TABLE 1. Incidence and Type of Secondary Tumors of the Orbit, University of British Columbia Orbit Clinic, 1976 - 1995

The main emphasis of Part I of this chapter will be on orbital extension of lesions of epithelial origin and selected tumors arising from the eye and intracranial cavity. Tumors of mesenchymal and hematopoietic origin have been discussed as separate entities elsewhere in these volumes.

The orbit is at risk when tumors develop in the nasal cavity and paranasal sinuses because it shares three thin, bony walls with these structures: the roof, medial wall, and floor. These neoplasias can extend into the orbit by bony destruction, through suture lines and natural dehiscences of walls (i.e., lacrimal fossa, inferior orbital fissure, infraorbital groove, and pterygopalatine fossa), and via the emissarial blood vessels and nerves that perforate the orbital walls.⁴

In Godtfredsen and Lederman's combined Scandinavian-British series of patients with primary nasopharyngeal tumors, 240 (36%) of 673 had ophthalmoneurologic manifestations.⁵ Smith and Wheliss⁶ found eye and orbital abnormalities in 29 (55%) of 53 patients with histologically proven nasopharyngeal tumors. More recently, Johnson and associates⁷ found that 47 of their 79 patients (59%) with known sinus and nasopharyngeal tumors had orbital involvement. Thirty-eight nasopharyngeal and sinus neoplasms accounted for 23% of secondary orbital tumors in our series. Secondary tumors of the orbit involving the sinus and nasopharynx seen at the University of British Columbia Orbit Clinic from 1976 to 1995 are outlined in Table 2.

TABLE 2. Secondary Tumors of the Orbit Involving the Sinus and Nasopharynx, University of British Columbia Orbit Clinic, 1976-1995

EPITHELIAL MALIGNANCIES OF THE SINUS AND NASOPHARYNX

Epithelial malignancies of the paranasal sinuses frequently spread to the orbit. Conley⁸ noted that 75% have extension beyond the sinus, 45% of whom have orbital invasion. Of 47 sinus and nasopharyngeal tumors with orbital invasion in the study by Johnson and colleagues,⁷ 37 (79%) were epithelial in origin. The specific site of origin and histologic types seen by us and by Johnson and associates⁷ are summarized in Table 3. Sixty-six percent originated from the maxillary sinus, and 60% were of the squamous cell type. Epithelial malignancies of the sinus and nasopharynx are classified according to the extent of local invasion and regional nodal spread (Tables 4 and 5).^3,9 Thus, by definition, orbital involvement reflects an advanced stage (T3 and T4).⁹

TABLE 3. Site and Histology of Epithelial Malignancies of the Orbit and Sinus/Nasopharynx*

TABLE 4. Staging of Maxillary Sinus Cancer

TABLE 5. TNM Staging of Nasopharyngeal Carcinoma

The clinical hallmark of secondary epithelial tumors arising from the nasopharynx and sinuses is nonaxial displacement of the globe associated with infiltration of orbital and paraorbital structures, leading to pain, paresthesia, decreased vision, and reduced extraocular movements. It is the features of chronic and relentless pain, paresthesia, and nonaxial displacement that help to clinically distinguish secondary epithelial malignancies from practically every other tumefaction of the orbit. In our experience, metastatic disease was painful only in approximately 25% of cases, and proptosis was usually axial. In contrast, the secondary malignancies were associated with pain and paresthesia in 60% of cases and nonaxial displacement in 48% (Table 6). Only 3 of the 25 patients (12%) in our series had proptosis without nonaxial displacement. The major nasal symptoms experienced were obstruction or epistaxis. The frequency and severity of ocular and orbital symptoms attest to the relatively silent origin and late stage of presentation reflected by orbital invasion.

TABLE 6. Signs and Symptoms of Sinus and Nasopharyngeal Carcinomas, University of British Columbia Orbit Clinic, 1976 - 1985

The site of origin is reflected in the dominant orbital signs. Because the majority of lesions arise within the maxillary sinus, the major clinical signs are upward displacement of the globe, fullness of the lower lid, infraorbital pain or paresthesia, and distortion of the maxilla (Fig. 1). In contrast, lesions arising from the ethmoid complex are characterized by outward and downward displacement of the globe. In all of these instances, inflammatory signs may be suggested by injection, chemosis, and edema; however, tenderness and significant rubor are unusual.

Radiologic findings consist of either focal or widespread destruction of the sinuses, with invasion of the adjacent structures by a solid tumor mass (Fig. 2). The mass is usually large; however, sometimes it may be relatively small but may extend to adjacent structures, particularly in the case of adenoid cystic carcinoma (Fig. 3). The sinus and orbit may be the only structures involved, but there is frequently extension to the base of the skull.

Batsakis¹⁰ divided epithelial malignancies into two groups: (1) those arising from metaplastic epithelium, including squamous cell carcinoma and “transitional” tumors; and (2) those arising from the mucoserous epithelium, including adenocarcinoma and salivary gland neoplasia (e.g., adenoid cystic carcinoma, mucoepidermoid carcinoma, rare malignant salivary neoplasia). Squamous cell carcinoma is by far the most frequent malignancy of the nose and paranasal sinuses, accounting for up to 80% of cancers in these locations.

Overall, the prognosis has been dismal, with a 5-year survival of approximately 35%.¹¹ Patients with T3 and T4 staging have had survival rates of 31% and 10%, respectively.¹² Mortality is largely related to the inability to eradicate local disease. Flores and colleagues,¹³ reporting on the recent experience at the Cancer Control Agency of British Columbia, emphasized that during the last decade encouraging results have been obtained with a combination of radiotherapy and surgery in the treatment of epithelial malignancies of the sinuses. Their overall crude 5-year survival for all patients was 46%; a combined treatment consisting of irradiation and surgery in selected patients generated a 5-year survival rate of 74%, as compared with 42% in patients receiving irradiation alone. They emphasized that the important factors in management consist of accurate surgical pathologic staging, a combination of a full course of curative irradiation (60 Gy in 25 treatments over 5 weeks or 50 to 55 Gy in 15 treatments in 3 weeks), and radical surgical resection as the treatment of choice for most paranasal sinus malignancies. In addition, patients with regional nodal disease but without distant metastases are potentially curable and should be treated aggressively. This individualized treatment based on a realistic knowledge of the exact extent of the disease has produced encouraging results in the management of these malignancies.

Tumors Arising from Metaplastic Epithelium

SQUAMOUS CELL CARCINOMAS.Squamous cell carcinomas of the paranasal sinuses do not declare themselves clinically until they have breached their sinus of origin in more than 90% of instances.¹⁴ Up to 80% arise within the maxillary sinus, with the ethmoids being the next most common site.¹¹ The frontal and sphenoid sinuses are uncommon sites of origin. The signs and symptoms of maxillary tumors are oral (pain in the teeth, trismus, a full alveolus, and palatal erosion), nasal (obstruction, epistaxis, and chronic sinusitis), ocular (tearing, diplopia, displacement, pain, and proptosis), and facial (paresthesia, swollen cheek, pain and facial asymmetry). Tumors arising from the posterior portion of the maxillary sinus have a worse prognosis because of the proximity to the orbit, cribriform plate, and pterygoid region. In fact, 10% to 22% of squamous cell carcinomas have regional lymph node metastases on initial presentation. Progression and ultimate death are usually related to complications of local invasion, but approximately 18% develop distant metastases.¹¹ Histopathologically, the majority of cases consist of moderately well-differentiated keratinizing squamous carcinoma, but they may be anaplastic.

TRANSITIONAL CARCINOMAS. Transitional carcinomas originate from the schneiderian epithelium of the nasal cavity and paranasal sinuses. The majority of lesions of this histopathologic type are benign papillomas characterized by multiple and multifocal occurrence and local recurrence. Histologically, they may be either papillary (exophytic) or inverted. They may occasionally have ciliated or cylindrical cells. Though recurrent, the large majority of schneiderian papillomas remain benign, but a small percentage undergo malignant transformation (7% to 9%),^15,16 particularly those of the lateral nasal wall or the inverted type. Thus, transitional carcinomas invading the orbit characteristically arise from the ethmoid sinuses or nasopharynx. Treatment is radical surgery, radiotherapy, or both.

Tumors Arising from the Mucoserous Epithelium

ADENOID CYSTIC CARCINOMAS.Adenoid cystic carcinomas arise in minor salivary glands and most commonly involve the maxillary antrum and lower nasal cavity. Biologically, these are locally aggressive tumors with extensive limits of resection (evident in 75% of cases at presentation)¹⁷; they may present as localized masses but are characterized by a course of indolence, recurrence (sometimes extending over very long periods of time), and ultimately death, usually from spread to contiguous structures. The hallmark of this tumor is perineural spread, which accounts for the severe facial pain noted by many patients, usually in the maxillary division of cranial nerve V. The tumor spreads into the pterygopalatine fossa via the infraorbital nerve and from there to the orbital apex¹⁸ and cranial fossa.¹⁹ The most likely cause of death is relentless and often prolonged local invasion of tumor into the skull base. In addition, 14% of these tumors spread to regional lymph nodes, whereas 40% produce hematogenous metastases.¹⁷ Overall, these tumors are seen in a slightly younger age group than are other sinus and nasopharyngeal tumors, and they are associated with less local reaction in the orbit and more indolent mass effect. In Henderson's series of secondary epithelial neoplasms of the orbit, 22 (85%) of 26 patients with adenoid cystic carcinoma of the sinuses had died (mean survival, 7.5 years).²⁰ The general trend in management is toward local, less aggressive surgery and radiotherapy to control local manifestations.

ADENOCARCINOMAS. Adenocarcinomas usually occur higher in the sinuses and nasopharynx, typically in the ethmoids. They are seen in unusually high numbers in woodworkers.⁷ Their local behavior is similar to that of adenoid cystic carcinoma, but they are less frequently well-differentiated and thus develop more rapidly. Aggressive surgical treatment is employed because these tumors are not significantly radiosensitive.

MELANOMAS. Melanomas rarely occur in the nasopharynx and account for approximately 3.5% of all sinonasal tract neoplasias.²¹ They tend to occur in the anterior part of the nasal cavity, presenting as bulbous masses with nasal obstruction and epistaxis, and 5-year survival is 17% to 38%.

ESTHESIONEUROBLASTOMAS. Esthesioneuroblastomas are rare tumors of neural crest origin that arise from the sensory olfactory epithelium and can invade the cribriform plate, ethmoid sinuses, and orbit. These tumors have a predilection for the young with a peak incidence in the second to third decades, but they do occur with advanced age as well.^22,23 Histologically, they are made up of sheets of small cells with or without rosettes. They are frequently mistaken for other small cell tumors. Ultrastructurally, they have dense core (neurosecretory) granules and neuritic processes. Olfactory rosettes differing from the Homer-Wright type may be seen in those that demonstrate olfactory differentiation; these are lined by pseudostratified columnar cells with central mucin in the lumina. Neuroblastomas have been divided into two groups based on the presence or absence of olfactory differentiation. The latter group may include ganglioneuroblastomatous differentiation (olfactory neurocytoma). Those with olfactory neuroblastomatous differentiation occur in patients with a mean age of 50 years, and the less differentiated neuroblastomatous type occurs in patients with a mean age of 20 years.

