PERSPECTIVE, PATTERNS OF SPREAD, AND PATHOLOGY
There is a trilogy of tumors in the orbit: EOM Sarcomas (Fig. 59.1) Lacrimal gland cancers (Fig. 59.2) with Orbital Lymphomas with different patterns of spread (Table 59.1 and Table 59.2).
PERSPECTIVE AND PATTERNS OF SPREAD
The third group of eye malignancies is made up of orbital sarcomas and lymphomas in addition to lacrimal gland carcinomas. Non-Hodgkin's lymphoma (NHL) is a new category for the eye in the seventh edition of the AJCC Cancer Staging Manual. Conceptually, these are mesodermal tumors from which embryonal rhabdomyosarcomas (ERMS) (muscle) and lymphomas (NHL) (lymphoid) arise. Both of these malignancies can occur in multiple sites anatomically, but tumors in the orbit have dramatic onset because of their proximity to the eye globe (Fig. 59.1; Table 59.1). Clinically, the presenting symptom/sign is a bulging eye, proptosis, and/or diplopia, or double vision due to malfunction of exocular muscle invasion (Fig. 59.2; Table 59.2).
• Proptosis can be confirmed by measurements of both eyes by an exophthalmometer placed on the lateral wall of the bony orbit and a measurement of the protrusion of the eye in millimeters. The differentiated diagnosis includes a number of possibilities.
• Exophthalmos due to hyperthyroid-associated eye protrusion, often with upper lid retraction resulting in a white rim between eyelid and pupil, can be emphasized by downward gaze resulting in a lid lag. Chemosis is often present, which is an edematous conjunctiva.
• Periorbital edema and proptosis combined can be a dramatic onset due to cavernous sinus thrombosis often due to an ethmoid/maxillary sinus infection. Periorbital edema without proptosis can be due to a variety of causes, from allergies to early onset of superior vena caval obstruction.
• Diplopia causing double vision is readily recognized with eyes being divergent or convergent on different gazes, that is, abduction, adduction, elevation, and depression.
Lacrimal gland tumors other than carcinomas can be due to Mikulicz's syndrome (NHL), in which an autoimmune inflammation can enlarge the gland, leading to downward depression of the eye, sometimes with swelling of the upper lateral lid.
There are two entirely different groups of orbital malignancy—in the pediatric age group, mainly ERMS, and in adults, the very uncommon adenocarcinoma of the lacrimal gland. Although ERMS can occur in multiple sites, the occurrence in orbits is not common (9%) but is often dramatic in presentation, with sudden swelling, proptosis, discoloration, and dystopia owing to limited extraocular motion. The histopathology is characteristic with blast cells that tend to differentiate into striated muscle with a tendency to cross-striations in 30% of patients. Most often cells are fusiform or stellate, but when undifferentiated, they can be diffuse in pattern akin to primitive noncommitted mesenchymal cells. There can be other associated pediatric abnormalities and genetic defects.
Lacrimal gland tumefactions tend to be associated with salivary gland infiltrations in an autoimmune inflammation (Mikulicz's disease) and in lymphomas (Mikulicz's syndrome). The lacrimal gland is one of the least common sites for adenocarcinomas. Investigations at the AFIP provided a histopathologic classification that is similar to that of salivary gland neoplasms.
Figure 59.1 | Patterns of spread. Orbital sarcoma. Primary tumors of orbit are color coded for progression: T0, yellow; T1, green; T2, blue; T3, purple; T4, red. The concept of visualizing patterns of spread to appreciate the surrounding anatomy is well demonstrated by the six-directional pattern (SIMLAP, Table 59.1).
Figure 59.2 | Patterns of spread. Lacrimal gland carcinoma. Primary tumors of lacrimal gland are color coded for progression: T0, yellow; T1, green; T2, blue; T3, purple; T4, red. The concept of visualizing patterns of spread to appreciate the surrounding anatomy is well demonstrated by the six-directional pattern (SIMLAP, Table 59.2).
HISTOGENESIS AND HISTOPATHOLOGY
Orbital sarcomas are mesenchymal malignancies and can range from rhabdomyosarcomas, to fibrosarcomas, and to angiosarcomas. Rhabdomyosarcomas are malignant tumors with characteristics of striated muscle differentiation that occur in young adults and children (Fig. 59.3A, B). There are four subtypes: embryoid, alveolar, pleomorphic, and botryoid (Table 59.3A).
Non-Hodgkin's lymphomas are highly varied as well and refer to a spectrum of T and B cell lymphomas that can occur (Table 59.3B, Fig. 59.3C). Typically, ocular adnexal lymphomas (OALs) are mainly B cell lymphomas of mucosa-associated lymphatic tissue type and more rarely T/NK cell lymphomas.
