PERSPECTIVE, PATTERNS OF SPREAD, AND PATHOLOGY
The uveal layer consists of three parts: the iris, ciliary body, and choroid.
PERSPECTIVE AND PATTERNS OF SPREAD
A nevus of the uveal tract may occur in the iris, ciliary body, or choroids (Fig. 57.1; Table 57.1). It can be recognized by its clinical appearance and course. The principal concern about a nevus of the eye is that it must be distinguished from a melanoma. This usually is possible because of its unchanging size, the absence of much elevation, and the fact that it interferes little with the function of the overlying retina when it occurs in the choroidal layer. However, differentiation of a large nevus from a small, dormant melanoma can be virtually impossible. In this case, routine, continued observation is mandatory. Hemangiomas of the uveal tract can be more troublesome and can show some signs of growth over a period of many years. It is usually possible to identify these tumors by the use of intravenous fluorescein combined with examination of the fundus with cobalt blue light. Under these circumstances, hemangiomas fluoresce brightly.
Intraocular malignant melanoma is estimated to occur in about 0.05% of the eye-patient population. It is a tumor of adults; the average age is 50 years. It is rare in blacks. Intraocular melanoma is the most common primary intraocular malignancy in countries with mainly white populations. Metastatic disease is the most common intraocular malignancy. There is no difference in distribution between the genders, nor is there any significant genetic relationship, except for the tumor's predilection for whites. It is rarely associated with other melanomas, such as those of the skin. Conversely, cutaneous malignant melanomas do not commonly metastasize to the eye.
The derivation of melanomas of the uvea has been the subject of a great deal of study and theory. It is possible that the stromal melanocytes of the uvea are the precursors of malignant melanoma. The pigmented epithelium of the retina (or of other neural crest–derived cells) is also implicated by some observers. Another hypothesis is that most melanomas arise in preexisting nevi.
Typical presentation depends on ophthalmoscopic examination. However, the term “intraocular melanoma” may refer to a tumor appearing in any part of the uveal tract; this may include the iris, in which case the tumor may be visible on direct inspection. Iris melanomas may be diffuse rather than discrete nodules, presenting as heterochromia, or darkening of the iris. Acquired heterochromia in the presence of elevated intraocular pressure is particularly suspicious.
When it occurs in the choroid, the tumor most characteristically appears in an equatorial position within the eye. It is possible for the tumor to reach a relatively large size before it produces symptoms, such as loss of side vision or a sensation of floating spots. Therefore, the investigation of minor visual symptoms may be important. Tumor growth produces deterioration of vision as the retina overlying the tumor loses its function. The tumor frequently produces secondary changes within the eye, such as the induction of cataract, secondary glaucoma, iridocyclitis, and retinal detachment.
Figure 57.1 | Malignant Melanoma. A. A mushroom-shaped melanoma of the choroid is present in this eye. Choroidal melanomas commonly invade through Bruch's membrane and result in this appearance. Patterns of spread.Primary melanomas of the uvea include iris and choroid. Cancers are color coded for progression: Tis, yellow; T1, green; T2, blue; T3, purple; T4, red. B. Iris. C. Ciliary body. D. Choroid. The concept of visualizing patterns of spread to appreciate the surrounding anatomy is well demonstrated by the six-directional pattern (SIMLAP; Table 57.1).
Primary acquired melanosis can be particularly difficult to manage because of its widespread involvement of the conjunctiva and eyelids. Because histopathologic examination of the involved tissue can differentiate melanosis from melanomas of low malignant potential, repeat biopsy of suspicious areas is indicated.
HISTOGENESIS AND HISTOPATHOLOGY
Melanocyte loci determine melanoma sites. Histopathology has relied on Callender's classification (Table 57.2, Fig. 57.2): Small, spindle-shaped cells with small condensed nuclei, referred to as spindle A, are the most benign. The 5-year mortality rate is less than 5%. Spindle melanoma type B is characterized by larger, more loosely packed spindle cells with prominent nucleoli. It is also relatively benign and has a 14% 5-year mortality rate. The pure epithelioid cell type occurs least commonly. This type is large and polygonal and has round nuclei and prominent cytoplasm and resembles epithelial tumors. The mortality rate is 69%. Half of the melanomas of the eye have a mixture of cell types. The dangerous epithelioid cell types exhibit a 51% 5-year mortality rate.
