General considerations

Uveal malignant melanoma is the most frequent intraocular malignancy encountered in a practice of ophthalmology^1,2.This neoplasm is important because of its potential to cause blindness and death due to systemic metastasis. Hence, clinicians should be familiar with uveal melanoma and make an accurate diagnosis and recommend referral to a subspecialist who manages this neoplasm. Approximately 85% of uveal melanomas arise in the choroid, 10% in the ciliary body, and 5% in the iris. This subchapter briefly discusses demographics, clinical features, differential diagnosis, diagnostic approaches, pathology, management, and prognosis for uveal melanoma.

Demographics

The annual age-adjusted incidence of uveal melanoma is six cases per 1 million population in the United States and Europe. Uveal melanoma is decidedly more common in adult Caucasians and is uncommon in children and dark-skinned individuals. In our experience with 8033 patients with uveal melanoma, the median age at presentation was 59 years (range 3 to 99 years) and the male/female ratio was 50/50%. The melanoma occurred in Caucasians in 98% cases followed by Hispanic (1%), African American (<1%), Asian <1%), Middle Eastern (<1%), Native American (<1%), and Asian Indian (<1%)³. Hence, it is diagnosed more often in Europe and America and infrequently in Africa and Asia. There is no predisposition for gender. Predisposing conditions for uveal melanoma include congenital ocular melanocytosis, Caucasian race, and possibly the dysplastic nevus syndrome and excess exposure to sunlight.

Clinical features

The clinical features of uveal melanoma are covered in detail in a comprehensive textbook and numerous articles on the subject¹. The clinical findings vary with the location of the lesion in the uveal tract.

Iris melanoma

Iris melanoma can be circumscribed (nodular) or diffuse. Circumscribed iris melanoma appears as a variably pigmented, well-defined mass in the iris stroma (Fig. 69.1). More than 80% are located in the inferior half of the iris. It can be totally pigmented, partly pigmented, or clinically amelanotic. The size and shape can vary considerably from case to case. Some are relatively small and almost flat and others are larger and more elevated. Like iris nevus, which is generally smaller, it can cause an irregular pupil and ectropion of the pigment epithelium at the pupillary margin.

Fig. 69.1 Iris melanoma.

The less common diffuse iris melanoma has a tendency to produce acquired hyperchromic heterochromia and secondary glaucoma due to tumor infiltration of the trabecular meshwork¹. It can diffusely affect the entire iris or it can appear as irregular geographic patches of pigment. Some patients with diffuse iris melanoma present with unilateral ipsilateral glaucoma and there is a delay in diagnosis while the ‘idiopathic’ or ‘pigmentary’ glaucoma is treated.

Ciliary body melanoma

In contrast to iris melanoma, ciliary body melanoma often attains a larger size before it is recognized clinically¹ (Fig. 69.2A). However, it is frequently associated with external signs that suggest the underlying diagnosis. The most important is one or more dilated episcleral blood vessels (sentinel vessels) that develop over the base of the tumor. A second sign is an epibulbar pigmented lesion characteristic of transcleral extension of the tumor. When the pupil is dilated widely in such cases, the ciliary body tumor can be visualized as a dome-shaped mass (Fig. 69.2B). Less often, it can assume a circumferential ring growth pattern (ring melanoma). Ciliary body melanoma frequently causes subluxation of the lens and cataract. It can grow posteriorly into the choroid (ciliochoroidal melanoma) and anteriorly into the anterior chamber angle and iris (iridociliary melanoma). It can infiltrate the trabecular meshwork, causing secondary glaucoma.

Fig. 69.2 Ciliary body melanoma. A. Sentinel vessel and pigmented foci of extrascleral extension. B. Appearance of the pigmented ciliary body mass.

Choroidal melanoma

Choroidal melanoma usually presents as a sessile, dome-shaped, or mushroom-shaped mass deep to the sensory retina (Fig. 69.3). It is usually moderately or deeply pigmented but it can be entirely non-pigmented, in which case the diagnosis can be more difficult. A posterior choroidal melanoma can display clumps of overlying orange pigment on its surface at the level of the retinal pigment epithelium. A secondary non-rhegmatogenous retinal detachment frequently occurs. In contrast to a rhegmatogenous detachment, in which the subretinal fluid does not shift, the fluid with melanoma and other tumors shifts with positional changes of the patient’s head. When the melanoma is amelanotic and mushroom shaped, dilated blood vessels in the tumor are visible ophthalmoscopically. When a choroidal melanoma breaks through Bruch’s membrane and assumes such a mushroom shape, it has a tendency to bleed into the subretinal space and vitreous, often obscuring a view of the underlying tumor. Choroidal melanoma can also assume a diffuse growth pattern with only minimal elevation of the tumor¹.

Fig. 69.3 Choroidal melanoma superior to the optic disc in the right eye.

Differential diagnosis

The differential diagnosis of uveal melanoma is discussed in more detail elsewhere¹. Iris melanoma can resemble iris nevus, epithelioma (adenoma) of the iris pigment epithelium, iris cyst, iridocorneal endothelial syndrome, leiomyoma, and miscellaneous other conditions. Ciliary body melanoma must be differentiated from tumors of the ciliary body pigmented epithelium and non-pigmented epithelium, leiomyoma, cyst, ciliochoroidal effusion, and several other tumors and pseudotumors. Pigmented choroidal melanoma can resemble a large choroidal nevus, subretinal hemorrhage, and a number of other tumors and pseudotumors. Non-pigmented choroidal melanoma must be differentiated from amelanotic choroidal nevus, choroidal metastasis, choroidal hemangioma, granuloma, and other conditions.

Diagnostic approaches

Iris melanoma can generally be diagnosed by slit-lamp biomicroscopy and gonioscopy. Ciliary body melanoma is more difficult to detect because of its hidden location. However, slit-lamp biomicroscopy, gonioscopy, transillumination, indirect ophthalmoscopy, ultrasound biomicroscopy, or standard ultrasonography generally discloses typical features. Choroidal melanoma is generally diagnosed by ophthalmoscopy. In atypical cases, fluorescein angiography and ultrasonography may assist in diagnosis. Atypical iris, ciliary body, or choroidal lesions can undergo fine needle aspiration biopsy with cytopathology study to confirm or exclude the diagnosis of melanoma.

Pathology

Most pathologists use the Mclean modification of the Callender classification, in which uveal melanoma is divided into spindle, epithelioid, and mixed cell types¹. Most iris melanomas and smaller posterior uveal melanomas are predominantly of spindle cell type, whereas larger melanomas contain a greater proportion of epithelioid cells. Histopathologic criteria for a worse prognosis include more epithelioid cells, greater mitotic activity, greater basal diameter of the tumor, diffuse growth pattern, and extrascleral extension of the melanoma. Genetic factors related to poor prognosis include chromosome 3 monosomy, especially with 8q addition.

Management

Management of uveal melanoma depends on several clinical findings and includes close observation, laser ablation, transpupillary thermotherapy, plaque brachytherapy, charged particle irradiation, local resection, enucleation, and a combination of methods. Plaque radiotherapy and enucleation are the two most commonly employed methods, with the goal being complete eradication of the malignancy. Studies comparing both methods have found similar survival rates⁴.

Prognosis

Useful features for predicting prognosis for vision and life are mentioned above and described elsewhere. Recently, cytogenetic alterations in uveal melanoma cells have emerged as the most reliable methods of predicting systemic prognosis. Monosomy of chromosome 3 and gain in chromosome 8 (trisomy 8) are most reliable for predicting a worse prognosis^5,6. These are also discussed in more detail elsewhere.

Summary

This brief introductory subchapter has outlined demographics, clinical features, differential diagnosis, diagnostic approaches, pathology, management, and prognosis for uveal melanoma. These topics are discussed in more detail elsewhere in this textbook and in the literature.