The embryogenesis determines the histogenesis, and in the orbit there are mainly mesodermal mesenchymal-derived tissues, each of which can give rise to a wide spectrum of malignancies. Prominent in retro-orbital tissues are the extraocular muscles, adipose tissue, peripheral nerves, connective tissues, fascia, lymphatics and lymphoid cells, retinal artery, and veins.
The major sarcomas that can arise are soft tissue sarcomas (refer to Chapter 52).
The proposed TNM classification of OALs defines the anatomic extent of disease in greater detail. This has been considered a prognostic value in the literature. Similar to nodal lymphomas, the International Prognostic Index (IPI) should be applied to subdivide patients with primary diffuse large B cell lymphomas of the ocular adnexa according to prognosis, thereby enhancing individual patient care. Similarly, the Follicular Lymphoma International Prognostic Index (FLIPI), which includes age, Ann Arbor stage, number of nodal sites, serum lactate dehydrogenase level, and hemoglobin level to build a three-category index, should be applied in patients with primary ocular adnexal follicular lymphomas.
The major lymphomas that can occur are listed in Table 59.3B.
The major malignant primary epithelial tumors are shown in Table 59.C.
Alveolar Rhabdomyosarcoma
This neoplasm occurs less frequently than the embryonal type and principally affects persons between ages 10 and 25 years; rarely, it may be seen in elderly patients. It is most common in the upper and lower extremities, but it can also be distributed in the same sites as the embryonal type. Typically, club-shaped tumor cells are arranged in clumps that are outlined by fibrous septa. The loose arrangement of the cells in the center of the clusters leads to the “alveolar” pattern (see Fig. 59.3B). The tumor cells exhibit intense eosinophilia, and occasional multinucleated giant cells are identified. Malignant rhabdomyoblasts, recognizable by their cross-striations, occur less commonly in the alveolar variant than in embryonal rhabdomyosarcoma, being present in only 25% of cases. Most alveolar rhabdomyosarcomas express PAX3–FKHR or PAX7–FKHR gene fusions, resulting from t(2;13)(q35;q14) or t(1;13)(p36;q14) translocations, respectively. In patients with localized tumors, the type of fusion does not correlate with the clinical outcome. However, in the presence of metastatic disease, PAX3–FKHR- positive tumors have a worse prognosis than do PAX7–FKHR- positive ones.
Pleomorphic Rhabdomyosarcoma
The least common form of rhabdomyosarcoma is found in the skeletal muscles of older persons, often in the thigh. This tumor differs from the other types of rhabdomyosarcoma in the pleomorphism of its irregularly arranged cells and can be categorized as one type of adult pleomorphic spindle cell sarcoma. Large, granular, eosinophilic rhabdomyoblasts, together with multinucleated giant cells, are common. Cross-striations are virtually nonexistent.
The historically dismal prognosis associated with most rhabdomyosarcomas has improved in the last two decades as a result of the introduction of combined therapeutic modalities, including surgery, radiation therapy, and chemotherapy. Today, more than 80% of patients with localized or regional disease are cured. Factors indicating a worse prognosis include age older than 10 years, tumor size greater than 5 cm, alveolar and pleomorphic histologic subtypes, and advanced stage of disease.
Figure 59.3 | Orbital sarcomas. A. Rhabdomyosarcoma. The tumor contains polyhedral and spindle-shaped tumor cells with enlarged, hyperchromatic nuclei and deeply eosinophilic cytoplasm. A few cells have clearly visible cross striations. B. Alveolar rhabdomyosarcoma. The neoplastic cells are arranged in clusters that display an alveolar pattern. C. Diffuse large B cell lymphoma. Tumor cells show prominent nucleoli. D. Small lymphocytic lymphoma/leukemia. On microscopic examination, the lymph nodal architecture is replaced by a diffuse infiltration of normal-appearing small lymphocytes.
TNM STAGING CRITERIA
TNM STAGING CRITERIA
Lacrimal gland cancers remain confined to the gland: T1, 2.5 cm; T2, 5 cm, but with extraglandular invasion; T3, in periosteum; and T4, into orbital soft tissues, optic nerve, globe, and brain (Table 59.3C).
Sarcomas of the orbit have minimal change in the seventh edition of the AJCC Cancer Staging Manual (Fig. 59.4A).
The embryonal RMS can invade the orbit and progress to involve the globe, optic nerve, and even bone (Fig. 59.4C). However, size is the dominant criterion in the staging system: early with T1, 15 mm; T2, >15 mm; T3, limited invasion of orbital tissue and bone wall; and T4, extensive invasion into the globe and periorbital tissues, central nervous system, and brain (Fig. 59.3C).
Lymphomas of the orbit are entirely new for the eye and are referred to as ocular adnexal lymphomas because they can arise in various regions of the eye and orbit—anteriorly in conjunctiva, lacrimal gland, and nasolacrimal duct or in the retro-orbital area behind the eye globe. OALs have a separate staging system as primary sites of origin, and this is not recommended for secondary adnexal involvement of the eye in a disseminated lymphoma. The basic features emphasize anterior–posterior origin and spread for T1 and T3 and juxtaorbital spread into adjacent structures for T4.