Necrosis is rare in melanomas and occurs in only 7% of tumors. When it occurs, it may create severe inflammatory signs and secondary glaucoma. Pigmentation of the tumor varies from intense to amelanotic. The degree of pigmentation correlates only slightly with the degree of malignancy. Reticulin fibers are frequent and heavy in some tumors and light in others. Reticulin content is only slightly correlated with prognosis. Newer prognostic parameters include number of mitotic figures per high-power field and inverse standard deviation of tumor cell nucleolar area.
• Conjunctiva: It is important to differentiate melanosis from melanoma of low grade potential (Fig. 57.2B).
• The iris has melanocytes and fibroblasts in loose connective tissue resting on pupil dilator muscle, then myoepithelial cells and a layer of epithelial cells. The color of the iris depends on the number of stromal melanocytes scattered in the connective tissue (Fig. 57.2B).
• The ciliary body epithelium consists of two layers—the outer pigmental layer with its melanocytes, and the inner nonpigment epithelium. The ciliary body contains the ciliary muscle and vascular connective tissue, with the ciliary epithelium producing the aqueous humor. The scleral venous sinus (canal of Schlemm) in close proximity to the iridocorneal angle drains the aqueous humor and regulates intraocular pressure. If it is invaded by the melanoma, glaucoma occurs (Fig. 57.2B).
• The choroid layer is between the retina and sclera and is the dominant vascular coat of the eye. It is a dark brown layer and is traversed by lamellae strands that originate from the suprachoroid lamina (lamina fusca) and consists of flat, large melanocytes between connective tissue. This is the largest collection of melanocytes in the eye and receives the most ultraviolet radiation. Therefore this is the most common site in the eye to transform into malignant melanomas (Fig. 57.2C).
• Retinal pigment epithelium (RPE) has pigmented cells that are the bottom layer of 10 layers that constitute the retina; some postulate that these also may give rise to melanomas (Fig. 57.2C).
The embryogenesis of neural ectoderm determines the epithelium of the iris, ciliary body, and choroid.
Figure 57.2 | A. Photomicrograph of a heavily pigmented melanoma of the choroid depicting epithelioid tumor cells with prominent nucleoli.
Figure 57.2 | B. Whole eye (sagittal section). Stain: hematoxylin and eosin. Low magnification. C. Retina, choroid, and sclera (panoramic view). Stain: hematoxylin and eosin. Medium magnification.
TNM STAGING CRITERIA
According to Reese, the distribution of melanomas is predominantly in the choroid (78%), then the iris (12%) and the ciliary body (10%). It is for this reason that choroidal melanoma will be emphasized and illustrated first. Other loci of origin will be presented more concisely because each has special anatomic features. The most common patterns of spread are intraocular via the choroidal venous network and then through the sclera extraocularly into the orbit. Distant spread is possible because melanomas of the choroid exit via retinal veins into the internal jugular vein. Remarkably, liver is the target organ rather than lung. In fact, severe hepatomegaly due to extensive metastatic disease without an obvious gastrointestinal tract cancer should suggest a search for an intraocular choroidal melanoma. The classic professorial diagnosis of choroid melanoma is made on rounds in which a patient with palpable hepatomegaly is noted to have a glass eye.
SUMMARY OF CHANGES SEVENTH EDITION AJCC
Major changes with numerous prognostic factors and size: Thickness and diameter are important for both choroid uveal and ciliary body (Fig. 57.3). The Stage Summary Matrix for Uvea Iris, and Ciliary body is shown in Table 57.3. Uvea choroid melanomas are compared by 3 criteria: Ciliary Body (CB), Extraocular extensions (EOE), and size (Fig. 57.4A), uvea iris melanomas (Fig. 57.4B), and conjunctiva (Fig. 57.5C).
Ciliary Body and Choroid
• The definitions of T1-T4 lesions have been modified.
• The definitions of T1a-c, T2a-c, and T3a have been modified, and T1-T3 has been divided into T1a-d, T2a-d, and T3a-d.
• T4 has been divided into T4a-e.
• T1 through T4 are defined as tumors representing tabulated combinations of largest basal tumor diameter and tumor thickness (height).
• T1a, T2a, T3a, T4a are defined as tumors without ciliary body involvement and without extrascleral extension.