Introduction

Uveal melanoma has traditionally been treated by enucleation, plaque brachytherapy, or external beam radiation with local resection or phototherapy in some cases. Brachytherapy with iodine-125 and enucleation have been evaluated prospectively in a multi-centered fashion by the Collaborative Ocular Melanoma Study (COMS). The COMS did not show mortality rates for medium-sized melanomas to be significantly worse after iodine-125 plaque brachytherapy than after enucleation⁷. Brachytherapy with iodine-125, which delivers gamma irradiation, is the favored treatment modality in the United States because it has good tissue penetration and its short half-life contributes to its ease of use. Furthermore, the dosimetry can be adjusted for each individual tumor by adjusting the number and distribution of the iodine-125 seeds, which are embedded in the resin lining the underside of the shell. In Europe, ruthenium-106, which mostly emits beta irradiation, is the preferred radioisotope for local treatment of uveal melanoma^8,9. Other radioisotopes have been utilized for brachytherapy including cobalt-60, palladium-103, and iridium-192.

Fundamental principles

The objective of brachytherapy for uveal melanoma is to deliver a dose of at least 80 Gy to all parts of the tumor and to the adjacent choroid, while minimizing collateral damage to the optic nerve, fovea, lens, and other ocular structures.

Goals of surgery

The goal of brachytherapy is to control local tumor growth by sterilizing the primary tumor while conserving the eye with as much useful vision as possible. It is not known whether brachytherapy or any other form of treatment for uveal melanoma alters patient mortality and if so in whom. Furthermore, treatments for metastatic uveal melanoma are not usually effective¹⁰.

Indications for surgery

Uveal melanomas up to 5 mm thick can be treated with a ruthenium-106 plaque, and tumors up to 10 mm thick may be treated with an iodine-125 plaque⁹. Tumors beyond 20 mm in the largest basal dimension are difficult to treat with episcleral plaque. Brachytherapy is also contraindicated by bulky extraocular extension, unless such tumors can be excised. Optic nerve involvement is not necessarily a contraindication if dosimetry suggests that the entire tumor can be irradiated. Notched iodine-125 plaques can be designed to allow adequate treatment to the nerve¹¹.

Preoperative assessment

In addition to a comprehensive ophthalmic and systemic evaluation, the tumor height and basal dimensions must be determined for radiation dosimetry. Indirect biomicroscopy and ultrasonography are useful means to obtain tumor dimensions. Routinely, the radial and transverse dimensions, tumor thickness, and distance from the optic nerve and fovea are obtained.

Anesthesia

Surgery may be performed under local or general anesthesia, according to the surgeon’s and patient’s preference.

Operation techniques

A 180–360° conjunctival peritomy is made and the sclera overlying the tumor is exposed. The rectus muscles are isolated and looped with 2-0 silk suture for scleral exposure. The muscles may be disinserted and preplaced on hang-back sutures to allow for adequate placement of the plaque. The tumor margins are localized by transillumination or indirect ophthalmoscopy and marked on the sclera with a pen.

Ruthenium-106 plaque

In Liverpool, 15 mm, 20 mm, and 25 mm ruthenium plaques are used for tumors with basal diameters not exceeding 10 mm, 15 mm, and 20 mm respectively. The intended location of the anterior plaque edge is marked on the sclera. A transparent template with four perforations is sutured to the sclera with releasable sutures and its position in relation to the tumor is checked by performing binocular indirect ophthalmoscopy with a right-angled 20-gauge transilluminator passed through the posterior perforation of the template. With tumors extending close to optic disk or fovea, the template is placed with its posterior edge at the posterior tumor margin. Once the template is correctly positioned, a mattress suture is placed in the sclera and left loose. The template is removed and replaced by the radioactive plaque, which is secured by sutures (Fig. 69.4). If trans-scleral tumor biopsy is performed (e.g. for genetic tumor typing), this is done after tumor localization and immediately before inserting the radioactive plaque. If the biopsy is trans-retinal, this is undertaken after radioactive plaque insertion.

Fig. 69.4 Radioactive plaque in position.

The plaque is removed once the desired radiation dose has been delivered. Some prescribe a dose of 80–90 Gy to the tumor apex, irrespective of the dose to base. The author (BD) prescribes a minimum dose of 350 Gy to the sclera and a minimum apex dose of 85 Gy. Various dosimetry software programs exist.

Intraoperative complications

Retinal perforation may occur while placing scleral sutures and may be treated by laser or cryotherapy. Softening of the globe with vitreous loss associated with this complication can be primarily managed with injection of balanced salt solution with a 30-gauge needle at the pars plana prior to evaluation by a vitreoretinal surgeon.

As with other surgical procedures for uveal melanoma, special care is necessary when performing transillumination, to avoid being misled by penumbras and amelanotic tumor extensions.

Postoperative care

Standard radioisotope precautions include wearing a lead eye-patch during the plaque placement period and avoiding unnecessary exposure to crowds of people. Restrictions are otherwise limited by any ocular discomfort and most patients may perform their usual activities.

Postoperative complications

Short-term complications include ptosis and diplopia, which frequently resolve by 6 months. Blepharoplasty or strabismus surgery may be considered if these problems persist.

Long-term complications include local tumor recurrence and radiation side effects. Marginal tumor recurrence is identified by lateral tumor extension, as indicated by comparing ophthalmoscopic appearances with baseline color photographs. Central tumor recurrence is demonstrated by increasing tumor thickness on repeated echography. This may be treated by further radiotherapy, local resection, or enucleation.

Iodine-125 emits relatively low energy photons, which theoretically decreases radiation-related complications. In spite of this favorable profile, iodine-125 brachytherapy can cause keratitis, cataract, neovascular glaucoma, maculopathy, and optic neuropathy^13,14.

Maculopathy is a frequent complication of plaque brachytherapy regardless of the location of the treated melanoma. To date, the management of this complication remains discouraging. Exudative maculopathy may be treated by transpupillary thermotherapy administered to the tumor (without safety margins), photodynamic therapy, intraocular anti-angiogenic agents, intraocular steroids, or tumor excision by endoresection or trans-scleral excision. Visual loss from radiation-induced optic neuropathy is the second most common complication and has not been shown to satisfactorily respond to therapies.

Occasionally brachytherapy of a large melanoma is followed by neovascular glaucoma and a blind painful eye requiring enucleation.

Assessment of surgery

The main quality indicator of brachytherapy is local tumor control. Following brachytherapy, the tumor size may vary within the first 2 months due to local inflammation. Ultrasonography may be performed at the 3-month postoperative visit to confirm a tumor response. Either stabilization of tumor growth or a decrease in tumor height by ultrasonography is considered a successful response to brachytherapy (Fig. 69.5). Rapid shrinkage of the melanoma actually portends a poor prognosis for the patient¹⁵.

Fig. 69.5 Superonasal choroidal melanoma in the left eye of a 60-year-old woman. (A) Preoperatively, the tumor measured 13.9 mm in basal diameter with a thickness of 3.5 mm. (B) Five months postoperatively, the tumor thickness had diminished to 2.1 mm. The visual acuity remained good at 20/17.

Introduction

External beam radiotherapy has the advantage over brachytherapy in delivering a uniform irradiation to the target volume. Additionally, its indication is less restricted by size, shape, and/or location of the tumor. Teletherapy can be delivered through photons (X-rays), electrons, gamma rays, or accelerated heavy particles (protons, alpha particles). Proton therapy was first applied in Boston in 1975¹⁶, in Lausanne and the Paul Scherrer Institut (PSI) in 1984^17,18, and is becoming available in a growing number of centers around the world^16–21.

