized mass formation, atypical presentation of SCC as a diffuse growth on the ocular surface or a masquerade lesion mimicking scleral keratitis or scleromalacia have also been reported.60 Atypical cases may show extensive invasion into the globe and orbit because of delayed treatment.60
The biological behavior of SCC depends on a number of factors including the histopathologic subtype of SCC, the proportion of differentiated cells within the tumor, the inciting cause of SCC, total tumor size, location, and depth of invasion.60,61 Specific histopathological variants of conjunctival SCC including spindle cell carcinoma and mucoepidermoid carcinoma behave in a rather aggressive fashion with recurrences, invasion of the globe, and orbit.62 The more poorly differentiated the tumor, the more likely it is to invade aggressively, recur locally, and metastasize following treatment.
33
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Fig. 1.48: A 70 year-old patient with left recurrent conjunctival squamous cell carcinoma demonstrating orbital invasion status postseveral incomplete excisions performed elsewhere
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Fig. 1.49: Axial orbital CT demonstrating left orbital invasion from the conjunctival SCC
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Fig. 1.50: Atypical epithelial squamous cells forming solid islands some of which contain keratin pearls (Hematoxylin-eosin, x40)
34
SCC originating from tissues scarred by ionizing radiation, heat and/or chemical burns, or those arising de novo behaves more aggressively.60,61 Tumors originating from solar keratosis behave less aggressively. SCCs originating from tarsal surfaces versus limbal location and long-standing extensive tumors with deeper invasion into the ocular surface are difficult to excise completely leading to recurrence and eventual orbital invasion.60,61 The risk of orbital and regional lymph node metastasis is estimated to be less than 10%.60 Distant metastasis in conjunctival SCC is rare.
 
Malignant Melanoma
Clinical features predictive of orbital extension of conjunctival melanoma (Figs 1.51 to 1.54) include poor initial visual acuity (visual acuity of 20/200 or worse), extralimbal location, amelanotic tumors, caruncular lesions, and tumors that present with histopathologic invasion deeper than 1 mm.63 It has been noted that lesions with invasion deeper than 1 mm do not respond well even to orbital exenteration in terms of avoiding dissemination of the tumor. Paridaens and coworkers reported that mortality ranges between 33 and 50% for melanomas with thicker than 1 mm invasion despite exenteration.64 The authors indicated that invasion of the lymphatics, blood vessels, and sclera as well as the incomplete excision at the time of the initial treatment resulted in poor outcomes.
Conjunctival melanoma spreads to the regional lymph nodes in 15-30% of cases.57,65 The most commonly involved lymph nodes are preauricular nodes in about 75% of the patients with lymph node disease.
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Fig. 1.51: A 70 year-old woman with right recurrent conjunctival melanoma. The patient had undergone several biopsies and finally enucleation of the right eye with implantation of a ball implant because of the recurrent conjunctival melanoma
35
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Fig. 1.52: Axial orbital CT showing right orbital invasion from conjunctival melanoma (arrows) and the ball implant presenting as a hyperdense object in the orbit
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Fig. 1.53: The tumor is composed of atypical pleomorphic cells with prominent nucleoli. Some tumor cells contain cytoplasmic brown pigment compatible with melanin (Hematoxylin-eosin, x200)
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Fig. 1.54: Six months after eyelid-sparing exenteration the eyelids have retracted nicely into the socket
36
Therefore, sentinel lymph node biopsy plays an important role in the management of patients with advanced orbital melanoma.66 Systemic metastasis to brain, lung, liver or other distant sites occur in 10-30% of patients treated at referral centers.65
 