In a review of olfactory neuroblastomas by Rakes and co-workers, opthalmic signs or symptoms occurred in 28 (73%) of 38 cases.²⁴ The most commonly reported ocular symptoms were periorbital pain, epiphora, decreased vision and diplopia. Patients presenting primarily with ocular complaints generally have a more advanced tumor stage than those presenting primarily with nasal or non-ocular symptoms. The most commonly detected ocular signs included eyelid edema, proptosis, globe injection, ptosis and cranial nerve palsies, while the most common nonocular signs and symptoms were nasal obstruction, bloody nasal discharge and headache. Henderson reported surgically proven orbital extension in 6 (23%) of 26 new cases of esthesioneuroblastoma registered at the Mayo clinic between 1976 and²⁵

These tumors have been staged according to site of confinement: Group A (nasal cavity), Group B (paranasal sinuses) and Group C (extension beyond the sinuses into the cranium or orbit). Elkon and co-workers have noted 5-year survival rates of 75% (Group A), 68% (Group B) and 28% (Group C).²⁶ In a review of 26 cases, Levine and associates noted a dramatic increase in survival with the advent of aggressive craniofacial surgery and adjunctive radiotherapy and chemotherapy.²⁷ They recommended combined preoperative radiotherapy and craniofacial resection for Group A and B disease, and the addition of preoperative and postoperative antineoplastic agents (vincristine and cyclophosphamide) for Group C disease.

ODONTOGENIC TUMORS. Odontogenic tumors (ameloblastoma, ameloblastic fibrosarcoma, and calcifying epithelial odontogenic tumor) and cysts may rarely involve the orbit.²⁸ Ameloblastomas are locally invasive, benign (2% are malignant)²⁹ epithelial tumors that arise from the mandible in 80% of cases.³⁰ Among the remaining 20% that originate from the maxilla, local growth and extension may lead to orbital involvement. Treatment is accomplished by local resection, after which about one third of tumors may recur. Radiotherapy is palliative, not curative.

NEUROENDOCRINE CARCINOMAS. Neuroendocrine carcinomas are rare epithelial malignancies arising in the nose or paranasal sinuses.

Summary

Epithelial malignancies arising from the nose, nasopharynx, and sinuses are characterized by an infiltrative, nonaxial mass effect with significant neurosensory and motor deficit. They are occult neoplasms, and orbital involvement represents a late presentation with a grim prognosis.

MENINGIOMAS

Meningiomas account for 18% of all adult intracranial tumors,³¹ and they are by far the most common intracranial tumor to extend into the orbit; invasion of the orbit by any other primary tumor is exceedingly rare. Most intracranial meningiomas that affect the orbital or visual structures arise from the dura of the sphenoid bone (i.e., ridge, planum, parasellar region, or optic canal).

The meningothelial cap cells of the arachnoid villi are considered the stem cell of meningiomas. Growth is slow and tends to be in cohesive clusters with or without evidence of encapsulation. When infiltrating soft tissues, the tumors frequently cause reactive desmoplasia. Infiltration of bone can cause hyperostosis, which may make meningiomas difficult to distinguish from primary bone tumors. These tumors tend to displace structures, extend along paths of least resistance through foramina or interstitial spaces, encase structures in dense fibrous connective tissue, or cause compression due to hyperostosis and expansion of bone.

There are a number of histologic patterns of meningioma, including meningotheliomatous, fibrous, transitional, angioblastic, and sarcomatous. The fundamental cell is usually round or polygonal but may be more spindle shaped. Varying admixtures of blood vessels, fibroblasts, and psammoma bodies account for the differing patterns. Although they usually arise as a cohesive mass that develops in continuity, concurrent multiple sites of occurrence and seeding have been described. Angioblastic and sarcomatous meningiomas are more aggressive than the other varieties. Angioblastic meningiomas constitute only 3% of meningeal tumors. They have a tendency to recur, and up to one third are reported to metastasize eventually. Sarcomatous intracranial meningiomas occur in a younger age group (second decade), are more pleomorphic and invasive, and may metastasize outside the central nervous system (CNS).

Intracranial meningiomas occur three times more frequently in women than in men and are generally seen in the fifth decade. Those occurring in young adults may be more aggressive. Multifocal simultaneous lesions may occur, and there is an increased frequency of intracranial and orbital meningiomas in neurofibromatosis.

Meningiomas of the sphenoid wing are prone to extend into the orbit along the lateral wall as an en plaque component (Fig. 4). These desmoplastic, infiltrative lesions generally have some element of hyperostosis. The orbital and visual manifestations reflect the location of the mass, with the more medial tumors causing cranial nerve palsies, visual deficits, and venous obstructive signs and symptoms (e.g., edema, chemosis). More remote tumors are manifested by raised intracranial pressure or mass effect. Tumors of the greater wing of the sphenoid are evidenced by fullness of the temporalis fossa and proptosis, with intracranial symptoms occurring as a late symptom (Fig. 5). Olfactory groove meningiomas present with lost sense of smell, personality changes, papilledema, or apical orbital infiltration or compression.

A combined frontotemporal orbitozygomatic surgical approach was developed at the University of British Columbia for excision of tumors of the sphenoid wing and orbit.^32,33 This approach provides excellent exposure of the orbital apex, anterior and middle cranial bases, upper clivus, petrous apex, and infratemporal and pterygopalatine fossae. Aggressive removal of tumor within the cavernous sinus is no longer advocated. Debulking and adjunctive radiotherapy are preferred to avoid causing disabling cranial nerve palsies. These tumors have a low, slow regrowth and recurrence rate, and the role of postoperative radiotherapy remains unclear. In a recent retrospective study, Peele and colleagues³⁴ reported that postoperative radiation appears to reduce the recurrence rate of these tumors.

CHORDOMAS

Chordomas are rare, relentless, slow-growing, locally malignant midline neoplasms that arise in the dorsum sella and clivus from remnants of the embryonic notochord that grow intracranially or into the nasopharynx. When the tumor originates from the caudal portion of the notochord, it results in a sacral or pelvic mass. Clinical behavior is determined by the rate and direction of growth. The majority extend upward and cause raised intracranial pressure, chiasmal compression, or palsies of the third, fourth, or sixth cranial nerves. They may also extend anteriorly, obstructing the nasal cavity. Orbital and ocular involvement reflects progressive mass effect, which can lead to compression of the optic nerve at the apex and structures within the superior orbital fissure.^35,36 With massive midline orbital growth, proptosis and hyperteloric displacement of one or both orbits may occur, whereas growth down the clivus leads to marching cranial nerve palsies.

On a computed tomography (CT) scan, this tumor appears as a nodular, inhomogeneous mass causing both expansile and destructive midline bony changes. Fine osseous trabeculae and calcification may be seen. Pathologically, chordomas are smooth, multilobular, gray-blue or reddish masses with indistinct or infiltrative bony margins. The distinguishing features are the presence of physaliferous cells, which are round to oval and have central nuclei and mucin-filled cytoplasmic vacuoles. The large cells group as nests, cords, and alveoli within a mucin-rich stromal matrix. In the cervical area, a cartilaginous variant of this tumor may be difficult to distinguish from a chondrosarcoma.

Ideal treatment is complete surgical excision, which is rarely achieved because of the tumor's location and indistinct margins. The slow growth is compatible with long survival, particularly when the tumor is anterior, but the general prognosis is poor. Repeated surgical debulking and adjunctive radiotherapy have been advocated.

INTRACRANIAL GLIOBLASTOMA MULTIFORME

Intracranial glioblastoma multiforme is a highly malignant tumor of glial origin. The tumor may enter the orbit by gross destruction of orbital bone,³⁷ by extension through the optic canal and superior orbital fissure along the optic and cranial nerves,³⁸ or by growing through a previous craniotomy site into the scalp and forehead, and then over the superior orbital rim into the anterior orbit.³⁹ Orbital invasion generally occurs with tumor recurrence after previous craniotomy; however, a case of extradural nasal and orbital extension has been reported without previous surgical intervention.⁴⁰

PITUITARY TUMORS AND CRANIOPHARYNGIOMAS

Pituitary tumors and craniopharyngiomas do not usually invade the orbit. Christmas and colleagues⁴¹ reported a single case of pituitary chromophobe adenoma with invasion of the optic nerve in a survey of autopsy results from patients with brain tumors. Cases of orbital invasion have been reported from an invasive pituitary adenoma⁴² and a malignant prolactinoma.⁴³ A single case of recurrent craniopharyngioma invading the orbit, cavernous sinus, and skull base has been reported.⁴⁴

PRIMARY NEOPLASIA OF THE CENTRAL NERVOUS SYSTEM

We have seen two cases of primary neoplasia of the CNS extending into the optic nerve.⁴⁵ One was a medulloblastoma that spread bilaterally along the optic nerves, and another was a dural melanoma of the spinal cord that subsequently presented as a large mass extending into the orbit around the peripheral and optic nerve structures.¹¹ Both were diagnosed by aspiration needle biopsy of the affected nerve sheath.

LEUKEMIC INVOLVEMENT OF THE CENTRAL NERVOUS SYSTEM

Intracranial tumors, either primary or metastatic, may extend by means of the subarachnoid space into the optic nerve sheath and orbit. In particular, leukemia can affect the CNS, and thus the optic nerve and eye, usually in the late and aggressive stages, because of the relative pharmacologic isolation of these sites. Leukemia frequently affects the optic nerve head, but may independently deposit in the arachnoid of the sheath as part of a widespread meningeal process. Kincaid and Green⁴⁶ found optic nerve involvement in 18% with acute leukemia and 16% with chronic leukemia in a series of 384 autopsies. Treatment may consist of a combination of intrathecal chemotherapy and radiation.

CARCINOMATOUS MENINGIOMATOSIS

Generalized carcinomatous meningiomatosis may also infiltrate the optic nerve. Typically, the patient presents with papillitis, a known history of carcinoma, and negative CT scan findings because of widespread superficial involvement of the meninges without significant mass effect. Little and co-workers⁴⁷ found no history of malignancy in 14 (48%) of 29 cases of meningeal carcinomatosis. The diagnosis may be more apparent on a gadolinium-enhanced magnetic resonance imaging (MRI) scan and can be confirmed by cytologic examination of the cerebrospinal fluid (CSF). We have encountered three cases of meningiomatosis due to metastatic tumors: two in patients with breast carcinoma and one in a patient with malignant melanoma of the skin. In all instances, the diagnosis was made on the basis of the cytologic results of a CSF tap in the presence of a normal CT scan.

LARGE CELL LYMPHOMA OF THE BRAIN

Large cell lymphoma (reticulum cell sarcoma) of the brain has a specific propensity for ocular involvement, usually as a cryptogenic chronic uveitis and vitritis.

BASAL CELL CARCINOMA OF THE LID

Basal cell carcinoma is the most common epithelial malignancy of the lid and accounts for more than 80%^48,49 of malignant eyelid tumors. In most series, however, its frequency in terms of orbital invasion equals squamous cell carcinoma, which is a reflection of the more aggressive nature of squamous cell carcinoma. The rather indolent and painless course of basal cell carcinoma (median duration about 3 years at presentation) may contribute to late presentation with orbital invasion. Orbital invasion is usually a part of advanced presentation, recurrence, or the morpheic variant.

Basal cell carcinoma generally occurs in the fifth to eighth decades with a male predominance, although approximately 3% of lesions occur in persons less than 35 years of age.⁵⁰ Overall, approximately 52% are seen in the lower lid, 27% in the inner canthus, 15% in the upper lid, and 6% in the outer canthus.⁴⁹ Orbital extension is more common with inner canthal lesions because of the anatomic intimacy of bone and lacrimal system, as well as the propensity for surgeons to undertreat lesions in this locale to avoid damaging the lacrimal apparatus. With modern controlled techniques of management, orbital extension from this site is no more frequent than from any other site.

The majority of basal cell carcinomas have a typical clinical picture, starting as pearly, raised nodules that develop central ulceration and characteristically extend radially (Fig. 6). These can ultimately ulcerate and erode through adjacent tissues, producing grotesque local disfigurement, yet they generally do not metastasize.

There are a large number of histologic variants, including solid (the majority), adenoid, keratotic, mixed, and sclerosing (morpheiform). It is the sclerosing variety that has a notorious reputation for extension, largely because it has clinically and pathologically indistinct margins. Clinically, the only clue to extension may be a tendency for the overlying skin to appear very thin and slightly telangiectatic, and to have lost its adnexa (i.e., cilia). Histopathologically, these carcinomas consist of minute cords of cells in a dense, fibrous stroma.