Fundamental principles

Protons cause maximal ionization at the place where they are absorbed (‘Bragg’s peak’). They are produced by a cyclotron, modulated and collimated, before reaching the patient, who is immobilized with the eye gazing in a fixed direction. An advantage of protons is the sparing of uninvolved eye tissues outside the collimator. Consequently – in order to avoid marginal recurrence – the tumor mass needs to be precisely localized through prior surgical insertion of tantalum markers.

Goals of treatment

As the treatment through which local tumor control is achieved (enucleation or conservative therapy) has no influence on its metastatic risk²², the main goal of protontherapy is to achieve maximal local tumor control while conserving a comfortable eye, and, if possible, useful residual vision.

Indications for proton beam radiotherapy

Some centers use proton therapy for nearly all uveal (iris, ciliary body, and choroidal) melanomas^17,20, whereas others reserve this modality for tumors that cannot adequately be treated conservatively by brachytherapy or local resection^19,23. In all centers, contraindications include: tumor volume of more than 50% of the eye, large extraocular extension, (sub)total retinal detachment, suspicion of optic nerve invasion and neovascular glaucoma.

Preoperative assessment

A general check-up (including blood tests, ECG, chest X-ray, and liver imaging) is performed. Specific examinations include photographic documentation of the tumor and an ultrasonic evaluation of its dimensions. The axial length of the globe is measured to generate a personalized computer model of the eye.

Anesthesia

Insertion of tantalum markers is done under local or general anesthesia, whereas proton therapy is administered with topical anesthesia.

Operation techniques for tantalum marker insertion

A 180–360° conjunctival peritomy is made. The eye is rotated with muscle slings or, if any rectus muscles have been disinserted, with traction sutures placed in the sclera. The tumor margins are localized by transillumination and marked on the sclera with ink or a pen. Transparent tumor margins are visualized by indentation and indirect ophthalmoscopy. Tantalum markers, four to seven in number, are sutured to the sclera close to the tumor margins (Fig. 69.6A). These buttons are 2.5 mm in diameter, inert, and non-magnetic. Measurements are taken of distances from each marker to: (i) the nearest tumor margin, (ii) the other markers, and (iii) the limbus. The limbus diameter is also recorded. Any disinserted muscles are reinserted and the conjunctiva is closed in the usual fashion.

Fig. 69.6 (A) Transillumination showing the base of a ciliochoroidal melanoma surrounded by markers. (B) Irradiation plan (beam view) showing the eye with the tumor (in red) surrounded by a 2 mm lateral safety margin. (Numbers 1–5 indicate the position of markers.)

Simulation

A face-mask and a bite-block are molded for each patient, to immobilize the head precisely in a frame that is secured to the delivery apparatus. The position of the patient’s chair is adjusted so that the tumor is in the target area. Radiographs are taken to localize the tantalum markers for computerized modeling of the tumor within the eye. A brass collimator is prepared for each patient, with an opening adapted to the projected tumor shape (Fig. 69.6B). The irradiation depth can be modulated by interposing absorbers in the proton beam trajectory. The optimal ocular position is determined, so that minimal doses of radiation are delivered to optic disc and other structures.

Proton beam radiotherapy

A total dose of 60–70 Cobalt Gy-equivalent is delivered in four to five fractions^16,17. The patient is seated with the head immobilized by the mask and bite-block, gazing at a strategically located target. The eyelids are usually retracted with a speculum. However, when the upper eyelid margin cannot be avoided, treatment is sometimes administered through closed eyelids, the patient fixating with the other eye.

Intraoperative complications

Intraoperative complications are rare, the most evident being retinal perforation when suturing a marker to the sclera. The most common is an over- or underestimation of the tumor margins on transillumination. A penumbra caused by oblique transillumination can cause an overestimation of the tumor extent. Conversely, relative differences in tumor pigmentation as well as the parallax phenomenon – the fact that the posterior tumor margin, to the tangentially placed observer’s eye, is projected about 1 mm anteriorly on the external scleral face – are responsible for an underestimation of the tumor margins²⁴.

Postoperative care

Postoperative care is the same as for other extraocular procedures.

Postoperative complications

Postoperative diplopia, related to the manipulation of extraocular muscles, usually resolves spontaneously.

Short-term radiation-induced complications include dermatitis of the irradiated part of the eyelids. The severity of the post-radiation uveïtis and associated increase of serous retinal detachment depend on the target volume.

Long-term complications such as radiation-induced optic neuropathy, maculopathy, and cataract can usually be predicted at the time of treatment planning and therefore occur unavoidably when the tumor extends close to those structures²⁵.

Maculopathy caused by edema or hard exudates can occur even when the macula receives little or no radiation. The risks of persistent retinal detachment and neovascular glaucoma increase with tumor volume¹⁸.

There is growing interest in treating radiation-induced complications with anti-angiogenic agents, laser treatment, and local resection of the irradiated tumor.

Though the lacrimal gland is systematically avoided in the irradiation plan, patients can experience a difference in lubrification of their eye, related to irradiation of the mucous surface glands or the canaliculi.

Assessment of surgery

Because survival is usually predetermined by the time the ocular tumor is detected and treated²²; the main quality indicator is local tumor control (Fig. 69.7). Local tumor recurrence ranges from 1–5% and figures among the lowest of conservative treatment techniques for uveal melanoma^{17,19–21,26,27}. Marginal tumor recurrence can occur if tumor extent is underestimated, which can occur with tumors involving ciliary body. Central tumor recurrences are rare. Conservation of the eye is mainly related to tumor dimensions, the main cause of secondary enucleation being neovascular glaucoma²⁰. Residual vision depends on tumor location and size rather than the type of conservative therapy.

Fig. 69.7 Peripapillary melanoma 3.5 years after proton therapy illustrating local tumor control. VA is 0.4.

Introduction

A variety of stereotactic radiotherapeutic techniques have been developed in the past two decades. Several studies have established radiosurgery and stereotactic radiotherapy as effective non-invasive treatment methods for many intracranial vascular malformations and tumors.

Fundamental principles

With stereotactic external beam irradiation (SEBI), ionizing radiation is directed at the tumor from multiple directions so as to focus a high dose of radiation at the target volume with limited irradiation of surrounding tissues. When the total dose of the multidirectional radiation is delivered in a single fraction it is termed ‘stereotactic radiosurgery’ (SRS); when it is fractionated over few days (2–10 days) it is called ‘stereotactic radiotherapy’ (SRT).

Goals of treatment

The aims of treatment are to sterilize the tumor with limited and acceptable damage to surrounding structures and organs.

Indications for stereotactic radiotherapy

At the authors’ institution, stereotactic radiation techniques are performed within clinical trials and reserved for uveal melanomas that are considered unsuitable for ruthenium brachytherapy, either because of large tumor size or because the tumor extends close to the fovea or optic disk.

Preoperative assessment

Tumor size and extent are determined by computerized tomography and magnetic resonance imaging. These images are fused so that a computerized 3D model of the eye and tumor is generated. Treatment plans based on 3D images are designed jointly by radiation oncologists, medical physicists, and ophthalmologists.

During SEBI the patient’s head is immobilized with a stereotactic head frame such as the Leksell head frame used for the GammaKnife^28–3034.

For the LINAC, non-invasive head masks are used and these are made from thermoplastic materials^31–3335.

Stereotactic radiotherapy (fractionated)

Stereotactic radiotherapy is performed using a LINAC with a specific device and the use of non-invasive head frames, in combination with non-invasive ocular monitoring systems. A robot-mounted LINAC ‘Cyberknife’ has recently been introduced for fractionated and one-fraction stereotactic treatments^36,37.

Fractionated treatment with the GammaKnife has been investigated in a study applying two and three fractions for uveal melanoma²⁸. More fractions are not clinically feasible.