• T1b, T2b, T4b, T4b are defined as tumors with ciliary body involvement but without extrascleral extension.
• T1c, T2c, T3c, T4c are defined as tumors with ciliary body involvement but with extrascleral extension equal to or less than 5 mm.
• T1d, T2d, T3d, and T4d are defined as tumors with ciliary body involvement and with extrascleral extension equal to or less than 5 mm.
• T4e is defined as tumor of any size with an extrascleral extension greater than 5 mm in diameter.
Malignant Melanoma of Uvea-Iris
In clinical practice, the largest tumor basal diameter may be estimated in optic diameters (dd, average: 1 dd = 1.5 mm). Tumor thickness may be estimated in diopters (average: 2.5 dd = 1 mm). However techniques such as ultrasonography and fundus photography are used to provide more accurate measurements. Ciliary body involvement can be evaluated by the slit-lamp, ophthalmoscopy, gonioscopy, and transillumination. However, high frequency ultrasonography (ultrasound biomicroscopy) is used for more accurate assessment. Extension through the sclera is evaluated visually before and during surgery and with ultrasound, computed tomography or magnetic resonance imaging.
Figure 57.3 | Classification for ciliary body and choroid uveal melanoma based on thickness and diameter. (From Edge SB, Byrd DR, Compton CC, et al., AJCC Cancer Staging Manual, 7th edition. New York, Springer, 2010, p. 556.)
UVEA CHOROID MELANOMA
Figure 57.4 | A. Choroid melanoma. TNM staging criteria are color coded bars for T advancement: Tis, yellow; T1, green; T2, blue; T3, purple; T4, red.
UVEA IRIS MELANOMA
Figure 57.4 | B. Uvea iris melanoma. TNM staging criteria are color coded bars for T advancement: Tis, yellow; T1, green; T2, blue; T3, purple; T4, red.
CONJUNCTIVA MELANOMA
Figure 57.4 | C. Conjunctiva Melanoma. 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 middle layer of the globe is best appreciated in an axial view through the isocenter of the globe at the pupil of the eye through to the optic nerve. The uvea is the rich vascular layer of the eye.
• Coronal: Anterior view of Iris (Fig. 57.5A).
• Sagittal: The pupil is surrounded by the iris and is the window of the eye. It is under control of the sympathetic and oculomotor nerves. Horner's syndrome results in a small pupil and lid lag or ptosis. The pupil of the eye often can provide a major insight into numerous systemic disorders. Dilation of conjunctival capillaries is often benign and due to irritation, allergy, or infection. The presence of ciliary injections as small capillaries surrounding a dilated pupil is an emergency suggesting glaucoma. The lens of the eye—the site of potential cataract formation—completes the middle layer of the eye and iris.
• Axial: As with most eye structures, this layer consists of three parts: (i) the iris (Fig. 57.5A), (ii) a ciliary body (pupil) (Fig. 57.5B), and (iii) the choroid (Fig. 57.5C). The eye also contains three chambers: (i) anterior between cornea and iris, (ii) posterior between the iris and lens, and (iii) the vitreous body, which fills the globe with a gelatinous substance between lens and retina. Because this layer is pigmented, it can give rise to melanoma at any site. The major anatomic feature is the extensive vascular mesh, and one can appreciate the access melanomas have to venous drainage via the vorticose vein.
Figure 57.5 | A. Iris. Anterior dissection of the orbital cavity. The eyelids, orbital septum, levator palpebrae superioris, and some fat are removed. Three-planar T-oncoanatomy. B. Ciliary body; sagittal. C. Choroid; coronal and transverse.
N-ONCOANATOMY AND M-ONCOANATOMY
N-ONCOANATOMY
The eye globe is immunologically privileged and has no lymphatics or regional lymph nodes (Fig. 57.6A).
This applies to only uveal melanomas with extrascleral extension but applies to all conjunctival melanomas.
M-ONCOANATOMY
The pterygoid plexus of veins drains the fine veins of the eyelids into the internal jugular vein (Fig. 57.6B). Metastases occur most commonly to liver (90%) and can be massive. The astute clinical observation is “patient with glass eye” and hepatomegaly can offer the diagnosis of metastatic choroidal melanoma at the bedside. Other metastatic sites are lung, bone, brain, and subcutaneous.