Secondary Orbital Involvement from Intraocular Tumors
 
Choroidal Malignant Melanoma
In Collaborative Ocular Melanoma Study (COMS) 8% of the eyes with choroidal malignant melanoma (Figs 1.55 to 1.59) that came to enucleation had extraocular extension and 56% of eyes had scleral invasion.67 Neglected choroidal melanomas particularly those presenting with corneal opacification, with phthisis and flat diffuse melanomas are at greater risk to invade the orbital soft tissues.68
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Fig. 1.55: A 51 year-old man with diffuse choroidal melanoma of the right eye presenting with total cataract and massive orbital invasion producing proptosis
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Fig. 1.56: T1-weighted axial orbital MRI shows the diffuse choroidal (arrow) and massive orbital melanoma with marked contrast enhancement
37
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Fig. 1.57: T2-weighted axial orbital MRI demonstrates the diffuse choroidal (arrow) and massive orbital melanoma that are hypointense to the extraocular muscles and cerebral gray matter
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Fig. 1.58: Histopathologic examination of the exenteration specimen shows that the tumor is composed of diffusely infiltrating pleomorphic epithelioid bizarre cells with prominent nucleoli and prominent dark brown pigment consistent with melanin (Hematoxylin-eosin, x400)
Most of choroidal melanomas demonstrating orbital invasion are of mixed cell and epidermoid cell types but spindle cell tumors may also occasionally extend into the orbit. In the early stages of extrascleral extension, the sclera is relatively intact and is often of normal thickness. Intraocular melanoma leaves the eye through emissarial channels extending onto the scleral surface and forming a nodule.69 As tumor growth continues, melanoma disseminates into the orbital soft tissues.38
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Fig. 1.59: Nodule of extraocular extension in an eye enucleated for a large choroidal melanoma with neovascular glaucoma
Secondary involvement of the orbit with uveal melanoma may also develop as a recurrence of an unnoticed extraocular tumor months or years after enucleation.70 The tumor may invade the cut end of the optic nerve resulting in CNS invasion and meningial melanomatosis.
 
Paranasal and Nasopharynx Tumors
Paranasal sinus cancers can secondarily invade the orbit. The maxillary sinus is the most frequent site followed by the ethmoid. The frontal and sphenoid sinuses rarely give rise to epithelial tumors. About 90% of paranasal sinus cancers are squamous cell carcinomas.71,72 Paranasal sinus cancers are usually diagnosed late. When clinical symptoms and signs ensue, the disease is usually in an advanced stage. In contrast, nasopharyngeal carcinomas usually presents at an early stage. Squamous cell carcinoma and its variant, lymphoepithelioma, constitute most of the nasopharyngeal carcinomas.71,72
 
Treatment and Prognosis
In many cases of orbital invasion from eyelid, conjunctival, or intraocular tumors, orbital exenteration is indicated.7375 The choice of an eyelid-sparing or eyelid-sacrificing technique depends on whether the eyelids are affected by tumor. On the other hand, in selected cases of indolent orbital basal cell carcinoma, a globe-sparing orbital resection can be possible. External-beam radiation therapy (50-60 Gy) is employed when the margins are found to be positive for tumor cells after surgery.
39
If there is bone involvement evident on CT scans, the bone and periorbita must be removed as well. Even though bone destruction is not seen on CT scans, it may be histologically present. Therefore, any suspicious bone or periosteum should be submitted for histologic examination. Paranasal and nasopharyngeal carcinomas with orbital involvement require a multidisciplinary approach involving specialists in head and neck surgery and neurosurgery.
For extensive eyelid tumors not amenable to surgical resection and in the presence of medical problems contraindicating surgery, chemotherapy and EBRT can be used.76 Cisplatin and doxorubicin based systemic and local chemotherapy regimens have yielded good results in small numbers of patients at short-term (Figs 1.60 and 1.61).77
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Fig. 1.60: A 71 year-old woman with extensive orbitopalpebral BCC. She had systemic problems contraindicating extensive eyelid surgery
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Fig. 1.61: Six months after cisplatinum and doxorubicin based systemic chemotherapy and external radiotherapy, the orbitopalpebral BCC has completely regressed
40
In certain tumors like sebaceous carcinoma of the eyelids or conjunctival malignant melanoma, sentinel lymph node biopsy (SLNB) and additional lymph node resection should be considered when planning exenteration.66 Patients with negative findings from SLNB still require careful long-term follow-up because they may develop regional or distant metastasis later.57
Extraocular extension of choroidal melanoma less than 3 mm in thickness can be treated with plaque radiotherapy.9,61 Care must be taken not to touch and disturb the extraocular tumor component. When the melanoma is greater than 3 mm in thickness, enucleation is performed to remove the melanoma nodule encased by normal appearing orbital fat. If there is extensive orbital involvement, exenteration is usually done.
 