With the LINAC, a single beam of radiation is aimed at the tumor from many different directions. Treatment can be delivered during an arc rotation of the LINAC beam around the target isocenter. Round collimators of different sizes and 5–12 arcs of rotation are generally used to cover the target volume. Radiation also can be performed with static conformal fields. Here, the beam shape is adjusted to the target contour by a micro multi-leaf collimator (Fig. 69.8).

Fig. 69.8 Dose distribution for a LINAC based stereotactic treatment.

The entire treatment and the total dose (50–70 Gy) are given in four to five fractions of 10–14 Gy over 2 weeks^31–3335. Because of the non-invasive and less rigid head and ocular fixation devices, a safety margin of 2.0–2.5 mm in all directions is usually added to the tumor margins.

Stereotactic radiosurgery (one fraction)

Stereotactic radiosurgery is defined as a single delivery of an effective therapeutic radiation dose to a defined limited target. Most patients undergoing radiosurgery have been treated with the Leksell GammaKnife (GK). This comprises 201 cobalt sources placed in a metal hemispheric device that is positioned around the patient’s head so that highly collimated beams of gamma rays converge on the tumor (Fig. 69.9). A total radiation dose of 25–40 Gy is delivered with a safety margin of 1–2 mm^{29,30,34,38,39}.

Fig. 69.9 GammaKnife radiation unit with the primary collimator.

Anesthesia, akinesia, and ocular fixation

A prerequisite for treating an intraocular tumor is immobilization of the eye during CT and MRI examinations as well as during radiation delivery.

For the GammaKnife and the Cyberknife treatment this is usually accomplished by a retrobulbar injection of an anesthetic to obtain akinesia of the periocular muscles^{28–30,34,36,37}. This technique is often combined with traction sutures, which are passed through two rectus muscles³⁰. For the GammaKnife, an alternative ocular fixation system with a suction-assisted contact lens has been described²⁸.

For stereotactic radiotherapy with a LINAC, different approaches have been used to stabilize the eye and thus the tumor. For most patients, a CCTV ocular monitoring system with a head fixation mask has been used^31,32,33,35. The patient is asked to fix a defined point or a flashing light. This approach is non-invasive and hence no injection is necessary (Fig. 69.10).

Fig. 69.10 Set-up of a LINAC treatment for intraocular melanoma.

Postoperative care

Most patients show partial tumor regression or stable disease. Response is mainly assessed by ocular examination und ultrasound. Complete tumor regression is rare. In all studies on SEBI, progressive or recurrent disease has an incidence of less than 10% and in most investigations the reported recurrence rate is less than 5% at 5 years.

Assessment of treatment-related adverse side effects

Acute side effects are negligible. As with brachytherapy and proton beam radiotherapy treatment-related, long-term adverse side effects include optic neuropathy, maculopathy, cataract, exudative retinal detachment, and neovascular glaucoma.

The success of treatment is assessed according to local tumor control, visual impairment, other adverse side effects and quality of life. Fractionated SRT leads to an actuarial rate of local control of 95% at 5 years. As with other forms of therapy for uveal melanoma, the influence of ocular treatment on survival is uncertain. Survival rates after SEBI are similar to those of other therapies.

Fractionated LINAC SRT is increasingly being used and is similar in principle to the proton therapy approach. At present, most centers use 50–70 Gy total dose delivered in five fractions with 14–10 Gy per fraction^31–3335.

An unanswered question is whether a moderate total dose delivered with single fraction SRS is superior or inferior to a fractioned somewhat larger total dose in SRT, in terms of local control and morbidity.

Both methods seem to produce similar results with regards to local control; however, the therapeutic window of single-fraction SRS with the GammaKnife seems to be narrower. High single-dose treatment (e.g. 50–80 Gy) was abandoned because of common and severe complications^38,39. Single radiation doses below 40 Gy (at the tumor margin) seem to lead to high local tumor control rates with an acceptable incidence of radiogenic side effects^29,30,34,39.

Beside the total dose, there is evidence that the amount of irradiated eye and tumor volume influences outcome²⁸.

With Cyberknife SRS, early good results are reported with a 22–18 Gy prescribed marginal dose³⁶.

It is worth mentioning that SEBI technologies are relatively cost effective because they are non-invasive, or minimally invasive, and because they require less capital outlay than methods such as proton beam radiotherapy. They are usually administered on an outpatient basis. Furthermore, surgery is not needed, unlike proton beam radiotherapy, which requires tantalum marker insertion, and in contrast to brachytherapy, which involves surgical insertion and removal of the radioactive plaque.

Further studies are required to determine whether SEBI should be combined with endoresection and, if so, in which cases.

Introduction

Local resection procedures include: iridectomy, irido-cyclectomy, trans-scleral choroidectomy with or without cyclectomy, and trans-retinal choroidectomy⁴⁰. Tumor resection may be primary, or secondary following radiotherapy.

Goals of surgery

The objectives of local resection are to conserve the eye with as much useful vision as possible, also stemming any flow of malignant cells into the circulation in case such spread shortens survival.

Indications

Primary local resection

Iridectomy is indicated for nodular melanomas involving up to 4 clock hours of iris and not extending to angle. In several centers, this has been replaced by brachytherapy or proton beam radiotherapy⁴⁰.

Iridocyclectomy is performed for tumors involving up to 4 clock hours of angle and/or ciliary body and is preferred to radiotherapy when tissue is desired for diagnosis and/or prognostic studies (Fig. 69.11)⁴⁰.

Fig. 69.11 Postoperative photograph of the left eye of 23-year-old woman after iridocyclectomy of a 4.5 mm × 3.9 mm × 2 mm ciliary body tumor involving the iris. Histology showed a spindle-cell melanoma, which on genetic testing was found to have a partial deletion of chromosome 3, indicating metastatic potential. Two years postoperatively, the visual acuity was 6/6.

Trans-scleral choroidectomy and cyclochoroidectomy are performed in few centers and then only if the tumor is considered unsuitable for radiotherapy because the thickness is too great for brachytherapy, and if proton beam radiotherapy or stereotactic radiotherapy is undesirable because of risks such as optic neuropathy or canalicular obstruction^40,41. Contraindications to trans-scleral local resection are: diffuse tumor spread, extensive retinal invasion, extraocular spread, involvement of optic nerve or more than 4 clock-hours of the ciliary body, and poor general health precluding hypotensive anesthesia (Fig. 69.12).

Fig. 69.12 Postoperative photograph of a 46-year-old man after trans-scleral local resection, adjunctive plaque brachytherapy, and transpupillary thermotherapy of a choroidal melanoma of the right eye. The tumor had measured 16.5 mm by 16.1 mm in its basal dimensions with a thickness of 12.2 mm, and its posterior margin was 3.9 mm from the optic disc. Seven years postoperatively, the patient was well and the visual acuity was 6/7.5 with pseudophakic correction. The fellow eye was amblyopic with a visual acuity of 6/48.

Endoresection is indicated for posterior tumors up to 10–13 mm in diameter as a means of avoiding radiation-induced optic neuropathy or maculopathy if the patient is keen to retain good vision and accepts the controversial nature of this surgery (Fig. 69.13).

Fig. 69.13 Right fundus 15 years after endoresection of a juxtapapillary choroidal melanoma of the right eye. The patient was 37 years old at the time of her initial surgery. The tumor had measured 4.6 mm × 4.2 mm in its basal dimensions with a thickness of 2.3 mm. Histology showed epithelioid cells, confirming the diagnosis of melanoma. The latest visual acuity with pseudophakic correction was 6/9, as at presentation.

Preoperative assessment

Assessment is aimed at: determining the tumor size and extent, identifying retinal or extraocular extension, and assessing suitability for hypotensive anesthesia, and the patient’s motivation for aggressive and controversial surgery.