Figure 57.6 | A,B. N-oncoanatomy. Lateral view. The sentinel node is the preauricular node. C. M-oncoanatomy of the eye. The choroid is drained by posterior ciliary veins, and four to five vorticose veins drain into the ophthalmic veins.
STAGING WORKUP
RULES FOR CLASSIFICATION AND STAGING
Clinical Staging and Imaging
The clinical assessment requires inspection by slit-lamp examination and ophthalmoscopy. Imaging is highly desirable, especially computed tomography (CT) and fluorescein angiography (Table 57.5; Fig. 57.7). If retinal detachment raises suspicion of choroidal metastases, films or CT of chest should be considered. In women, mammography is worthwhile.
Clinical Staging
The assessment of cancer is based on inspection, slit-lamp examination, and palpation of the regional lymph nodes. All conjunctival surfaces are inspected and photographed with eversion of the upper eyelid. High-frequency ultrasound (UBM) imaging should be performed when the tumor is found to be affixed to the globe and when intraocular invasion is suspected. Low-frequency ultrasound may also be used to evaluate the sclera, eye, and orbit. Radiologic examinations (computed axial tomography, magnetic resonance imaging, and positron emission tomography [PET]/CT imaging) can be used to examine regional lymph nodes, paranasal sinuses, the orbit, brain, and chest. There are ongoing studies to clarify the role of sentinel lymph node involvement and sentinel lymph node biopsy.
Conjunctival carcinoma has been particularly associated with AIDS, neurodermatitis (atopic keratoconjunctivitis), other forms of immunosuppression (including iatrogenic), ultraviolet radiation, and human papillomavirus (HPV 16 and 18).
PATHOLOGIC STAGING
Complete resection of the primary site is indicated (if possible). Cryotherapy and/or topical chemotherapy (mitomycin, 5-fluoruracil, and/or interferon alpha-2b) may be considered as adjunctive therapies. Extensive tumor involvement of orbital soft tissues may require exenteration with or without adjuvant external beam radiation therapy. The specimen should be thoroughly sampled for histologic study of surgical margins, type of tumor, and grade of malignancy.
Resection of primary site with margins is essential and may include iridectomy to eye wall resection to enucleation of globe. Measurements should include size (height and depth) of choroidal lesion, measurements of iris uveal lesion in clock-hours of involvement, and margin of resection. Sentinel and/or palpable regional nodes include size and location.
PROGNOSIS AND CANCER SURVIVAL
PROGNOSTIC FACTORS
See Table 57.6.
CANCER STATISTICS AND SURVIVAL
The eye and orbit only account for 2,750 new diagnoses annually, excluding carcinomas of the eyelids. Deaths attributed to ocular malignancy are less than 10% of the entire group (240). Some of the most elegant proton and three-dimensional conformal radiation stereotactic techniques allow for cure of choroidal melanomas and retinoblastoma with preservation of vision. Results from ocular melanomas are presented in Fig. 57.8. Survival is impressive, with 90% long-term survival.
Figure 57.7 | Sagittal view magnetic resonance imaging. The MRI can be correlated with Fig. 57.5C. 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.
• Radiation isotopic plaque and enucleation were found to be comparable treatments in posterior uveal/choroidal melanomas in the Collaborative Ocular Melanoma Study group, consisting of 1,300 patients over 11.5 years. Recurrence rates with radiation range from about 15% to less than 5% with surgery.
• The probability of choroid melanoma control by Harvard proton beam control is 96.3%. The absolute local recurrence rate after helium ion therapy is less than 3%. Custom plaque irradiation appears to be an effective method for treating iris melanomas as well.
Figure 57.8 | Survival and eye retention probability. A. Kaplan–Meier plot of eye retention probability after proton therapy in 1,006 patients with small (3 mm high and 10 mm in diameter), intermediate (3.1–8 mm high and/or 10.1–16 mm in diameter), and large (>8 mm high and >16 mm in diameter) uveal melanomas. B. Kaplan–Meier plot of the probability of retaining useful vision in patients with tumors 3 mm from the optic disc (D) and fovea (F) and >3 mm from the optic disc and/or fovea in 562 eyes with initial visual acuity 20/200 (6/60) or better. C. Ten-year survival for patients with uveal melanoma. (Data for part C from Edge SB, Byrd DR, Compton CC, et al., AJCC Cancer Staging Manual. 7th edition. New York, Springer, 2010.)