Invasion of the orbit usually occurs after incomplete and often multiple excisions. It is heralded by infiltrative features affecting the anterior structures, including restriction of extraocular movements, cicatrization and induration of the lid structures, and fixation to adjacent bone. Henderson has noted that the soft tissues of the lid are frequently involved in a circumferential manner before deep orbital invasion occurs.²⁰

The management of basal cell carcinoma with orbital invasion demands a firm resolve to use radical therapy that incorporates the entire lesion. Wide excision should be controlled by pathologic confirmation of free borders and may require exenteration, bony removal, and even extirpation of dura. Reconstruction may require a craniofacial surgical team. Leshin and Yeats⁵¹ reported a success rate of greater than 95% with excision of basal cell carcinoma using Mohs' microscopic surgical technique in a large series. Anscher and Montano⁵² had equal success with modern radiotherapy techniques, particularly in treating smaller lesions. Avoiding surgery that could be cosmetically disfiguring may be advantageous for persons unwilling to undergo the surgery or who are medically unfit for surgery.

Chemotherapy with cisplatin alone⁵³ or in combination with doxorubicin⁵⁴ has been used primarily to decrease tumor size before local excision and in conjunction with radiotherapy for patients who refuse or must delay exenteration. Neudorfer and co-workers⁵⁵ reported that a patient with recurrent invasive basal cell carcinoma of the medial canthus and orbit who was treated with cisplatin and doxorubicin had complete remission during 5 years of follow-up.

SQUAMOUS CELL CARCINOMA OF THE LID

Squamous cell carcinoma is far less common, accounting for 7% to 9% of all malignant eyelid lesions.^49,56 The major predisposing factor for the development of this malignancy is sun exposure in fair-skinned persons, but exposure to carcinogenic agents (e.g., arsenic, irradiation, psoralenultraviolet A [PUVA]) as well as genetic predisposition (e.g., xeroderma pigmentosum) are other important factors.

The clinical signs of squamous cell carcinoma (mean, 1 year) develop faster than the signs of basal cell carcinoma, consisting of focal hyperkeratotic lesions that slowly extend and ulcerate. They are more common at the lid margin and in the lower lid versus the upper lid, by a ratio of 1.4:1.⁵⁶ Rarely, papillary forms may be seen. Orbital extension of squamous cell carcinoma is usually preceded by a history of chronic and repeated recurrence of lesions following treatment or long-term neglect by the patient (Fig. 7). Once the orbit is invaded, the tumor tends to spread along fascia and fatty planes relatively rapidly compared with basal cell carcinoma. Perineural invasion may occur and is associated with pain or ophthalmoplegia (Fig. 8).^57–60 Also in contrast to basal cell carcinoma, squamous cell carcinoma is capable of metastasis, usually to the regional preauricular or submandibular lymph nodes. The incidence of regional spread varies from 1% to 21%, but is generally closer to the lower figure. In a review of large series documented in the literature, the overall mortality rate was found to be approximately 15%.⁵⁶ Management of squamous cell carcinoma of the lid is usually surgical, with care being taken to obtain adequate controlled margins with the use of frozen sections or Mohs' technique. Fitzpatrick and associates⁶¹ reported a control rate of 93% with radiotherapy; however, squamous cell carcinoma is thought to be less sensitive to radiotherapy than basal cell carcinoma, so higher doses are usually recommended. For deep orbital invasion, radical therapy is indicated; this may constitute either exenteration or radical radiotherapy, according to the circumstances outlined in the discussion on basal cell carcinoma.

SEBACEOUS CARCINOMA OF THE OCULAR ADNEXA

Sebaceous carcinoma represents 1% to 5% of all eyelid malignancies⁶² and occurs more commonly than sebaceous carcinomas elsewhere in the body. It is interesting to note that of epithelial malignancies invading the orbit from the eyelid, about one third are sebaceous carcinomas. These carcinomas seem to be more prevalent in Asian populations.⁶³ The upper lid is the usual site of involvement, occurring in approximately 67% of cases; approximately 20% of cases involve the lower lids or are diffuse, and a small percentage involve the caruncle.⁶² It is characteristically a lesion of the elderly (maximum occurrence in the seventh decade) and has a slight female predominance.

Sebaceous carcinoma has achieved a notorious reputation because it can be difficult to diagnose correctly in the early stages. Clinically, the tumor may masquerade as a chronic chalazion, blepharoconjunctivitis, basal cell carcinoma, keratoconjunctivitis, or very rarely as a primary orbital tumor. Another cause for confusion has been pathologic misdiagnosis of sebaceous carcinoma, most commonly being mistaken for basal cell carcinoma or squamous cell carcinoma. Increasing awareness of the characteristic presentation, along with earlier and more accurate clinical and pathologic diagnosis, has decreased the mortality associated with this tumor. The blepharoconjunctivitis associated with this lesion is the result of intraepithelial (pagetoid) spread of sebaceous carcinoma. The usual clinical appearance is a thickening of the conjunctiva associated with frank injection in areas of invasion (Fig. 9). A careful biomicroscopic examination reveals yellowish, plaque-like foci within the affected epithelium.

The incidence of orbital extension varies from 6% to 35% in large series^64–66 and is associated with a 70% mortality rate. These tumors have a propensity to spread to the lymphatic system and subsequently to the lung, liver, brain, or skull. Those that extend into the orbit have approximately a 70% association with preauricular, cervical, or submaxillary adenopathy compared with an overall incidence of approximately 19% for all sebaceous gland carcinomas of the lid and adnexa.

The pathologic diagnosis is based on evidence of sebaceous origin. These carcinomas are usually lobular or consist of cords of cells with a varying degree of sebaceous differentiation and infiltration. The degree of differentiation tends to progress from the periphery toward the center of lobules, mimicking the normal pattern of sebaceous glands. Cells that are differentiated have a foamy or vacuolated, slightly basophilic cytoplasm. In contrast, the less differentiated tumors have cells that are more deeply basophilic and anaplastic, and they display more mitotic figures. The peripheral location of the basophilic, less vacuolated cells produces a pattern similar to basal cell carcinoma, but the cells are more anaplastic. Sebaceous carcinomas have a propensity toward pagetoid spread, invading the basal layers of skin and mucous membranes in a radial fashion. These tumors characteristically contain fat; thus, frozen sections and fat stains are useful in diagnosis and at the time of controlled resection.

The overall 5-year mortality rate for sebaceous carcinoma of the lids is approximately 15%.⁶² According to Rao and colleagues,⁶⁷ the clinical and pathologic features associated with a bad prognosis are as follows: vascular or lymphatic invasion, upper and lower lid involvement, orbital invasion, poor differentiation, pagetoid invasion, and tumors larger than 10 mm.

Sebaceous carcinoma of the lid is best managed surgically.⁶⁸ Doxanas and Green⁶⁶ emphasized the improvement in mortality afforded by early recognition and wide excision with frozen-section control. Although microscopically controlled excision may be attempted in instances of orbital invasion, this circumstance usually necessitates exenteration. The frequent association with lymphatic spread indicates a need to assess spread, obtain histologic proof of involvement, and carry out radical resection of parotid, submaxillary, and cervical nodes. Several reports on radiotherapy indicate that when given in adequate doses (generally more than 45 Gy), this tumor can be treated in patients who refuse to undergo excision or who have contraindications to surgery.^69,70 In addition, radiotherapy is a useful palliative modality.

MALIGNANT MELANOMA OF THE SKIN

Malignant melanoma arising from the skin of the lid is exceedingly rare, constituting 1% of all malignant eyelid lesions and less than 1% of secondary orbital tumors. At the UCLA Medical Center from 1955 through 1990, only 8 (0.19%) of 4301 cutaneous melanomas involved the eyelids.⁷¹ We encountered only one melanoma arising from the skin of the lid that led to orbital invasion and required exenteration. Comparatively, conjunctival melanoma is a more common precursor of orbital invasion, perhaps because of later recognition and contiguity. Despite their rarity, melanomas of the skin are important to recognize and understand because of their potentially lethal nature.

Clark and colleagues^72–75 are primarily responsible for the classification and framework of our understanding of the biologic behavior of cutaneous melanomas. Most melanomas arise de novo but some are thought to develop in relationship to preexistent moles. There are three recognizable precursor lesions. The most important in terms of the lid is lentigo maligna (Hutchinson's melanotic freckle), followed by dysplastic nevus (B-K mole) syndrome and giant nevocytic nevi. Giant nevocytic nevi are childhood lesions that rarely occur in the scalp and are readily recognized. The dysplastic nevus may occur either as an autosomal-dominant⁷⁶ or sporadic⁷⁷ trait. It is first seen in childhood and then progresses throughout life. These patients are at high risk for developing cutaneous melanomas. The major features that differentiate these nevi from other nevi are their multiple early occurrence, large size (generally over 5 mm to 10 mm), and flat, irregular surface with haphazard pigmentation.

Melanomas are thought to undergo two phases of growth: a radial intraepidermal pattern, followed by vertical downward growth into the deeper layers of the skin. Nodular melanomas are the exception to this biphasic growth pattern, since they have no clinically discernible radial growth phase. Cutaneous melanomas have been divided into four different types based on patterns of clinical development and histopathology: superficial spreading melanoma (70%), lentigo maligna (5%), acral lentiginous melanoma and others (9%), and nodular melanoma (de novo, 16%).

Superficial spreading melanoma can occur anywhere but is more common in the areas of the body exposed to intermittent and sudden bursts of sun, such as the lower legs of women and the chest and back of men. These appear as raised nodules, 2 to 3 cm in diameter, with bizarre coloration varying from black or brown to rose. Characteristically they have an irregular border. Lentigo maligna usually arises in middle-aged and elderly persons with sun-damaged facial skin. Clinically, they are usually large, irregular, pale brown patches with a fine, peppered distribution of increased pigmentation. The lesions usually have a long history of radial extension, which may wax and wane. It is believed that approximately 25% to 30% undergo malignant transformation, which is heralded by the development of nodular, elevated black or brown areas. Acral lentiginous melanoma occurs primarily in the distal extremities or mucosal surfaces, particularly vaginal mucosa. Nodular melanoma is a relatively rapidly developing focal tumor without clinically perceptible antecedent radial growth. It may be brown to black or amelanotic and can involve exposed areas of skin or mucous membrane. It invades more deeply than the other types of skin melanoma.

The prognosis of melanoma correlates with the depth of penetration and clinical stage. Clark's levels of invasion of malignant melanoma are presented in Table 7. The revised staging system for malignant melanoma is based on the measured depth of invasion (in millimeters), Clark level, and the presence of nodal or distant metastases (Table 8).⁷⁸ Stage IA primary cutaneous melanomas treated with wide excision are associated with a 95% 10-year survival, whereas distant metastases are common in stage IIB (50% survival) and stage III (60% to 85% survival).⁷⁹ Other factors indicative of poor prognosis include tumor type (nodular worse than superficial spreading), amelanosis, and lack of inflammation.