Anesthesia

Except for iridectomy, local resection is best performed under general anesthesia, with moderate systemic hypotension for endoresection and profound hypotension for trans-scleral choroidectomy.

Operation techniques

Intraoperative complications

The main intraoperative complications of trans-scleral local resection include: malposition of scleral flap, buttonholes in superficial or deep sclera, uncontrolled hemorrhage, lens touch, retinal tear, and incomplete tumor resection⁴⁰. With endoresection, the most common complications are: uncontrolled hemorrhage, incomplete tumor resection, lens touch, and entry-site tears⁴⁰.

Postoperative care

For the first postoperative day, the patient is postured so that any hemorrhage gravitates away from the macula. Inflammation and infection are prevented by local and systemic steroids and antibiotics.

Postoperative complications

Conservation of vision depends on the size and location of the tumor and the avoidance of complications⁴⁴. Local tumor recurrence is most likely to occur with large, high grade melanomas extending far posteriorly and if adjunctive brachytherapy has not been administered⁴⁵. Recurrent disease can occur many years after the local resection⁴⁵. It usually arises at the margin of the coloboma but can develop anywhere in the eye. If not treated quickly, the tumor can extend extraocularly. After endoresection, recurrent tumor can extend trans-sclerally or through the retinotomy to seed around the vitreous cavity^46,47.

Rhegmatogenous retinal detachment usually occurs within the first postoperative month and requires urgent surgery, as proliferative vitreoretinopathy tends to develop rapidly⁴⁸.

Vitreous hemorrhage is rare in the absence of a retinal break.

Hypotony can occur after trans-scleral cyclectomy, especially if adjunctive brachytherapy is administered at the time of the local resection, which is why such radiotherapy is delayed for about a month until healing has occurred.

Other complications include: cataract, macular edema, subretinal hematoma, wound dehiscence, and ocular motility disturbances.

Metastatic disease is related to tumor size and extent, histological grade, and genetic type^49,50. There is no evidence that ocular treatment influences survival⁵¹.

Assessment of surgery

Indicators of success include: local tumor control, avoidance of retinal detachment, and visual acuity, taking account of the initial tumor location in relation to the macula.

Introduction

Phototherapy is useful as primary treatment for small choroidal melanomas, as a means of avoiding radiotherapy⁵². It is also administered as an adjunct to radiotherapy, to prevent local tumor recurrence⁵³. Secondary phototherapy can induce regression of exudation after radiotherapy, thereby improving vision⁵⁴.

Fundamental principles

’Trans-pupillary thermotherapy (TTT)’ heats the tumor to 60–65°C by means of a diode laser. This method supersedes photocoagulation, which heats to tumor to temperatures exceeding 65°C⁵². Photodynamic therapy (PDT) is an investigational method that uses light energy of the appropriate wavelength to activate an agent such as verteporfin with the production of toxic free radicals^55,56. Photocoagulation is regarded as obsolete and is not considered in this subchapter⁵⁷.

Goals of treatment

The goal of treatment is to sterilize the melanoma, with minimal damage to surrounding tissues.

Indications and contraindications

On its own, TTT is associated with a high rate of local tumor recurrence so that it is reserved for small tumors, less than 3 mm thick. TTT therefore tends to be combined with brachytherapy, as part of the primary treatment to reduce any chances of local tumor recurrence (i.e. ‘sandwich therapy’)^53,57,58. It is also useful as a secondary procedure, as a treatment for radiation-induced tumor exudation. Contraindications include: media opacities, small pupil, peripheral tumor location and, if used as sole treatment, tumor thickness exceeding 3 mm. TTT tends to be less effective with amelanotic melanomas, which are more likely to respond to PDT than pigmented tumors⁵⁵. Optic disc involvement increases the risk of local tumor recurrence.

Anesthesia

A 1 ml volume of local anesthetic is injected into the retrobulbar area to achieve pain control while preserving ocular movements, thereby facilitating access to the tumor.

Transpupillary thermotherapy

A contact lens with an anti-reflective coating is used. Overlapping spots of diode laser are administered to the entire tumor surface and a surround of 2–3 mm, with a beam diameter of 3 mm, each application having a duration of 1 minute. The initial power setting is around 400 mW and is increased in 50 mW increments until retinal blanching begins to occur at 45 seconds. At this intensity, it should be possible to treat the tumor without damaging any overlying retinal vessels. If the TTT is administered as a treatment for radiation-induced exudative maculopathy, then only the visible tumor is treated, without safety margins (Figs 69.14 and 69.15)⁵⁴.

Fig. 69.14 Primary transpupillary thermotherapy of choroidal melanoma. (A) Pre-treatment and (B) post-treatment appearance.

Fig. 69.15 Secondary transpupillary thermotherapy of choroidal melanoma as treatment for exudation after brachytherapy. (A) Before TTT when the visual acuity was 6/18 and (B) after TTT when the visual acuity had improved to 6/9.³

Photodynamic therapy

Several PDT protocols exist. In Liverpool, this therapy is administered as for choroidal neovascular membranes (Fig. 69.16)⁵⁶.

Fig. 69.16 Choroidal melanoma in the left eye of a 67-year-old woman (A) before and (B) after two sessions of PDT. The melanoma (biopsy proven) had an initial thickness of 1.4 mm and became completely flat after the completion of treatment. The final visual acuity was 6/18. Two years after treatment there was no evidence of local tumor recurrence.

Postoperative care

Patients are examined every 3–6 months by ophthalmoscopy, color photography, and echography. The purpose of the echography is to confirm reduction of tumor thickness and exclude extraocular recurrence. Tumor regression occurs slowly over several months, eventually resulting in an area of choroidal atrophy with residual pigment.

Postoperative complications

The main complication is tumor recurrence, which can be marginal, central, or retro-ocular. Excessive laser energies can cause retinal traction and epiretinal membrane formation. Iris burns can occur, resulting in posterior synechiae, a distorted pupil, and lens opacities. With TTT, treatment of the fovea causes immediate visual loss. With PDT, visual deterioration tends to occur when sub-foveal tumor atrophies.

Assessment of treatment

Primary phototherapy is assessed by local tumor control, visual acuity, and absence of retinal and anterior segment complications. Secondary TTT is judged according to whether there is resolution of any exudative maculopathy.

Introduction

Choroidal hemangiomas are benign, vascular tumors that occur posteriorly, usually involving the retina at the optic disc and/or near the macula. Circumscribed hemangiomas are solitary, whereas diffuse hemangiomas tend to be associated with the Sturge–Weber syndrome (Fig. 69.17). On ophthalmoscopy, circumscribed choroidal hemangiomas appear as round to oval, orange subretinal lesions. Diffuse choroidal hemangiomas tend to cause a widespread reddish thickening of the choroid with indistinct edges, usually involving more than half of the entire choroid. Ultrasonography is routinely performed to measure tumor dimensions and it typically displays a high internal acoustic reflectivity⁵⁹. Additional ancillary studies may include fluorescein and indocyanine green angiography as well as OCT for the assessment of macular edema^60,61. Patients with diffuse choroidal hemangioma and Sturge–Weber syndrome require a systemic and neurological workup⁶².

Fig. 69.17 Circumscribed choroidal hemangioma involving the macula with inferior exudative retinal detachment in a 41-year-old male patient. The visual acuity was counting fingers.

Although thought to be present from birth, choroidal hemangiomas may remain asymptomatic or cause symptoms only later in life, usually during the 2nd to 5th decades⁶³. Visual symptoms are caused by exudative retinal detachment and macular edema, which may lead to secondary changes of the RPE, retinal atrophy, and permanent visual loss. The natural history varies considerably. Choroidal hemangiomas may enlarge clinically; this is thought to be caused by venous congestion, and not by multiplication of cells⁶⁴.