Lymphomas do not arise in the eye interior because the eye is immunologically a privileged site and has no lymphatic drainage (Fig. 59.4B).
SUMMARY OF CHANGES SEVENTH EDITION AJCC
• A listing of site-specific categories is now included in T4.
• The anatomy description was expanded.
• Regional lymph nodes were defined.
Carcinoma of the Lacrimal Gland
The staging system for lacrimal gland carcinomas has been made consistent with that for salivary gland carcinomas by:
• Proposing changes in the size cutoffs between T1, T2, and T3
• By subdividing T4
• By expanding the histologic categories to those used for salivary gland malignancies, since all of these have been reported in the lacrimal gland
• Lacrimal sac tumors have been removed from this section.
Although each of the tumors has T and N categories, none are stage grouped.
Figure 59.3 | E. Adenoid cystic carcinoma showing cribriform growth in which cystlike spaces are filled with basophilic material. The cyst spaces are really pseudo-cysts surrounded by myoepithelial cells.
LACRIMAL GLAND ADENOCARCINOMA
Figure 59.4 | A. Lacrimal gland adenocarcinoma. TNM staging criteria are color coded bars for T advancement: Tis, yellow; T1, green; T2, blue; T3, purple; T4, red.
ORBITAL SARCOMA
Figure 59.4 | B. Orbital sarcoma. TNM staging criteria are color coded bars for T advancement: Tis, yellow; T1, green; T2, blue; T3, purple; T4, red.
ORBITAL LYMPHOMA
Figure 59.4 | C. Orbital lymphoma. TNM staging criteria are color coded bars for T advancement: Tis, yellow; T1, green; T2, blue; T3, purple; T4, red.
TNM STAGING CRITERIA
T-ONCOANATOMY
The isocenter of the bony wall of the orbit, the eye socket, is through the optic nerve exiting at the optic foramen in its posterior wall. The orbital content anteriorly is the location of the lacrimal gland on its superior lateral wall.
• Coronal: The true content is posterior to the globe, with the extraocular muscles and their innervation by cranial nerves III, IV, and VI, which enter through the medially placed optic nerve, as well as cranial nerve V and the nasociliary nerve (Fig. 59.5A).
• Sagittal: The extraocular muscles (EOM) and fat are appreciated in relation to the bony eye socket (Fig. 59.5B) and EOM function (Fig. 59.5D, Table 59.4).
• Axial: This provides the medial entry of cranial nerves, particularly the optic nerve, which offer access to the subarachnoid space and accounts of blurring of the optic disc when intracranial metastatic disease occurs. Note the lateral superior location of the lacrimal gland (Fig. 59.5C).
Figure 59.5 | T-oncoanatomy. A. Coronal. This coronal view shows the important relationships between the paranasal sinuses and the orbit. The frontal sinus is superior, the ethmoid sinus is medial, and the maxillary antrum is inferior and extends posteriorly. This is the most common site of sinus cancers, and, when invading superiorly, there is perineural invasion of infraorbital nerve. A focus of hypesthesia develops in the cheek below the eye. B. Sagittal. C. Axial.
• Extraocular Muscles are often impaired with orbital malignancies causing strabismus and proptosis.
Movement from the primary position always involves more than one muscle acting synergistically. When testing muscles, it is desirable to test actions produced by one muscle acting independently. Because the axes of the orbits diverge and do not correspond to the axis of gaze in the primary position, responsibility for elevation and depression changes with abduction and adduction. When the eye is adducted, the oblique muscles are solely responsible; when the eye is abducted, the rectus muscles are solely responsible.
Figure 59.5D | Muscle groups and eye movement.
N-ONCOANATOMY AND M-ONCOANATOMY
N-ONCOANATOMY
The orbit and lacrimal glands drain predominantly into the preauricular nodes, except for its medial margin, which follows medial lymphatics into the submandibular nodes (Fig. 59.6A, B; Table 59.5). The most likely sentinel node is the preauricular node and can be determined with 99mTc lymphoscintography. Once lymphatic spread occurs, the superficial ring of nodes is at risk, including occipital, mastoid, parotid, and submandibular nodes. When orbital tumors invading into paranasal sinuses are ethmoid or extending into nasopharynx, the retropharyngeal are at risk. This places the deep cervical jugular nodes at risk. The incidence of lymph node involvement for orbital rhabomyosarcomas compared to other head and neck sites, is 0–8%; for other body sites, the incidence ranges between 10–25%.
Figure 59.6 | A. Superficial cervical lymph node. B. Deep cervical lymph node.