TABLE 7. Clark Levels of Invasion of Malignant Melanoma

TABLE 8. Staging System for Malignant Melanoma of the Eyelid

With increasing awareness of epidemiologic factors (e.g., ultraviolet light, fair skin, hair color) and the nature of melanoma types and premelanotic lesions, the emphasis of management is shifting to prevention and early identification.⁸⁰ Because melanomas have a propensity to regional nodal and widespread systemic metastases, treatment is accomplished with wide local excision with or without nodal resection or systemic chemotherapy. The role of node dissection is controversial,⁸¹ and chemotherapy remains palliative.⁷⁹

OTHER ADNEXAL TUMORS

Merkel cell carcinoma is a relatively uncommon eyelid neoplasm. Overall, 50% of these tumors occur in the head and neck region and 10% in the eyelid or periocular region.⁸² Merkel cell carcinoma generally occurs near the lid margin as a bulging reddish lesion with overlying telangiectatic vessels in the elderly (sixth to seventh decades). The tumor may mimic lymphoma or undifferentiated carcinoma, and the diagnosis can be confirmed by the characteristic immunocytochemical and electron microscopic features. Merkel cell carcinoma is associated with local recurrence and satellite lesions in one third of all cases, regional nodal metastases in two thirds, and distant metastases and death in about one half. Orbital invasion is generally associated with tumor recurrence and may lead to intracranial spread. Because chemotherapy and radiation for distant metastases is only palliative, early aggressive surgical excision with wide margins and postoperative radiotherapy are recommended.

The adnexa may also give rise to rare apocrine and eccrine carcinomas that may invade the orbit.⁸³ This includes the mucinous sweat gland adenocarcinoma, which tends to occur in the elderly and rarely invades the orbit and adjacent structures (there are only five reported cases).^84–86 An unusual and exceedingly rare eccrine adenocarcinoma with a tendency for orbital invasion is the infiltrating signet-ring carcinoma. Because of its histiocytoid appearance, metastases from other sites (especially breast) should be ruled out. Finally, apocrine gland carcinomas arise from the gland of Moll. At least one case of orbital invasion by this locally aggressive tumor has been reported.⁸⁷

SQUAMOUS CELL CARCINOMA OF THE CONJUNCTIVA

Squamous cell carcinoma of the conjunctiva usually occurs at the limbus, arising in a preexisting carcinoma in situ, solar keratosis, or epithelial dysplasia.⁸⁸ It is an indolent lesion seen primarily in men in the sixth and seventh decades and is believed to arise secondary to longstanding actinic exposure or chronic irritation; thus in the tropics it is more often seen in young adults.⁸⁹ Additional factors that contribute to its more common occurrence in these regions are nutritional disorders, recurrent infection, and racial predilection.

The initial clinical appearance is a whitish, rough, dry, irregular leukoplakic lesion or a telangiectatic, gelatinous, epibulbar mass. In rare instances, these tumors may be papillary, exophytic, or fixed to the underlying sclera. When confined to the conjunctiva, it can masquerade as conjunctivitis.⁹⁰ The usual course is superficial invasion and slow growth because the majority are welldifferentiated tumors. It can be a locally aggressive tumor and invade intraocularly in less than 10% of cases.⁹¹ In about an equal percentage of cases, orbital invasion or nodal metastases may occur. Orbital invasion may be heralded by the development of a mass lesion with fixation of the globe. In addition, because these lesions develop insidiously, patients may present with apparent orbital cellulitis⁹² or draining fistulas (Fig. 10). Orbital invasion may follow multiple attempts at excision. In underdeveloped countries, higher rates of orbital invasion and metastases have been noted because of late presentation.⁹³ Even with orbital invasion, death from metastases is exceedingly rare.

Histologically, the majority are well-differentiated squamous cell carcinomas. The two more aggressive variants, spindle cell carcinoma⁹⁴ and mucoepidermoid carcinoma,⁹⁵ have a greater tendency to invade the orbit. A pigmented variant of ocular surface squamous cell carcinoma has been described.^96,97

Local lesions of the conjunctiva can be treated adequately with histologically controlled conjunctival resection, with or without superficial sclerectomy.⁹⁸ In addition, local cryotherapy is useful adjunctively in the management of these lesions.⁹⁹ Recurrence rates after excision average 30%, but may be as low as 5% if free surgical margins are obtained.¹⁰⁰ Local excision combined with brachytherapy has also been proposed in selected cases.^101,102 Massive conjunctivectomy may be necessary for more rapidly developing and diffuse lesions, whereas orbital extension is managed with exenteration. Evidence of regional nodal involvement should be managed with radical node dissection. Radical radiotherapy may be considered for the elderly or for extensive lesions.

MALIGNANT MELANOMA OF THE CONJUNCTIVA

Primary malignant melanoma of the conjunctiva is much less common than intraocular or skin melanomas. In Sweden, only two new cases of primary malignant melanoma of the conjunctiva were diagnosed in 1987, whereas 70 patients with uveal melanomas and 1243 with skin melanomas presented in the same year.¹⁰³ In Henderson's series,¹⁰⁴ orbital extension from intraocular melanomas outnumbered orbital extension from conjunctival melanomas by a ratio of 23:4; however, in our series, the reverse was true by a ratio of 5:9.

Theoretically, conjunctival melanomas may arise in primary acquired melanosis, from preexistent nevi, or as de novo lesions. It may be difficult to ascertain the precursor lesion in many instances. Reese¹⁰⁵ estimated that approximately 50% arise in primary acquired melanosis, 25% from nevi, and 25% as de novo lesions. In other large series, similar findings have been reported,^106,107 although Folberg and co-workers¹⁰⁸ suggested that primary acquired melanosis was present in 75% of cases.

Primary acquired melanosis is typically a lesion of middle-aged whites and, along with malignant melanomas, are extremely rare in the younger population. In fact, McDonnell and colleagues¹⁰⁹ found most conjunctival melanocytic lesions in patients less than age 20 to be nevi (92%), with infrequent occurrences of racial or primary acquired melanosis (4%) or malignant melanoma (4%). The natural history of primary acquired melanosis begins with the development of superficial epithelial pigmentation, with a characteristic peppered distribution of variegated pigment. These lesions can evolve over many years, extending in a radial fashion over larger areas of conjunctiva and skin. In addition, they may wax and wane over time. Ultimately, nodular melanomas may arise within primary acquired melanosis lesions, proceeding to invade deeper tissues and metastasize (Fig. 11). Biopsy of primary acquired melanosis lesions may help to predict the ones that are prone to progression. Folberg and associates¹¹⁰ found that primary acquired melanosis with cytologically atypical melanocytes progresses to melanoma in 46% of cases, whereas primary acquired melanosis without atypia does not progress to melanoma.

Malignant melanomas arising from nevi usually appear as a change in known pigmented lesions of the conjunctiva, but it may be impossible to establish a clear clinical history of a preexisting history of nevus. At the time of excision of a melanoma, however, nevoid rests are seen histologically in about one third of cases and are noted in about one quarter of melanomas in primary acquired melanosis. Development of a melanoma from a nevus may be heralded by increasing nodularity, variegated pigmentation, bleeding, or inflammation.

Melanomas arising de novo in conjunctiva parallel the so-called nodular melanoma of skin in that a clinically and histologically recognizable radial growth phase is not noted. Epibulbar melanomas arising de novo can be ulcerative, amelanotic, papillary, or fungating. It is important to be aware of the possibility of satellite lesions in the conjunctiva and local lymphatic spread, which should be sought carefully on a prospective basis.

In a recent clinicopathologic study of 256 cases of conjunctival melanoma, Paridaens and colleagues¹¹¹ found 5- and 10-year survival rates of 83% and 69%, respectively. The following prognostic factors associated with a higher mortality are listed in increasing order of mortality risk¹¹¹:

  Two-fold risk: Tumors in unfavorable locations (e.g., palpebral conjunctiva, fornices, plica, caruncle, lid margins)
  Three-fold risk: Mixed cell types compared with pure spindle cell types
  Four-fold risk: Histologic evidence of lymphatic invasion; initial thickness greater than 4 mm for tumors in unfavorable locations only (Fig. 12)
  Five-fold risk: Multifocal tumors in patients with lesions in favorable (epibulbar) locations only

Understanding of the clinicopathologic characteristics of premalignant and malignant melanocytic lesions of the conjunctiva has advanced considerably in recent years.¹¹² This increased recognition along with biopsy and treatment of potentially aggressive lesions should lead to decreased morbidity and mortality. The primary treatment for conjunctival malignant melanoma is wide surgical excision combined with cryotherapy.¹¹³ Even extensive conjunctival disease is amenable to removal of the nodular component and repeated local treatment with cryotherapy. Lederman and co-workers¹⁰⁶ reviewed a series of 184 melanomas of conjunctiva treated with radiotherapy and found that lesion site, macroscopic appearance, and type of lesion bear significantly on the type of treatment and likelihood of response. Limbal tumors arising from nevi respond well, nodular de novo melanomas respond poorly, and widespread malignant acquired melanosis responds less well than localized lesions.

Significant orbital invasion indicates the necessity for exenteration; however, subtotal exenteration can be carried out if there is no evidence of radial extension of the lesion to the skin of the anterior lid. Nodal involvement indicates widespread metastatic disease, but occasionally there have been cases in which lesions were restricted to regional nodes and cured by node resection.

EXTRASCLERAL AND ORBITAL EXTENSION OF UVEAL MELANOMA

Uveal melanoma has a number of distinct biologic characteristics that have made it the center of some controversy in recent years. The core of the controversy centers on the role of extirpation (whether by local resection, enucleation, or in the case of extrascleral extension, exenteration) in the management of this tumor. Zimmerman and associates¹¹⁴ summarized the major controversies regarding pathogenesis of spread, including (1) trauma of enucleation, (2) decreased host resistance incurred by removal, and (3) increased virulence concomitant with the appearance of clinical symptoms. These issues have led to more “conservative” management in selected circumstances (including observation, local radiotherapy, and local resection), greater attention to atraumatic enucleation techniques and prospective multicenter studies aimed at ultimately resolving these important issues.

The cumulative mortality rate associated with uveal melanoma after enucleation is 30% at 5 years, 40% at 10 years, and 1% per year thereafter.¹¹⁵ The major negative factors affecting survival are larger intraocular tumor size, the presence of mixed or epithelioid cell type, evidence of extrascleral extension, and mitotic activity.^116,117 Melanomas gain access to the orbit by paraemissarial extension and less often by intraemissarial growth. The incidence of orbital recurrence is approximately 3% in patients enucleated for melanoma and increases to 18% when there is histologic evidence of extrascleral extension at the time of enucleation.¹¹⁸ Factors that increase orbital recurrence rates include larger tumor size; epithelioid, mixed, or necrotic cell types; and nonencapsulated or surgically transected epibulbar tumors.^118–120 Transection of the tumor is associated with a 50% orbital recurrence.

Extrascleral extension occurs in 10% to 15% of patients with uveal melanomas^118–120 and may present clinically as a visible anterior nodule, as proptosis in patients with known intraocular tumor (Fig. 13), with phthisis and unsuspected tumor, or as a mass in orbital recurrence. Orbital recurrence associated with hepatic metastasis has been described as late as 42 years after primary enucleation.¹²¹ Orbital extension may only become evident at the time of surgery; however, the use of ultrasonography and CT scan may lead to increasing preoperative detection of extrascleral nodules.

The controversy over the management of orbital recurrence parallels that of intraocular melanoma. It does seem that by the time extrascleral and orbital extension is evident, other biologic factors are already in play that dominate the grave mortality rate, which is 73% to 81% in these circumstances.^119,122 The role of exenteration has not yet been defined in a prospective controlled study but there is strong retrospective evidence suggesting that exenteration does not afford protection from metastases, except perhaps in cases of frank transection or nonencapsulation at enucleation.¹²² Shields and colleagues have summarized their current management (Table 9)¹²³ based on the type of extrascleral extension (flat, nodular, vortex vein, or recurrence after enucleation) and the timing of detection (clinical examination, at surgery, or pathologically after enucleation). Essentially, the trend is toward resection only of adjacent tissues when the lesion is nodular, whereas exenteration (which can usually be subtotal) is reserved for instances where there is evidence of tumor transection at the time of enucleation. In these circumstances, exenteration may be only a palliative measure. The role of preoperative and postoperative radiotherapy has not been clearly determined. Orbital recurrence for similar reasons requires exenteration, although low-grade spindle cell tumors may be curable in such circumstances. The biologic factors previously outlined appear to dominate the poor prognosis in orbital melanoma.