Previously, circumscribed hemangiomas were treated by photocoagulation, but this has been superseded by radiotherapy, which has in turn been largely replaced by photodynamic therapy (PDT)^63,65,66. Treatment of diffuse choroidal hemangiomas remains a challenge; most cases may be too extensive for PDT and are more likely to be treated with radiotherapy⁶⁵.

Fundamental principles

Photodynamic therapy uses an infra-red, diode laser to activate verteporfin, a benzopyran derivate, thereby producing toxic, free radicals that induce vascular obliteration.

Goals of treatment

The goals of treatment are to induce resolution of any retinal detachment or macular edema in order to stabilize or improve visual function. In diffuse choroidal hemangiomas, or very advanced cases of circumscribed choroidal hemangiomas, the goals of treatment are to prevent persistent severe exudative retinal detachment and neovascular glaucoma.

Indications for treatment

Asymptomatic choroidal hemangiomas can be observed, as can macular tumors in amblyopic eyes without significant exudation and tumors associated with long-standing macular edema with low potential for functional improvement. Treatment is indicated when macular edema or retinal detachment causes visual symptoms, or when the advanced stages of diffuse choroidal hemangioma contribute to secondary glaucoma.

Anesthesia

No anesthesia is required for PDT.

Photodynamic therapy

Since the introduction of PDT for choroidal hemangiomas, treatment strategies have changed. Initially it was thought that more powerful treatment settings compared to standard parameters for AMD were necessary in order to induce regression in these highly vascularized tumors⁶⁶. Changes included bolus injection vs. infusion of verteporfin over 10 minutes, increased laser energy, longer exposure time, and re-treatments. However, this may have resulted in over-treatment, as visual loss secondary to chorioretinal atrophy following PDT for choroidal hemangioma has been described and excellent outcomes have now been reported using standard PDT parameters^60,67 (Fig. 69.18). There is also a current tendency to reduce the number of re-treatments with PDT; it seems that, in the vast majority of cases, regression can be achieved with only one treatment⁶⁰.

Fig. 69.18 Circumscribed choroidal hemangioma 2 years following PDT with standard parameters. Regression of the hemangioma and the exudative retinal detachment. The visual acuity improved to 20/20.

The photodynamic therapy is delivered by single or confluent spots over the entire tumor surface. Usually, one or two 8 mm diameter spots are sufficient to achieve this aim.

Radiotherapy

External beam radiotherapy can be delivered using a lens-sparing technique and administering a dose of up to 20 Gy in ten divided fractions⁶⁵. Proton beam radiotherapy comprising 18–27 Gy in four fractions is preferred by some because it minimizes radiation to healthy tissues^65,68. Plaque radiotherapy may be considered for tumors not extending close to the optic disc or fovea, with an apical dose of 48 Gy being recommended⁶⁹.

Postoperative care

After photodynamic therapy, patients are assessed after about 2 months to determine whether repeated treatment is necessary. This includes the monitoring of clinical signs of evolving atrophy within the hemangioma, measurements of tumor dimensions, and evaluation of associated exudative changes, including OCT for macular edema⁶⁰. After any form of treatment, patients are reviewed after about 6 months and then intermittently thereafter, if at all.

Postoperative complications

From a theoretical point of view, the most serious complication is radiation-induced malignancy, which can take several decades to develop. For this reason, several centers aim to avoid radiotherapy or to use proton beam radiotherapy or brachytherapy to minimize radiation to healthy tissues.

After PDT, the tumor may not respond fully, making it necessary for the treatment to be repeated. However, it has to be kept in mind that a residual thickening of the choroid can sometimes be detected despite regression of the hemangioma. It also may take several months before a significant regression of tumor thickness or associated exudative retinal changes can be seen, and that over-treatment may result in unnecessary visual loss⁶⁷. Such complications that have been associated with PDT for choroidal hemangioma are choroidal atrophy resulting in visual loss and polypoidal choroidal vasculopathy^67,70.

Assessment of treatment

Improvement in vision is likely to occur if the patient presents with mild visual loss and a short history (i.e. less than 3 months). This can currently be achieved in about 70% of treated cases⁶⁰. Eyes with subfoveal hemangiomas tend to be irreversibly amblyopic as a result of hypermetropia, suggesting that these tumors are congenital. Regression of macular tumors following PDT may also result in atrophy of the overlying RPE and visual loss⁶⁷. In some advanced cases, particularly in diffuse choroidal hemangioma associated with Sturge–Weber syndrome, the disease cannot be controlled with current treatment methods, resulting in total retinal detachment and intractable neovascular glaucoma (Fig. 69.19).

Fig. 69.19 Diffuse choroidal hemangioma with extensive exudative retinal detachment in a 27-year-old female patient with Sturge–Weber syndrome.

Introduction

Uveal metastasis are the most common form of intraocular malignancy, with an estimated annual incidence of 20 000 patients in the USA⁷¹. They are usually overshadowed by the underlying disease; however, it is often the ophthalmologist to whom the patient presents.

Clinical features

Although metastasis may occur anywhere in the uvea, they are usually seen in the choroid. In women, the most common primary sites are the breast in 70–80% and the lung in 10% of patients⁷². In men, by far the commonest primary site is the lung⁷³. Rare sources include the gastrointestinal tract (adenocarcinoma and neuroendocrine carcinoma), thyroid, prostate, kidney, cutaneous melanoma, and lymphoma/leukemia^72,74. Metastasis from the lung are usually the initial manifestation of this disease, whereas secondaries from the breast tend to present after treatment of the primary tumor.

Most patients complain of blurred vision, floaters, and photopsia, as a result of the intraocular mass itself and the associated exudative retinal detachment. Uveal metastasis may, however be, asymptomatic in as many as 11% of all patients⁷⁵. In many patients, choroidal metastasis are bilateral and multifocal, tending to involve the posterior pole (Fig. 69.20). Those occurring in the iris are rapidly growing uni- or multifocal, non-pigmented tumors with associated inflammation, hyphema, or pseudohypopyon⁷⁶.

Fig. 69.20 Fundoscopy picture of a female patient with a large unpigmented choroidal metastasis involving 6 clock hours of the optic nerve.

Fundamental principles

Ocular treatment is palliative. The main goals of treatment are to conserve useful vision and to prevent the eye from becoming painful.

Indications for ocular treatment

Treatment is indicated for tumors causing visual loss, with asymptomatic tumors being kept under observation. Rapid growth is a characteristic of most uveal metastasis; therefore, close follow-up is required to limit the extent of retinal detachment. Ocular therapy may be withheld if the tumor is considered likely to respond to systemic therapy that the patient is about to receive.

Preoperative assessment

Baseline measurements of tumor dimensions, severity of serous retinal detachment, and visual acuity are required to be able to assess the tumor response to therapy. Tumor biopsy may be indicated to confirm the diagnosis of a suspected metastasis, and, in patients with an unknown primary, to direct systemic investigation according to the differential diagnosis. Informative samples can be obtained using a 25-gauge needle or vitreous cutter via a trans-scleral or trans-retinal approach, albeit at a small risk of tumor seeding or hemorrhage (Fig. 69.21)^77,78.

Fig. 69.21 Cytospin of the 25-gauge transretinal biopsy showing numerous large atypical cells with eosinophilic cytoplasmic rims, pleomorphic nuclei, and discrete nucleoli (H&E stain, ×60 objective).