METASTATIC ORBITAL TUMORS
 
Clinical Features
Like metastatic uveal tumors, most orbital metastases reach the orbit by the hematogenous route. Most metastatic orbital tumors are carcinomas; rarely, melanomas and sarcomas occur.78 Approximately, 8% of all orbital tumors are metastatic in origin.
Breast, lung, and prostate are the common primary tumor sites; bronchial carcinoid, metastasis from thyroid carcinoma, hepatic carcinoma, and renal cell carcinoma are less common (Fig. 1.62).7880 Interestingly, hepatocellular carcinoma is the most frequent metastatic orbital tumor in Japan, but is rarely seen in Western countries.81
Clinically, a metastatic orbital tumor presents with rapid onset of proptosis and displacement of the globe. Pain, diplopia, and blurred vision can also be the presenting signs and symptoms. Disease is usually unilateral, although occasionally it is bilateral in about 10% of the cases.80 Fibrotic tumors of the breast and stomach may cause enophthalmos.82
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Fig. 1.62: A 50 year-old woman with orbital metastasis from breast carcinoma presenting with left upper eyelid edema and pain
41
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Fig. 1.63: An 80 year-old woman with inoperable rectum adenocarcinoma metastatic to the right orbit producing proptosis, lateral displacement of the eyeball, and conjunctival edema
Most patients have a known primary prior to the diagnosis of the orbital lesion. However, in 10% of metastatic orbital tumors, the origin of the primary tumor remains unknown at the time of the diagnosis.81 Most instances of unknown primary site carcinomas turn out to be adenocarcinomas or undifferentiated tumors. Metastasis from the adenocarcinoma of rectum can invade the orbit and cause proptosis and displacement of eyeball (Fig. 1.63). One of the most important aspects in the evaluation of patients with presumed orbital metastatic disease is history taking. Elderly patients who had primary tumors in other body sites removed many years prior to eye manifestations may forget or intentionally deny history of cancer.
Breast carcinoma is probably the most common metastatic cancer to the orbit.80,81 The most common subtype of breast carcinoma making metastasis is the invasive ductal carcinoma.
 
Radiologic Features
Neuroimaging studies, including computed tomography and magnetic resonance imaging, may reveal a well-circumscribed lesion in the case of orbital metastasis from lung cancer, carcinoid, melanoma, thyroid carcinoma, or and renal cell carcinoma.78,79,81 On the other hand, metastases from breast carcinoma often have a diffuse and ill-defined infiltrative appearance (Figs 1.64 and 1.65).8082 Prostate carcinoma may demonstrate hyperosteosis, which is best delineated on CT scan. CT scan can also help in the diagnosis of secondaries from the adenocarcinoma of the rectum (Fig. 1.66). Increase in serum prostate-specific antigen (PSA) in association with hyperosteotic bony changes strongly point out prostate cancer metastasis in the orbit.42
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Fig. 1.64: T1-weighted orbital MRI shows the superiorly located breast carcinoma isointense to the extraocular muscles (long arrow). Simultaneous brain involvement is also seen (short arrow)
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Fig. 1.65: Tumor cells stain positive for estrogen receptor (ER, x100)
Isolated extraocular muscle enlargement can be seen with metastatic breast carcinoma and melanoma.81
 
Treatment and Prognosis
Treatment of metastatic orbital tumors consists of an incisional biopsy if the diagnosis cannot be established on the basis of a previous history or imaging studies and if the location of the mass allows for a low-risk biopsy procedure. Treatment options for orbital metastasis include: Systemic chemotherapy, hormone therapy, surgical resection or local radiation therapy to the orbit (30-50 Gy depending on the indication).81,8343
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Fig. 1.66: Orbital CT depicting the oval-shaped orbital mass located in the medial orbit
In selected cases of isolated metastasis, surgical treatment may be used. Carcinoid metastasis in the orbit is one of the few instances where excisional surgery is done to prolong survival.81
Hormonal therapy is an option for breast and prostate carcinomas.82 Treatment of metastatic breast carcinoma usually involves hormone therapy or chemotherapy with or without the monoclonal antibody trastuzumab (Herceptin). Trastuzumab is used in tumors overexpressing HER2-neu. The median survival is 18-24 months but some patients may experience longer survivals. Therapy with tamoxifen (estrogen receptor modulator) has been reported to reduce eyelid and orbital metastasis of breast carcinoma. Tamoxifen is used in postmenopausal women if the tumor is estrogen receptor (ER) positive or progesterone receptor (PR) positive (see Fig. 1.65). ER(–), PR(–) tumors and those that have progressed despite hormone therapy are candidates for chemotherapy.84
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