TABLE 9. Management of Uveal Melanomas with Extrascleral Extension

ORBITAL EXTENSION OF RETINOBLASTOMA

Retinoblastoma is the most common intraocular tumor of childhood, accounting for 1% of childhood cancer deaths in the United States and 5% of blindness in children. The incidence is 1 in 15,000 to 1 in 20,000 live births.^124,125 Overall mortality from retinoblastoma decreased from 95% a century ago to 18% in¹²⁶ With modern diagnostic and therapeutic advances, the mortality rate from metastatic or recurrent retinoblastoma has been as low as 5%.¹²⁷ In underdeveloped countries, patients characteristically present with extensive local and widespread disease; thus, mortality rates range between 90% and 100%.¹²⁸ The most common clinical presentations are leukocoria or strabismus; however, ocular inflammation, hyphema, and glaucoma also occur.

A major biologic characteristic of retinoblastoma, like all other malignancies, is the ability to invade and spread. Most retinoblastomas remain for a long time within the confines of the globe, except perhaps for blood-borne metastases, but the barriers to egress are ultimately penetrated. Depending on the site of the primary lesion, retinoblastoma may spread by means of the choroid to the adjacent orbital structures, by the optic nerve (particularly when the origin is peripapillary) to the CNS, and by the vascular system to distant metastatic sites.

Bruch's membrane initially resists invasion, but is eventually eroded, leading to choroidal growth. Once the tumor cells reach this choroidal network of fine vascular channels, growth appears to accelerate, as evidenced by three clinical features: (1) rapid growth over a period of days or weeks; (2) high elevation on a narrow pedunculated stalk; and (3) a yellow color at the summit, suggesting that the lamina vitrea has been pushed forward ahead of the tumor. Once in the choroid, the tumor spreads diffusely and rapidly in a lateral fashion. Choroidal invasion is more frequent in retinoblastoma than was previously thought, but does not necessarily carry a grim prognosis.^129,130 Metastases relate more closely to a critical mass of the tumor within the sponge-like network of choroidal vessels than to the mere presence of cells within the choroid.

As soon as Bruch's membrane is broken, egress from the confines of the globe follows. Routes of retinoblastoma spread from the globe to the surrounding tissues are shown in Fig. 14.¹³¹ An enucleated globe has three features that may suggest the possibility of orbital recurrence: (1) spread in continuity to episcleral nodules; (2) periemissarial retinoblastoma not extending to the surface; and (3) significant invasion of the choroid. The loose periemissarial connective tissue provides a natural plane for tumor growth; therefore, massive posterior choroidal involvement has a greater opportunity for access to the many posterior emissaria.

Lateral growth from the adventitial coats of the intrascleral emissaria may also lead to lamellar separation of the sclera and ultimately destruction of the ocular coats. Once outside the globe, the orbit provides a rich, loose tissue plane and growth accelerates further, leading to a large orbital mass.

Retinoblastoma may gain direct egress by means of the optic nerve to the CNS (Fig. 15A through H).¹³² Access to the subarachnoid space occurs by growth along the optic nerve to the site of penetration of the central retinal artery and vein; however, other modes of extension also occur. Although many cases resulted in a death due to invasion of the CNS, the tumors had not invaded much beyond the lamina cribrosa but were noted to occupy the nerve immediately adjacent to the pial lining (see Fig. 15G). Some cases also had evidence of pial erosion and thus direct egress from the nerve into the subarachnoid space (see Fig. 15E and F). The degree of optic nerve extension has been correlated with prognosis^133–135 and more recently with mortality rates, as follows: (1) superficial invasion of the optic nerve head, or grade 1 (10%); (2) involvement up to and including the lamina cribrosa, or grade 2 (29%); (3) involvement posterior to the lamina cribrosa, or grade 3 (42%); and (4) involvement to the line of surgical transection, or grade 4 (78%).¹³⁵

A more unusual mode of egress into the CNS is via the posterior ciliary circulation (see Fig. 15C, D, and H). Tumors that involve the peripapillary choroid can also reach the subarachnoid space along the radicals of the posterior ciliary vessels that supply the optic nerve head and the piaarachnoid of the distal optic nerve. Another unusual route of spread into the optic nerve is by means of the orbit into the subarachnoid space. Once in the CSF, the tumor circulates and sets up malignant rests even in the opposite optic nerve sheath.

Awareness of the significance of optic nerve invasion led to the development of adequate techniques of enucleation and improvement in survival in the last century. Although invasion up to but not beyond the lamina cribrosa has relatively little prognostic significance, invasion to the line of transection carries a poor prognosis and suggests the need for cytopathologic examination of the CSF and possibly additional therapy. Tumor extending beyond the lamina cribrosa, but not to the line of transection, may also carry a poor prognosis if it extends to the pia-arachnoid and indicates a need for cytologic study of the CSF.

Retinoblastoma has widespread metastatic potential in addition to its capacity for local invasion. Tumor-related death occurs solely from CNS involvement in 29% to 75% (average, 46%) and from distant metastases in 25% to 71% (average, 54%).^{130,136–138} The combined potentials of orbital, intracranial, and systemic spread determines the form of therapy after primary enucleation. Spread from the orbit may reach regional lymph nodes, and autopsy studies have revealed both regional and widespread involvement in 33% to 47% of cases. The sites of hematogenous spread are bone (especially the long bones and skull) and viscera (most often the liver, but also the pancreas, kidney, spleen, testes, ovaries, and uterus).

Management after enucleation for retinoblastoma is based on the presence or likelihood of extraocular spread as determined by pathologic examination of the globe. Therapy consists of adjuvant combined chemotherapy with local orbital and CNS irradiation if CNS spread is confirmed. The pathologic criteria that suggest orbital or systemic spread and indicate treatment of the orbit as well as systemic chemotherapy are extrabulbar retinoblastoma, orbital recurrence, and massive (particularly posterior) choroidal extension with periemissarial invasion.

There are three pathologic criteria that suggest a need to investigate and treat the CNS: tumor cells in the CSF, extension in the optic nerve to the line of transection, and extension beyond the lamina cribrosa with retinoblastoma adjacent to the pia arachnoid.

Although orbital extension of the tumor has been associated previously with a mortality of 67% to 100%,¹³⁰ modern chemotherapeutic and radiotherapeutic techniques are now producing better results. Orbital recurrences of retinoblastoma are managed by an aggressive chemotherapeutic and radiotherapeutic regimen directed toward systemic and CNS spread.

ORBITAL EXTENSION OF NEUROEPITHELIAL TUMORS OF THE CILIARY BODY

The neuroepithelial tumors of the ciliary body can be divided into congenital and acquired tumors, either of which may be benign or malignant (Table 10).¹³⁹

TABLE 10. Classification of Neuroepithelial Tumors of the Ciliary Body

1. Congenital
   1. Glioneuroma
      
   2. Medulloepithelioma
      1. Benign
         
      2. Malignant
         
      
      
   3. Teratoid medulloepithelioma
      1. Benign
         
      2. Malignant
         
      
      
   
   
2. Acquired
   1. Nonpigmented
      1. Benign
         1. Pseudoadenomatous hyperplasia
            
         2. Adenoma
            1. Solid
               
            2. Papillary
               
            3. Pleomorphic
               
            
            
         
         
      2. Malignant
         1. Glandular and papillary
            
         2. Pleomorphic, low-grade
            
         3. Pleomorphic with hyaline stroma
            
         4. Anaplastic
            
         
         
      
      
   2. Pigmented
      1. Benign
         1. Adenoma
            
         2. Vacuolated adenoma
            
         
         
      2. Malignant
         1. Adenocarcinoma
            
         
         
      
      
   3. Mixed pigmented and nonpigmented
      1. Benign
         
      2. Malignant
         
      
      
   
   

Medulloepitheliomas

Medulloepitheliomas are embryonal tumors that arise from the neuroepithelium in the ciliary body region in children (mean age = 5 years at diagnosis). More rarely, they occur adjacent to the optic nerve and extend into the nerve substance. Histologically, they are composed of cords of nonpigmented and pigmented cells resembling the optic vesicle or optic cup. They often have areas of undifferentiated cells that resemble retinoblastoma with Homer-Wright and Flexner-Wintersteiner rosettes. The tumor cells can elaborate vitreous-like material. Heteroplastic elements, such as cartilage, brain tissue, and striated muscle, may be noted in the so-called teratoid medulloepitheliomas.¹⁴⁰

Medulloepitheliomas may be divided pathologically into benign and malignant variants. In a series of 56 cases, Broughton and Zimmerman¹⁴¹ noted 66% had histologic evidence of malignancy, although they emphasized the characteristic slow growth and locally invasive nature of the tumor. The single most important life-threatening prognostic factor was evidence of extraocular spread. The typical presentations are poor vision, pain, leukocoria, and ciliary body mass in childhood. Of the 56 patients, 8 presented with proptosis or an orbital mass. Of the four patients who died of medulloepithelioma, all had orbital extension; nodal metastases developed in one patient, and the remaining three died because of local extension of the tumor into the intracranial structures. Of the remaining cases of extraocular extension, the major factor in survival appeared to be complete local excision. Tumors occurring in the optic nerve region are more treacherous because they tend to be identified later and because they have easier access to the orbital and intracranial structures.

Treatment is accomplished with wide local excision. Recent advances in imaging may allow for clearer identification of extension and preoperative planning.

ACQUIRED NEUROEPITHELIAL TUMORS OF THE CILIARY BODY

The majority of acquired neuroepithelial tumors are benign hyperplasias or adenomas. Malignant variants, which vary from well-differentiated to pleomorphic tumors, are rare. Most arise in previously traumatized, chronically inflamed eyes. Tumor-related mortality is generally due to contiguous invasion, but widespread metastatic disease may occur. Treatment is accomplished with wide local excision.

Stefanyszyn and co-workers¹⁴³ recently reported on 115 cases of lacrimal sac tumors from the Armed Forces Institute of Pathology (AFIP) and combined their data with other large series.^{142,144–148} Primary epithelial neoplasms accounted for 73% of all lacrimal sac tumors (73% of these were malignant) and mesenchymal tumors accounted for 14% (62% of these were malignant). Lymphomas (8%), malignant melanomas (4%), and neural tumors (1%) were also noted.

The general clinical progression of epiphora followed by simulated dacryocystitis, nonreducible swelling, and eventual tumor extension outside the sac was recognized by Jones.¹⁴⁹ The benign lesions have a tendency toward slower growth, obstructive symptoms, and recurrent dacryocystitis that may mimic inflammation of the lacrimal sac. The malignancies may initially present similarly; however, the infiltrative nature of tumors in a higher risk category will eventually dominate the clinical picture (Fig. 16). Features suggestive of malignancy include a mass extending above the medial canthal ligament, telangiectasis or ulceration of the overlying skin, serosanguineous discharge or bloody reflux after irrigation, local invasion of the adjacent bone and orbit with occasional pain, restricted extraocular movements, nonaxial proptosis, and an overall relentless progressive course. Dacryocystogram may be helpful in the diagnosis of suspected lacrimal sac tumors.^146,150,151 Findings suggestive of neoplasia include a distended lacrimal sac with a mottled density or filling defect, and delayed emptying.