Pathology

Pathological examination entails: (i) light microscopy of either cytological spin preparations or sections of cell blocks stained with conventional stains, and (ii) staining with immunohistochemical panels selected according to the cytomorphology and differential diagnosis (Fig. 69.22)⁷⁹. In breast and lung cancers, the cytospins reveal medium to large sized atypical cells on a necrotic or hemorrhagic background. These will be highlighted in pancytokeratin stains, with specific markers being immunoreactive in particular malignancies (e.g. estrogen or progesterone receptors in some breast cancers; prostate-specific antigen (PSA) in prostate cancer, and chromogranin or synaptophysin in neuroendocrine carcinomas)⁸⁰.

Fig. 69.22 Immunocytological staining showed immunoreactivity for pancytokeratin, confirming the lesion to be metastatic carcinoma (PAP, ×60 objective).

External beam radiotherapy

In focal disease, external beam radiotherapy is recommended: this usually consists of a total dose of 30 Gy, delivered in daily fractions of 3 Gy. A dose of 45–50 Gy in smaller fractions may be administered to patients with a good prognosis (e.g. breast carcinoma). Using this approach, visual acuity can be stabilized or improved in most patients⁸¹.

Brachytherapy

Plaque radiotherapy may be useful for solitary choroidal metastasis. This treatment has the advantage of being completed within a week. Brachytherapy may also be useful for persistent tumor after previous external beam radiotherapy⁸².

Other methods

Photodynamic therapy and transpupillary thermotherapy are reported to achieve local tumor regression in some patients, but these treatments are currently to be considered investigational. In patients with vitreous metastasis from cutaneous melanoma, vitrectomy may provide the required palliation⁷⁴. Otherwise, the only remaining surgical option is enucleation because the eye is blind and painful as a result of secondary glaucoma.

Postoperative care

Patients are reviewed after about 1 month, then every 4–6 months postoperatively to ensure that the tumor responds to treatment and to exclude or detect any new metastasis at an early stage.

Postoperative complications

Treatment of choroidal metastasis with radiotherapy and/or systemic chemotherapy is usually effective, preserving vision in most cases. The main complications are radiation retinopathy and cataract, which are more likely to occur in patients with prolonged survival⁸¹. The life expectancy of these patients, however, is poor with a median survival of 7 months.

Assessment of treatment

Treatment is assessed by local tumor control and avoidance of radiation retinopathy, cataract, and other complications.

Introduction

Retinoblastoma is the most common intraocular cancer of childhood^83,84. It represents approximately 4% of all pediatric malignancies.

Epidemiologic considerations

Retinoblastoma affects approximately one infant in 15 000–20 000 live births in the United States each year. Most studies indicate that the incidence of retinoblastoma among the various geographic populations is relatively constant. The role of environmental influences in the development of this malignant intraocular tumor remains unclear. It is estimated that 250 to 300 new cases of retinoblastoma are diagnosed in the United States each year and 5000 cases worldwide. Large countries like India and China individually estimate approximately 1000 new cases of retinoblastoma per year. Over 95% of children with retinoblastoma in the United States and other medically developed nations survive their malignancy, whereas about 50% survive worldwide. The reason for the poor survival in undeveloped nations relates to late detection of advanced retinoblastoma, often presenting with orbital invasion or metastatic disease.

Terminology

Retinoblastoma is basically classified in three different ways: familial or sporadic, bilateral or unilateral, and heritable (germline) or non-heritable (somatic). From a clinical standpoint, the first two classification schemes are most often employed. Thus, a case is classified as unilateral sporadic, bilateral sporadic, unilateral familial, or bilateral familial. About two-thirds of all cases are unilateral and one-third are bilateral. From a genetic standpoint, it is simpler to discuss retinoblastoma with the latter classification of germline or somatic. Bilateral and familial retinoblastoma are caused by a germline mutation and are thus a heritable tumor^85,86. Unilateral sporadic retinoblastoma is usually somatic and thus not heritable. However, it is estimated that approximately 15% of children with unilateral sporadic retinoblastoma have a germline mutation. Genetic testing using DNA analysis of the patient’s tumor and peripheral blood can help identify those patients with a germline mutation^86,87. Patients with germline mutation retinoblastoma are at risk for related second cancers^88,89.

Genetics

The retinoblastoma gene is located on the long arm of chromosome 13 (13q). The 13q deletion syndrome can manifest as several phenotypic abnormalities⁹⁰. Many patients have minimal or no visible abnormality. The characteristic findings include dysmorphic features such as microcephaly, broad prominent nasal bridge, hypertelorism, microphthalmos, epicanthus, ptosis, protruding upper incisors, micrognathia, short neck with lateral folds, large prominent low set ears, facial asymmetry, imperforate anus, genital malformations, perineal fistula, hypoplastic or absent thumbs, toe abnormalities, and psychomotor and mental retardation.

Clinical features

The clinical manifestations of retinoblastoma vary with the stage of the disease at the time of recognition. In its earliest clinical stage, a small retinoblastoma, under 2 mm in basal dimension, appears ophthalmoscopically as a subtle, transparent or slightly translucent lesion in the sensory retina^83,84. Slightly larger tumors lead to dilated retinal blood vessels that feed and drain the tumor. Some larger tumors show foci of chalk-like calcification that resemble cottage cheese. A retinoblastoma of any size can produce leukocoria (Fig. 69.23). Larger tumors more often present with leukocoria. This white pupillary reflex is a result of reflection of light from the white mass in the retrolental area. Some normal eyes show leukocoria from the reflection of the normal optic disc through the pupil.

Fig. 69.23 Leukocoria of the left eye from retinoblastoma.

Retinoblastoma growth patterns are subdivided into intraretinal, endophytic, exophytic, and diffuse^83,84,91 (Fig. 69.24). Intraretinal tumors are those listed above, limited to the substance of the retina. An endophytic retinoblastoma is one that grows from the retina inward toward the vitreous cavity. Hence, it is characterized by a white hazy mass with obscuration of the retinal blood vessels. Because of its friable nature, an endophytic tumor can seed the vitreous cavity and simulate endophthalmitis or toxocariasis. An exophytic retinoblastoma is one that grows from the retina outward into the subretinal space. Such tumors produce a progressive retinal detachment, with the retina often displaced anteriorly behind a clear lens. An exophytic retinoblastoma can clinically resemble Coats’ disease or other exudative retinal detachment. Occasionally a retinoblastoma can assume a diffuse infiltrating pattern, characterized by a relatively flat infiltration of the retina by tumor cells without an obvious mass⁹¹. In such cases, the diagnosis can be more difficult and this pattern can simulate uveitis or endophthalmitis. Less frequently, the presenting feature can be pseudohypopyon due to tumor seeding in the anterior chamber, hyphema secondary to iris neovascularization, vitreous hemorrhage, or signs of orbital cellulitis.

Fig. 69.24 Growth patterns of retinoblastoma. (A) Endophytic retinoblastoma with tumor seeding into vitreous cavity. (B) Exophytic retinoblastoma with tumor growth beneath the retina and presence of subretinal fluid.

Classification

Several classifications of retinoblastoma have been developed to assist in prediction of globe salvage. The Reese Ellsworth classification was employed from the 1960s to current day. The International Classification of Retinoblastoma (ICRB) has been proposed to simplify the grouping scheme and allow a more practical approach to judging results of chemoreduction^92,93 (Table 69.1).

Table 69.1 International Classification of Retinoblastoma (ICRB), long form

Introduction

Therapeutic advances have improved the retinoblastoma survival rate from 5% to 99% in the developed world, with more than 90% of children retaining normal vision in at least one eye⁹⁵. The therapeutic goals are: (i) tumor eradication, (ii) vision preservation, and (iii) prevention of second tumors in patients with germline RB1 mutations⁹⁶.

Treatment of individual patients is largely based upon disease staging using the international classification system for intraocular retinoblastoma (Table 69.4)^97,98.