M-ONCOANATOMY
The orbital plexus of veins drain into 3 different veins: (1) Lacrimal gland drains into the supra-orbital vein, then the facial vein (2) the orbit drains via the superior and inferior ophthalmic veins into the cavernous sinus and also (3) the pterygoid venous plexus into the internal jugular vein. Eventually the lung is the target organ for metastases (Fig. 59.6C).
CRANIAL NERVE ONCOANATOMY
The frequency of cranial nerve involvement in orbital malignancies supports the need to be aware of the cranial nerve oncoanatomy. Equally important are tumors that can invade the orbit from surrounding anatomic sites and present with neurologic impairments (Fig. 59.6D; Table 59.6). Nasopharyngeal carcinomas can invade cavernous sinus via foramen lacerum and involve CN VI, IV, and III in that order.
Figure 59.6 | C. M-oncoanatomy of the eye. The orbital vein drains into the cavernous sinus posteriorly or the facial vein anteriorly. D. Major cranial nerves (CN) of eye and muscles CN activate.
STAGING WORKUP
RULES FOR CLASSIFICATION AND STAGING
Clinical Staging and Imaging
Careful examination is undertaken, preferably under anesthesia if deep in orbit. Imaging is essential to determine whether the orbital mass is primary or metastatic. Cross-sectional imaging such as enhanced computed tomography and magnetic resonance imaging is worthwhile (Fig. 59.7). Ultrasound-guided biopsy deserves consideration (Table 59.7; Fig. 59.7).
Pathologic Staging
For lacrimal gland cancer resections, complete specimen should be studied for margins. Perineural and sentinel preauricular/parotid node evaluation needs to be recorded if positive.
Figure 59.7 | Orbit A. Sagittal view. Note the relationship of the eye globe and orbit to the cranial cavity and brain and the optic nerve chiasm. 1. Orbicularis oculi, 2. Eyeball, 3. Inferior Oblique Muscle, 4. Extracoronal Fat, 5. Interior Rectus Muscle, 6. Dural and Arachnoid Sheath, 7. Retrobulbar Fat, 8. Superior Rectus Muscle, M. Maxillary Sinus. B. Axial transverse view. Note the relationship of extraocular muscles in the orbit. 1. Optic Nerve, 2. The Lateral Rectus Muscle, 3. The Medial Rectus Muscle, 4. The Ethmoid Sinus, 5. Lacrimal Gland.
PROGNOSIS AND CANCER SURVIVAL
PROGNOSTIC FACTORS
Lacrimal Gland Prognostic Factors
Required for staging: none.
Clinically significant:
Ki-67 growth fraction
Nuclear nm23 staining
Sarcomas
Required for staging: none.
Clinically significant: none.
Lymphomas
Clinically significant:
Tumor cell growth fraction (Ki-67, MIB-1)
Serum lactate dehydrogenase (LDH) at diagnosis
History of rheumatoid arthritis
History of Sjögren's syndrome
History of connective tissue disease
History of recurrent dry eyes syndrome (sicca syndrome)
Any evidence of a viral infection (e.g., hepatitis C or HIV)
Any evidence of a bacterial infection (e.g., Helicobacter pylori)
Any evidence of an infection caused by other microorganisms (e.g., Chlamydia psittaci).*
CANCER STATISTICS AND SURVIVAL
The eye and orbit only account for 2,090 new diagnoses, excluding carcinomas of the eyelids. Deaths attributed to ocular malignancy are 10% of the entire group (200 patients/year). Some of the most elegant proton and three-dimensional conformational radiation stereotactic techniques allow for cure of choroidal melanomas and retinoblastoma with preservation of vision. Survival remains impressive; 90% achieve long-term survival (Fig. 59.8).
*Preceding passage from Edge SB, Byrd DR, Compton CC, et al., AJCC Cancer Staging Manual, 7th ed. New York: Springer, 2010, p. 573, 579, 588.
• Optic nerve gliomas are extremely curable by stereotactic radiation therapy. The University of Pittsburgh group reports 96%, 90%, and 90% survival at 5, 10, and 15 years, respectively; 86% retain vision.
• Orbital lymphomas and orbital rhabdomyosarcomas are 100% locally controlled with chemoradiation.
• The most recent IRS (IV) has achieved a 100% successful outcome, compared with 83% in IRS III.
Figure 59.8 | Event-free survival of patients treated on Intergroup Rhabdomyosarcoma Study IV by stage and site. A. For patients with nonmetastatic favorable site tumors (stage 1), the best outcome was seen for orbital primary tumors. B. For patients with nonmetastatic unfavorable site tumors (stage 2 or 3), the best outcome was for those with genitourinary (bladder-prostate) tumors, whereas those with extremity tumors had an inferior outcome. GU B/P genitourinary tract (bladder or prostate); GU non B/P genitourinary tract (non-bladder, non-prostate).