EPITHELIAL TUMORS

Ryan and Font¹⁵⁰ divided the epithelial malignancies into papillomas and de novo tumors. The papillomas display three growth patterns: exophytic, inverted, and mixed types. Additionally, they can be subdivided histologically into squamous, transitional, and mixed cell papillomas. The exophytic papillomas tend toward multiple occurrences that affect the whole of the epithelium of the nasolacrimal system, particularly when they are of the transitional cell type. The inverted papillomas are more prone to developing focally invasive carcinoma, usually of a low-grade variety. Mixed papilloma have mixed clinical and histopathologic features of exophytic and inverted types. In the AFIP series,¹⁴³ papillomas occurred in persons aged 9 to 88 years (mean, 44 years). Stefanyszyn and co-workers also reported that 6 (14%) of 44 papillomas developed into carcinoma or had foci of carcinoma. De novo carcinomas have been divided into papillary and nonpapillary types on the basis of their gross pattern of involvement.¹⁵⁰ In the AFIP series,¹⁴³ carcinomas occurred in persons ranging in age from 16 to 89 years (range, 59 years). De novo carcinomas may include squamous cell, transitional cell, adenoid cystic, mucoepidermoid, and poorly differentiated carcinomas as well as adenocarcinomas; however, the majority are squamous cell carcinomas. Other less commonly reported epithelial lesions of the lacrimal sac include oncocytomas, which tend to be noninvasive, and benign mixed tumors.

Management should be based on histopathologic type and degree of extension.¹⁵² The papillomas, particularly when focal invasion is demonstrated, should be treated with total excision of the lacrimal system, followed by careful observation for any evidence of recurrence in the nose. More aggressive carcinomas should be treated with wide local excision, including the bone of the nasolacrimal system, the adjacent orbit, and the sinus wall. Postoperative radiotherapy is advocated for more aggressive lesions, and significant orbital involvement is an indication for exenteration. In our experience, both transitional cell carcinoma and squamous cell carcinoma of the lacrimal sac with orbital invasion have also been responsive to radical local radiotherapy alone (see Fig. 16).

NONEPITHELIAL TUMORS

Nonepithelial tumors include mesenchymal lesions (fibrous histiocytoma, hemangiopericytoma, and lipoma), lymphomas, malignant melanomas, granulocytic sarcoma, and neural tumors (neurilemmoma and neurofibroma).^143,153 Locally aggressive lesions such as fibrous histiocytomas should be widely excised and carefully followed, whereas malignant lesions should be treated with wide local excision, with or without radiotherapy. Lymphomas should be treated with radiotherapy and/or chemotherapy, depending on the systemic status of the patient. Malignant melanomas of the lacrimal sac share the grim prognosis of other malignant melanomas of mucosal surfaces because of the lack of early detection.^153,154

Basal cell carcinoma is by far the most common epithelial eyelid malignancy; however, the frequency of orbital invasion is roughly equivalent to that for squamous cell carcinoma (which may be more invasive) and sebaceous cell carcinoma (in which diagnosis is often delayed). The majority of conjunctival squamous cell carcinomas and malignant melanomas arise from precursor lesions, and early invasion may be clinically silent. The incidence of orbital extension of ocular tumors has declined, in large part due to screening programs and earlier diagnosis of retinoblastoma, as well as to advanced diagnostic modalities and treatment options for both retinoblastoma and choroidal melanoma. Lacrimal sac tumors are uncommon and may go unrecognized until dacryocystorhinostomy is performed for nasolacrimal duct obstruction.

Recognition of the individual clinical features of these tumors is based on anatomic location and tumor biology. Defining the extent of the lesion and structures involved may require directed imaging studies. Ultimately tissue diagnosis, extent of the lesion, and individual patient characteristics will guide specific therapy in each case. Surgical excision, radiotherapy, or other local modalities in combination may be indicated. The goal of treatment is generally complete eradication of the tumor; however, when this cannot be achieved, preservation of visual function, cosmesis, and comfort direct the interventions.

Although the prognosis for patients with metastatic cancer remains grim, combined therapy can be palliative and may induce remission and even cure in some patients. In Part II of this chapter, the prevalence, diagnosis, and management of metastatic orbital tumors is discussed, with an emphasis on the syndromes of clinical presentation, specifics of tumor biology, and tumors for which there is currently good treatment. An extensive combined review of the University of British Columbia Orbit Clinic experience with 207 cases of orbital metastases was reported in 1990 by Goldberg and associates.¹⁵⁶ The following discussion includes a summary of their article along with updates from more recent work by other authors. The topics of lymphoma and leukemia are intentionally excluded because they have been discussed elsewhere in these volumes.

Godtfredsen¹⁵⁷ found ocular metastases in only 6 (0.7%) of 8712 patients with known metastatic disease in a 1944 clinical survey. In 1967, Albert and colleagues¹⁵⁸ found that of 213 clinical cases of known metastatic cancer, 10 (4.7%) had orbital or ocular metastases. Clinically occult tumors are undoubtedly missed in clinical surveys, since Bloch and Gartner¹⁵⁹ found evidence of ocular and orbital metastases in 12% of cases in a careful histologic survey.

Historically, the ratio of intraocular to orbital metastases has been found to be from 2.3:1 to 8:1 in large histopathologic series.^159–161 In a 1987 clinical study using modern orbital diagnostic capabilities, Freedman and Folk¹⁶² found a ratio of 1.4:1.

It is also clinically useful to determine the prevalence of orbital metastases among all orbital diseases. Large clinical^163–166 and radiographic^167,168 orbital series have put the proportion of metastatic tumors at 1.5% to 3.3% of all orbital cases, and a large pathologic series¹⁶⁹ found a proportion of 2.5%. In the Mayo Clinic series,¹⁷⁰ Henderson found 111 metastatic tumors in 1376 orbital neoplasms (8%). Analysis of the University of British Columbia Orbit Clinic experience from 1976 through 1995 revealed that of 740 orbital neoplasms, 55 (7%) were metastases.

Combining large series^{158,161–163,171–174} from the literature gives a relative prevalence of the various primary tumor types that present clinically to the ophthalmologist (Fig. 17). It is apparent that breast, lung, and prostate cancer and melanoma constitute the largest groups of metastatic cancer to the orbit; cases in which the primary tumor could not be identified also represent a significant proportion. These combined clinical and pathologic series do not reflect the true distribution of primary tumors metastatic to the orbit as well as would a large, meticulous autopsy series. For example, metastatic lung cancer, which has a fulminant course and typically metastasizes to the orbit when the patient is already quite ill systemically, will be underrepresented in a clinical series compared with breast cancer, which runs a slower course and is more likely to be present in a patient who is able to ambulate to the ophthalmologist's office. Other tumors with rare orbital metastases have been described: hepatocellular carcinoma,^176–178 pleural malignant mesothelioma,¹⁷⁹ paravaginal alveolar rhabdomyosarcoma,¹⁸⁰ and leiomyosarcoma.¹⁸¹

The superior and medial orbit previously has been suggested to be the most common location of orbital metastasis.^173,184 Combining data from reported cases regarding quadrantic location, however, Goldberg and colleagues¹⁵⁶ discovered the following distribution: lateral 39%, superior 32%, medial 20%, and inferior 12%.

The principal tissue destination of orbital metastases is often difficult to determine with certainty because by the time localizing procedures (e.g., CT scan, autopsy) are performed, the tumor mass has grown to involve bone, muscle, fat, and other orbital tissues. In most cases, however, a reasonable assumption can be made as to the primary tissue destination of orbital metastasis. Goldberg and associates¹⁵⁶ found that the overall ratio of tissue destination in a combined series of reported cases showed bone and fat to be more common than muscle by a ratio of 2:2:1. However, different primary tumor types demonstrated distinct preferences for certain tissues. Prostate carcinoma had a strong tendency to metastasize to bone as opposed to fat or muscle; the bone-fat-muscle ratio was found to be 4:1:0. In contrast, breast carcinoma had a tendency to localize in orbital fat and muscle (bone-fat-muscle ratio, 1:3:2). Melanoma had the strongest preference for muscle (bone-fat-muscle ratio, 1:4:4) of all the tumor types.

Diagnosis of metastasis can be quite challenging when tumor enlarges the extraocular muscle discretely without other orbital involvement (Fig. 18).^185–189 The differential diagnosis of discrete extraocular muscle enlargement includes Graves' disease, myositis, lymphoma and other primary neoplasms, varix, arteriovenous malformation, carotid cavernous fistula, acromegaly, amyloidosis, trichinosis, and cysticercosis.

Before 1960, occult malignancy was the most common clinical presentation; however, there has been an increasing frequency of patients with a known primary presenting with metastatic tumors to the orbit. In reports since 1980, only 28% of metastatic tumors presented first as orbital masses. Thus, there has been an increasing tendency toward diagnosis of the primary tumor before it presents as an orbital metastasis, which is likely a reflection of increasing clinical awareness and diagnostic acumen regarding primary cancers. However, the fact that systemic metastatic cancer will manifest first as an orbital process in more than one quarter of cases places an important diagnostic burden on the ophthalmologist, who will be the first physician to evaluate these patients. A high suspicion of metastatic disease may help lead to an earlier diagnosis of systemic cancer, which could have profound implications for the patient.

Tumors with a drawn-out temporal course (e.g., breast, carcinoid) are typically diagnosed long before the patient presents to the ophthalmologist, and survival after orbital metastasis is also relatively prolonged, often measured in years instead of months. Breast cancer is well known for having a lengthy delay from diagnosis of the primary to the appearance of metastasis (average delay, 3 years).

Another tumor with a drawn-out temporal course is thyroid cancer. In our combined cases, an average of 5 years passed from the time of diagnosis of primary thyroid cancer until the appearance of orbital metastasis (the longest interval among all primary types), and average survival after ophthalmic presentation was 42 months. Thyroid cancer is challenging because of the potential difficulty in accurately diagnosing the primary malignancy. If careful sectioning of the excised thyroid mass is not performed, the area of malignant follicular (or less likely papillary) cells may be overlooked. This may account for cases in which apparently benign tumors have been noted to metastasize.^173,190

Melanoma is somewhat intermediate, having an average of almost 2 years between diagnosis of the primary cancer and orbital presentation and a recorded latency of up to 46 years.¹⁹¹ Once metastasis has occurred, however, the disease is rapidly progressive. Tumors with a fulminant course (e.g., lung, gut) are diagnosed shortly before or sometimes after orbital presentation and run a rapidly progressive course with survival typically less than 6 months after ophthalmic presentation. Because these cancers metastasize early, patients may present with orbital findings and systemic wasting before their primary cancer has been diagnosed. Thus, they have become known as “silent” primaries.

Concurrent metastases to other sites were noted clinically in 47% of cases, including 14 cases with concurrent choroidal metastases. In reality, it is probable that few orbital metastases are truly solitary, despite the clinical inability to demonstrate other concurrent metastases. The only exceptions might be in cases of metastatic carcinoid tumor and renal cell carcinoma. Carcinoids arise from neuroendocrine precursor cells in the gut or bronchi and are very slow growing. Survival as long as 20 years after ocular or orbital metastasis has been described.^192–194 Clinically, solitary orbital metastases of carcinoid primary may be for practical purposes truly isolated, and this combined with the excellent prognosis for lengthy survival has led many authors to recommend surgical extirpation of isolated carcinoid metastases.^{172,192,194,195} Patients with renal cell carcinoma may also present with solitary metastases, and isolated metastatic tumors of renal cell carcinoma have been managed surgically in the orbit¹⁹⁶ and elsewhere in the body.^197,198

Proptosis and motility disturbances are the most common presenting symptoms and signs (Table 11). Motility disturbance out of proportion to the degree of proptosis can occur and is somewhat characteristic of an orbital metastasis.¹⁷³ Pain was noted in 23% of cases and may be present early in the course, in contrast to other tumors in which pain is typically a late symptom. The single exception to this is tumors that invade by contiguity, where pain or paresthesia are the most frequent early symptoms. Palpable mass, blepharoptosis, and decreased vision were also common signs and symptoms. Pulsation of the orbit may occur when destruction of orbital bone allows transmission of CSF pulsation. Vascular metastases, particularly of thyroid and renal origin, can demonstrate intrinsic pulsation due to high internal blood flow.^{173,199–203}

TABLE 11. Presenting Symptoms and Signs

Enophthalmos is a frequently overlooked sign that is seen in 10% of reported cases, of which metastatic breast cancer accounts for approximately 80%. The common mechanism of enophthalmos is contraction of fibroblasts in the diffuse scirrhous orbital tumor leading to posterior traction on the globe.^173,204,205 Destruction of the bony walls of the orbit, resulting in a “biologic orbital decompression,” may play a role in some cases.

Although the tabulation of signs and symptoms is helpful, it does not by itself provide a clinical framework with which to evaluate and categorize the diverse group of patients with orbital metastases. Clinical presentations of orbital metastatic disease can be generalized into five basic types and are presented in decreasing order of frequency in Table 12.

TABLE 12.Clinical Presentations of Orbital Metastatic Disease

CASE 1: MASS PRESENTATION

An 83-year-old white woman reported experiencing occasional swelling of the right eye without pain, numbness, or redness lasting 1 year, and a prominence of the same eye lasting 2 months. Clinical examination revealed 3 mm of proptosis, 2 mm of upward displacement of the globe, and marked restriction of ductions in all fields of gaze (Fig. 19A). CT scan revealed a slightly inhomogeneously contrast-enhancing retrobulbar mass lesion (Fig. 19B) displacing the optic nerve superiorly; it was inseparable from the inferior rectus muscle (Fig. 19C). Needle aspiration biopsy showed a carcinoid tumor (Fig. 19D and E); however, systemic evaluation was negative. The patient refused local therapy and had a minimal increase in proptosis over a 3-year period, after which she died of a bowel obstruction due to a primary carcinoid tumor.

CASE 2: INFILTRATIVE PRESENTATION

A 73-year-old white woman presented with progressive right enophthalmos associated with diplopia and restricted eye movements lasting 2 years. She was aware of a palpable lump in the right lower lid for several months. Her past history was significant for a partial colectomy for bowel cancer 7 months before presentation. On examination, the orbits were firm to retropulsion bilaterally with a palpable mass in the right lower lid and 3 mm of relative left proptosis (Fig. 20A). She had a narrow interpalpebral fissure on the right and limited extraocular movements in all fields of gaze. CT scan revealed diffuse, contrast-enhancing, abnormal soft tissue within both orbits surrounding the globes (Fig. 20B) and extending posteriorly along the extraocular muscles and optic nerve sheaths. Orbital biopsy was consistent with metastatic adenocarcinoma from the bowel. Two months after orbital radiotherapy, the subdermal lid infiltrates were gone and her upper lid sulci reappeared. Her proptosis was reduced and extraocular movements improved (Fig. 20C).

SYNDROMES OF PRESENTATION

The syndromes of presentation are rarely pure, but the overall pattern is clear in the majority of cases. In one series,¹⁷⁴ a dominant presentation was apparent in 24 (63%) of 38 cases; in the remainder, a main syndrome of presentation could be determined accompanied by one or more secondary syndromes. In a combined review of cases reported in the literature,¹⁵⁶ a main syndrome of presentation could be identified in 193 cases (84%).

The mass syndrome of presentation is most common (66%), with globe displacement as the predominant sign; pain, inflammation, and secondary motility disturbance are often present as well. Second in frequency is the infiltrative syndrome of presentation (24%), characterized by restricted motility and enophthalmos. Notably, in cases of metastatic breast carcinoma, particularly scirrhous-type, the infiltrative pattern was most common, with patients tending to present with enophthalmos and motility disturbance. The infiltrative pattern (in relation to enophthalmos) can also be seen in gastrointestinal, prostate, lung, and other primary tumors. Functional and inflammatory syndromes of presentation (5% each) were noted less frequently. Kattah and co-workers²⁰⁶ recently described five patients with metastatic prostate cancer to the optic canal presenting with optic neuropathy.

An interesting syndrome of presentation may be seen with seminoma, which in rare instances can present as a bilateral nonspecific inflammatory or Graves' disease-like orbitopathy.^207–209 The etiology of the proptosis is not known; nevertheless, it does not appear to be related to direct orbital metastasis, as demonstrated by autopsy in one case,²⁰⁷ and has shown regression in response to steroids or excision of the primary tumor. An endocrine mechanism has been proposed, and although two of the three reported cases were associated with an elevated serum human chorionic gonadotropin level, no direct link has been established. Direct orbital metastasis of seminoma must be carefully excluded in these cases.^210,211

MISDIAGNOSIS: DIAGNOSTIC PITFALLS

Misdiagnosis and lengthy delay in diagnosis are common in metastatic cancer to the orbit for the following reasons: protean clinical manifestations, lack of suspicion on the part of the clinician, and difficulty in obtaining a complete history with regard to previous cancer. The most common misdiagnoses occur in patients presenting with inflammatory syndromes, including cellulitis,^174,212 myositis,¹⁸⁸ endophthalmitis,²¹³ and idiopathic orbital inflammatory syndrome.^{172,174,214,215} The clinician does not automatically consider an orbital metastasis in a patient who presents with a “hot” orbit and, indeed, this differential diagnosis properly resides fairly low down on the list. A history of previous cancer should alert the clinician to the possibility of metastasis; however, in some patients the inflamed orbit will be the first sign of cancer and a negative history will be obtained. From a clinical point of view, features that will suggest orbital metastasis are a firm orbit associated with brawny induration and a progressive (usually throughout a period of weeks), unrelenting course dominated by these features along with infiltrative phenomena.

The infiltrative syndrome of presentation has been misdiagnosed as dysthyroid ophthalmopathy²¹⁶ or idiopathic orbital fibrosis.¹⁷⁴ Patients with a functional syndrome of presentation have been misdiagnosed as myasthenia gravis^189,217,218 and sixth nerve palsy.¹⁷⁴ The remaining misdiagnoses reflect the lengthy differential diagnoses of orbital masses, including lacrimal gland tumor,^219–221 mucocele,¹⁷⁴ meningioma,^222,223 and chocolate cyst.²²⁴ Although history, examination, and special diagnostic studies will often narrow the likely possibilities, biopsy is required in the majority of cases for definitive diagnosis of metastatic disease.

DIAGNOSTIC MODALITIES

History and Clinical Examination

Directed history taking, combined with routine ophthalmologic and orbital examination, is the cornerstone of evaluation of patients with orbital metastasis.²¹³ A general physical examination is indispensable in patients with known or suspected metastatic disease. Breast and prostate primaries in adults, for example, and abdominal neuroblastoma in children often can be readily detected on physical examination. The diagnosis of orbital metastasis often can be confirmed by diagnosis of the primary lesion during the initial visit to the ophthalmologist.¹⁷⁵

Laboratory Tests

Both nonspecific and specific laboratory tests are available to help in the diagnostic work-up of patients suspected of harboring orbital metastasis. A nonspecific test that can be useful in the differential diagnosis of an orbital mass of suspected metastatic origin is the carcinoembryonic antigen (CEA). The CEA may be elevated in patients with metastatic cancer, and the degree of elevation may relate to total tumor load. Bullock and Yanes¹⁷¹ found that an elevated CEA level was specific for metastasis in their series of 42 patients with proptosis. This test was not very sensitive, however, considering that only 5 of 13 patients with metastatic orbital tumors had CEA levels that were significantly elevated (greater than 5 ng/mL). Therefore a negative test may not rule out metastatic disease.

Specific tests can be useful in tumors that elaborate a measurable substance into the blood stream. Of the tumors that frequently metastasize to the orbit, prostate cancer (producing prostatic acid phosphatase)²²⁵ and seminoma (producing human chorionic gonadotropin)^207,211 elaborate specific substances that can be measured for diagnosis, staging, or treatment follow-up. Carcinoid tumors may elaborate 5-hydroxyindolacetic acid into the urine, particularly in the presence of hepatic metastases and in association with the carcinoid syndrome (i.e., flushing, diarrhea, lacrimation, conjunctival injection, and other vasomotor instabilities), which usually indicates a significant tumor load.¹⁹²

A general evaluation for other metastases is important for diagnosing and cancer staging. After a confirmation of the metastases by tissue diagnosis, general evaluation is best accomplished by an oncologist so that a careful, directed investigation based on the nature of the primary lesion is performed.

Computed Tomography

CT is the practical standard for the diagnosis of orbital disease, and metastatic tumors are no exception. It not only allows for localization of the tumor within the orbit, but can also provide important clues regarding tissue characteristics.^226,227 The CT findings in metastatic orbital tumors are variable, but they can be simplified into four basic categories, which are presented in Table 13.

TABLE 13. Computed Tomographic Findings in Metastatic Orbital Tumors

The most common CT presentation is a mass (58%), followed by bone (25%), muscle (9%), and diffuse involvement (8%). Breast carcinoma favors a mass presentation and muscle involvement, prostate carcinoma strongly tends toward bone involvement, and melanoma has the highest affinity for muscle.

Tumors that metastasize to bone can produce either type of bony response with corresponding hypodense or hyperdense changes on CT. Prostate carcinoma particularly tends to produce a hyperostotic response with increased density and thickness of bone,²²⁸ and thyroid metastases commonly cause a hypostotic response.^173,202

Magnetic resonance imaging provides similar and in some ways superior anatomic information, including direct sagittal images. Superior soft tissue differentiation of magnetic resonance imaging over CT may substantially augment our diagnostic capabilities.^229–231 For example, signal intensity on T2-weighted images is helpful in distinguishing idiopathic orbital inflammatory tumor (low density) from lymphoma or metastasis (high intensity).²³² Certainly CT scan is better for evaluating bone involvement.

Needle Biopsy

One of the best orbital applications of needle biopsy is in the setting of suspected metastatic tumors.²³³ When it is successful, it can save the patient the expense and risk of open biopsy. If an adequate specimen can be obtained, hormone receptor and surface antigen studies for tissue source identification can be performed directly on the tissue fragment recovered from the needle (e.g., in cases of metastatic prostate carcinoma).^234,235 In sclerosing lesions, such as scirrhous breast and gut metastases, needle biopsy tends to produce “dry taps” with little or no tissue retrieval.

Pathologic Techniques

The overwhelming majority of metastases are poorly differentiated or “round cell” tumors; thus, diagnosis often requires special histochemical, immunohistochemical, and electron microscopic techniques.²³⁶ Furthermore, in the case of hormonally responsive tumors, steroid receptor studies on the biopsy tissue are important from a therapeutic standpoint. If metastasis is being considered in the differential diagnosis, the surgeon should discuss the case with the pathologist in advance and provide an adequate amount of nontraumatized fresh tissue so that the appropriate receptor or immunohistochemical studies can be carried out. The range of typical histologic features, variants, and specific distinguishing features of the common orbital metastasis are outlined in Table 14. The field of immunohistochemistry is rapidly evolving, developing a broader range of specific monoclonal antibodies that identify tissue of origin. Careful, delicate handling and appropriate transmission of an adequate biopsy are critical responsibilities of the ophthalmic surgeon.

TABLE 14. Histologic, Histochemical, and Electron Microscopic Features of Orbital Metastases

TREATMENT

Although it is generally true that patients with orbital metastases have a short expected life span, there are many cancers for which excellent treatment exists, and the list of treatable tumors continues to expand. Even in the case of tumors for which no direct treatment is available, troubling symptoms such as decreased vision or pain can often be relieved through the use of orbital radiotherapy or chemotherapy. To a person with a limited number of weeks or months of life remaining, the ability to maintain visual function and comfort is profoundly important. The principal modalities for treating patients with metastatic cancer are radiation, hormonal therapy, chemotherapy, and surgery. The diverse clinical behaviors and treatments of the common metastatic tumors to the orbit are summarized in Table 15.

TABLE 15. Summary: Characteristics of Common Primary Types

Radiotherapy

Radiotherapy has proved extremely useful in the treatment of orbital metastasis. Typically, a total of 30 to 40 Gy is given in divided doses in a period of 1 to 2 weeks. Dramatic improvement in orbital signs and symptoms, including recovery of vision when impairment is secondary to orbital mass effect, is not uncommon. In published series (which include patients with lymphoma and leukemia), the success rate has been reported to be 70% to 90%.^237–239 Even in metastatic carcinoid tumors, which are traditionally considered to be fairly radioresistant,^172,221 success with orbital radiotherapy has been reported.^240–242 Radiotherapy for orbital metastasis is generally associated with few complications, particularly if care is taken with dosing, field placement, and shielding of the globe.^237,239 However, Mortada noted a 50% occurrence of cataract in 13 patients undergoing radiotherapy for orbital metastasis.¹⁶⁷ As patients treated for orbital metastatic cancer continue to survive longer, we may begin to observe more ocular radiation complications. Still, because of its ability to ameliorate symptoms of otherwise untreatable orbital tumors, radiation therapy remains the mainstay of treatment of orbital metastatic disease.

Hormonal Therapy

Certain cancers originating in organs that participate in hormonal axes have hormone receptors on their cell surfaces, and if these cancers remain fairly well differentiated, they may show a modulation of growth in response to therapeutic hormonal manipulation. The primary examples in the orbit are metastatic prostate and breast carcinoma. The presence of hormone receptors on the surface of these tumors can be detected and measured in the laboratory with adequate specimens of fresh tissue. The orbital surgeon can play a vital role by obtaining an adequate tissue specimen.

Excellent results have been obtained with hormonal therapy of prostate and breast carcinoma metastatic to the orbit. Particularly in the case of prostate carcinoma, virtual reversal of orbital symptoms and occasional long-term survival have been reported.^203,228,243 Diethylstilbestrol, with or without orchiectomy, has been the mainstay of hormonal therapy for prostate cancer since the 1950s. More recently, specific luteinizing hormone-releasing hormone agonists have been introduced, which may avoid the feminizing side effects of diethylstilbestrol or orchiectomy.²²⁵ However, the leutinizing hormone-releasing hormone agonists do not seem to offer improved palliation or survival over diethylstilbestrol, and they are associated with an initial testosterone surge and tumor growth period of several weeks' duration.²²⁵ This contraindicates their use in compressive spinal cord lesions and presumably in compressive orbital apex lesions as well.

Metastatic breast carcinoma is temporarily responsive to hormonal manipulation in the majority of cases.²⁴⁴ The importance of screening for estrogen receptors on tissue biopsy is illustrated by McGuire,²⁴⁵ who found that 55% to 60% of metastatic breast tumors with positive estrogen receptors are responsive to endocrine therapy. The presence of progesterone receptors adds even greater predicative value.²⁴⁶

Chemotherapy

With the advent of more aggressive and specific chemotherapeutic protocols, chemotherapy for metastatic disease has become increasingly important. Of the common metastases to the orbit, small cell carcinoma of the lung and neuroblastoma are particularly chemosensitive. Chemotherapy often plays an important adjunctive role in palliative therapy of orbital metastases.

Surgery

In general, patients with metastatic orbital tumors are not candidates for therapeutic surgical intervention. Their disease is systemic, and radical surgery cannot offer a cure. Furthermore, radiotherapy and in some cases hormonal therapy offer alternative treatment modalities that often provide significant palliation.

Regardless, there are cases in which surgery is indicated. Metastatic carcinoid tumors sometimes grow so slowly that for practical purposes they are isolated tumors. In these cases, excision of the metastatic tumor (along with the primary if it can be found and safely excised) can provide long-term relief of symptoms and perhaps improved survival. Renal cell carcinoma may also present with solitary metastases^197,198; although the prognosis is still rather poor, surgical excision may be indicated for apparently isolated orbital metastases.¹⁹⁶

Some metastatic tumors produce intolerable symptoms, such as pain or gross proptosis. If radiotherapy, chemotherapy, or other medical approaches are unsuccessful at relieving symptoms, then surgical debulking may be indicated for palliation despite the poor prognosis for survival.

NEUROBLASTOMA

Neuroblastoma is the most common solid tumor of childhood, accounting for 10% to 15% of all pediatric cancer.²⁵⁰ It is second only to rhabdomyosarcoma as the most frequent orbital malignancy of childhood, and it constitutes greater than 90% of pediatric orbital malignancies.²⁵¹ Neuroblastomas arise from embryonic neural crest tissue of the postganglionic sympathetic nervous system. The most common site of origin is the abdomen; however, they may originate in thoracic, cervical, or pelvic sites. The tumor may present any time in the first two decades, although the vast majority present before 3 years of age.²⁵²

The orbital presentation is characterized by sudden onset and rapid progression of proptosis, which may be unilateral or bilateral, and is often accompanied by periorbital edema, ecchymosis, and ptosis. This presentation evokes a differential diagnosis, including orbital cellulitis, other rapidly developing orbital tumors (e.g., rhabdomyosarcoma, Ewing's sarcoma, medulloblastoma, Wilms' tumor), and hemorrhage into a preexisting lymphangioma. The most common orbital sites of involvement are the superolateral orbit and zygoma with secondary extension. A combination of bone and soft tissue involvement is common, and there may be evidence of bone destruction and other foci of cranial metastases on radiologic evaluation. Other ophthalmic manifestations may include Horner's syndrome due to mediastinal or cervical sympathetic chain involvement,^252,253 opsoclonus and myoclonus,²⁵⁴ tonic pupils as a paraneoplastic effect,²⁵⁵ and metastasis to the iris²⁵⁶ or choroid.²⁵⁷ Histology and distinguishing features of neuroblastoma are presented in Table 14.

The prognosis in metastatic neuroblastoma remains poor and varies with age (i.e., more favorable in patients less than 1 year), site of primary (i.e., thoracic lesions better than abdominal), and extent of disease. Musarella and associates²⁵⁴ found that 3-year survival rates correlated with type of ocular involvement: orbital metastases (11%), Horner's syndrome (79%), and opsoclonus-myoclonus (100%). Orbital lesions are treated with radiotherapy and chemotherapy in combination with surgery for systemic disease. Aggressive combination chemotherapy with a variety of agents (e.g., cisplatin, adriamycin, cyclophosphamide, vincristine, carmustine, melphalan), with or without total body irradiation and autologous bone marrow rescue, are required for disseminated disease.^258–262 Elevated urinary vanillylmandelic acid levels due to catecholamine secretion by the tumor are found in 90% of patients and can be helpful in diagnosing disease and monitoring treatment.

EWING'S SARCOMA

Ewing's sarcoma is a highly malignant, small, round cell tumor of primitive mesenchymal cells in the bone marrow. The majority arise in the lower extremity or pelvis, but they occasionally arise from soft tissue as an extraskeletal variant. Four percent of primary tumors occur in the head and neck, with maxilla and mandible affected more commonly than the orbital roof.²⁶³ The tumor most commonly presents in the second decade and is rare in Asians and black Americans. Orbital presentation is generally a rapidly progressing proptosis with or without orbital hemorrhage.²⁵¹ On a typical CT scan, the involved bone has a “moth-eaten” appearance associated with a soft tissue component of the tumor. The histologic and distinguishing features of Ewing's sarcoma are presented in Table 14. Treatment generally involves a combination of radiotherapy and chemotherapy.^264,265 Local disease control may consist of resection of the primary tumor after a course of induction chemotherapy. Clear margins may obviate the need for radiotherapy, although these tumors are quite radiosensitive. With modern chemotherapeutic regimens in combination with surgery or radiation, the 5-year survival rate has improved to 80%. There is a risk of both late recurrence and development of a second primary (typically osteogenic sarcoma); therefore, these patients should have long-term follow-up.

ORGAN-SPECIFIC METASTASIS

Why does breast carcinoma dominate orbital metastasis, whereas other common cancers, particularly those of gastrointestinal origin, are much less frequently observed at this site? What accounts for the tendency for tissue-specific metastasis, such as prostate to bone or melanoma to muscle? What causes breast carcinoma to lodge frequently in the choroid, whereas neuroblastoma,²⁵¹ Ewing's sarcoma,²⁶⁶ and prostate metastases seem to lodge in the orbit instead?

Three hypotheses have been advanced as explanations for organ-specific metastasis: mechanical, seed and soil, and specific tumor-cell adherence.^267,268 The mechanical theory ascribes organ-specific metastasis to variations of blood flow and capillary sieving due to vascular architecture, a phenomena said to explain left-sided dominance of orbital metastases. The seed and soil theory and the specific tumor-cell adherence theory are similar in that they hypothesize that tumor cell-host tissue interactions of the microenvironment and cellsurface antigens, respectively, are the primary factors accounting for organ-specific metastasis. A recent review documents experimental data regarding organ-specific metastasis, including recent characterization of surface carbohydrates, which may be the locus of host tissue-tumor cell recognition.²⁶⁸ It is likely that all three mechanisms are responsible in some combination for organ- or site-specific metastasis.

METASTATIC CANCER OF UNKNOWN ORIGIN

An important group of orbital metastases are those in patients with unknown primaries, which consisted of 11% of the patients in a combined series (see Fig. 3).¹⁵⁶ In large series of patients with metastatic cancer of unknown origin,^269–271 more than one half of the patients remained undiagnosed despite extensive investigations, and even autopsy was unsuccessful at diagnosing the primary cancer in approximately 10% to 30% of cases.^270–272 Tumors that are typically “silent,” metastasizing early in their course, constitute the majority of these unknown primaries, including lung, stomach, colon, pancreas, thyroid, and ovarian cancers.²⁷⁰ Diagnostic efforts in this difficult group of patients are best directed toward ruling out as efficiently as possible those cancers for which there is reasonably effective treatment or palliation.^272,273

Breast, prostate, and endometrial cancers have the potential for successful palliation with hormonal therapy. Germ cell tumors, lymphomas, and leukemias can sometimes be virtually cured with combination therapy. Ovarian and small cell lung cancers have curative potential, and thyroid and pancreatic tumors can be successfully palliated. A thoughtfully directed oncologic work-up can investigate these possibilities while minimizing the need for time-consuming, painful, and potentially invasive tests in these patients, for whom the limited time remaining is of great importance.

The clinical presentations of metastatic tumors are diverse, but some general trends help differentiate them from other orbital tumors. A history of cancer may be obtainable (sometimes requiring considerable diligence), but in many cases the orbital symptoms are the first manifestation of systemic cancer. The onset of symptoms is typically rapid, unrelenting, and progressive over a few weeks or months. Motility disturbance is common, sometimes out of proportion to the degree of proptosis, and when present, pain often occurs early in the clinical course. Patients with breast and other scirrhous carcinomas can present with a diagnostically challenging infiltrative syndrome characterized by enophthalmos and limitation of eye movements; these signs are easily overlooked or misinterpreted.

Investigative goals include identification of the orbital tumor as a metastasis and, when possible and without undue hardship to the patient, diagnosis of the underlying primary cancer. The ophthalmologist can play a role not only in the former, utilizing advanced imaging and needle or open biopsies where necessary, but in the latter by facilitating special histologic studies on orbital tissue. A multidisciplinary approach involving the ophthalmologist, family doctor, pathologist, and oncologist is essential for proper diagnosis and management of this challenging group of patients.

Treatment from an ophthalmologic standpoint includes preservation of vision and relief of pain. Radiotherapy and hormonal therapy can often achieve these goals, sometimes dramatically. Radical surgery is contraindicated except in extreme cases requiring palliative debulking or in cases of unusual tumors, such as carcinoid and renal carcinoma, which may have isolated metastases that can be afforded long-term cure via surgery. It is important to avoid having a hopeless or helpless attitude. With modern treatments, patients with metastatic cancer are surviving longer, and virtual cures are occasionally possible. Even in patients with limited survival, preservation of vision has a dramatic impact on the quality of life.

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