Treatment methods

Systemic chemotherapy

The primary goal of systemic chemotherapy in retinoblastoma is to reduce tumor volume to allow focal therapy (chemoreduction) (Fig. 69.25)¹⁰². Systemic chemotherapy for retinoblastoma is also indicated when the risk of systemic disease is high. Most chemotherapeutic protocols use two- or three-drug regimens with carboplatin, etoposide, and vincristine; however, inter-institutional variability exists in the exact protocol chosen^103,104. The major complications of chemotherapy using the CEV regimen are: (i) renal toxicity, ototoxicity, and myelosuppression with thrombocytopenia from carboplatin; (ii) secondary malignancy caused by etoposide; and (iii) peripheral neuropathy from vincristine.

Fig. 69.25 Patient who presented with leukocoria of the right eye (A). Treatment effect after 29 weeks, following six cycles of chemotherapy with consolidative focal therapy (B).

Treatment strategies

Introduction

Vasoproliferative tumor is a benign retinal tumor characterized by peripheral location, exudation, and epiretinal membrane formation. It is usually primary but can be secondary to conditions such as uveitis, retinal detachment, Coats’ disease, and retinitis pigmentosa^106,107. The typical clinical picture is of an orange or pink retinal mass in the peripheral fundus, associated with retinal vascular changes and exudation (Fig. 69.26). Vasoproliferative tumors can be solitary or multiple and are usually pre-equatorial, mostly in the infero-temporal region (Fig. 69.27). All age groups can be affected, but the disease is most commonly seen between 40 and 60 years of age¹⁰⁸. Histologically, the tumors consist of proliferating retinal glial cells, which stain positively for GFAP (glial fibrillary acid protein), and retinal pigment epithelial cells, with a rich capillary network and neovascularizations^109,110. Vasoproliferative tumors tend to cause hard exudates, serous retinal detachment, and epiretinal membranes, all of which can affect the macula (Figures 69.26–69.28). On slit-lamp examination, cells in the anterior chamber are almost always present. In addition, teleangiectatic retinal vessels and retinal pigment epithelial proliferations surround the tumor¹⁰⁹. In contrast to retinal hemangioblastoma, the feeder vessels are only mildly dilated, if at all. In the advanced stages, the disease can be associated with: epiretinal neovascularizations on the disc and elsewhere, subretinal neovascularization, total retinal detachment, vitreous hemorrhage, and rubeosis iridis^{106,108–110}. The early stages of the disease can be asymptomatic, and the tumor may be diagnosed on routine fundus examination; however, in most cases, patients present with visual loss, metamorphopsia photopsia caused by retinal exudation or floaters, photophobia, or red eye caused by intraocular inflammation. The natural course is thought to be slowly progressive. The disease may advance to total retinal detachment with intractable neovascular glaucoma.

Fig. 69.26 Small vasoproliferative tumor of the inferior pre-equatorial retinal periphery with teleangiectatic changes of the retinal vessels and associated retinal exudation.

Fig. 69.27 Vasoproliferative tumor of the temporal inferior retinal periphery with associated retinal exudation.

Fig. 69.28 OCT of the macula demonstrating a thick epiretinal membrane (arrow) and a lamellar macular hole (*).

Goals of treatment

The main goals of treatment are to prevent visual loss and preserve the eye. These are achieved by eradicating the tumor, eliminating exudation and macular edema, and, in many patients, treating epiretinal membranes¹¹¹.

Indications for ocular treatment

Not all vasoproliferative tumors cause visual loss, so that observation may be appropriate in asymptomatic cases¹¹². Treatment is indicated for symptomatic tumors and those threatening to cause visual loss^109,111.

Preoperative assessment

The diagnosis is usually established by the typical clinical appearance on indirect ophthalmoscopy. The initial work-up includes echography, which usually demonstrates an inhomogeneous, high internal acoustic reflectivity, and a tumor thickness of 2–6 mm. Measurement of tumor dimensions, photographic documentation of exudates, and OCT measurement of macular edema are required in order to assess the efficacy of any treatment. Fluorescein angiography is rarely necessary; when performed, it usually demonstrates a connection of tumor vessels to mildly dilated retinal feeder vessels and marked epi- and subretinal leakage of the dye from the tumor vasculature¹⁰⁹. Systemic investigation is indicated if retinal hemangioblastoma cannot be excluded with certainty.

Ocular treatment

Various forms of treatment are possible and there is no consensus as to which is the best method. Early disease is most commonly treated by laser photocoagulation or cryotherapy^107,108. Our approach is to start with photodynamic therapy¹¹³, repeating this once or twice if the initial response is inadequate. If this approach is unsuccessful, we then attempt cryotherapy, using a retinal probe with the triple freeze–thaw technique. Persistent disease is treated with brachytherapy^109,111,114. Intravitreal injections of anti-VEGF agents can be used to treat secondary macular edema; a positive effect of this treatment on the tumor itself has also been reported¹¹⁵. Vitrectomy with epiretinal membrane peeling may be required in some patients¹¹¹. In the advanced stages, trans-scleral tumor resections have been performed^110,116. Intractable, painful neovascular glaucoma associated with end-stage disease may require enucleation^109–111.

Postoperative care

Follow-up is aimed at detecting and treating unresponsive tumors and managing any maculopathy. Epiretinal membranes may develop following initiation of treatment and usually become apparent once exudation has regressed. Some patients may develop bilateral disease or additional tumors in the initially affected eye^109,117.

Postoperative complications

Apart from an inadequate response to treatment, the most common complication is maculopathy, caused by either exudation or epiretinal membrane formation. Increasing exudation has been described following cryotherapy of tumors with a thickness of ≥2 mm¹⁰⁹. Epitretinal membrane formation is more common following treatment of advanced stages of the disease and after plaque radiotherapy¹¹¹. In a minority of patients, the disease cannot be controlled with current treatment modalities. This is usually associated with advanced stages of the disease at the initiation of treatment, in particular neovascular glaucoma^110,111.

Assessment of treatment

Treatment is assessed by the control of exudation and management of maculopathy. In our experience, the response to treatment is usually slow, and regression of associated changes can take many months. Photographic documentation, repeated ultrasound measurements, and OCT examinations are essential in order to assess response to treatment.

Introduction

Retinal capillary angioma (syn. retinal hemangiomblastoma) can occur in isolation or as part of von Hippel–Lindau (VHL) disease¹¹⁸. This syndrome is caused by a mutation on chromosome 3¹²⁰, which is inherited in an autosomal dominant fashion with incomplete penetrance^118,119. Retinal capillary angioma can be classified on the basis of the location within the retina (peripheral and juxtapapillary), morphology (endophytic, exophytic, and sessile), effects on the retina (exudative form and tractional form), and the relationship to VHL disease (with or without VHL disease)¹¹⁸.

Fundamental principles

Treatment of retinal angiomas can be challenging because of the presence of bilateral multiple tumors. The treatment is determined mostly by the size of the tumor, location, activity, and the secondary effects on the retina and vitreous¹²⁰. As juxtapapillary retinal capillary angioma tends to remain stable, initial observation in an asymptomatic case without evidence of exudation should always be considered^121,122.

Goals of treatment

The goals of treatment are to prevent, treat, or minimize secondary complications caused by the tumor. The presence of small residual gliotic remnants of the tumor without exudation or visually significant traction is an acceptable outcome.

Indications for ocular treatment

In general, retinal capillary angioma (except some cases of juxtapapillary tumor) should be treated promptly, because the best results occur when the tumor is small and before any fibrosis has developed.

Preoperative assessment

The fundus findings of retinal capillary angioma are characteristic and diagnosis of retinal capillary angioma can usually be made based solely on ophthalmoscopic examination. The retinal capillary angioma is usually a circumscribed, round retinal lesion with an orange-red color but it can vary in appearance depending upon whether the retinal capillary hemangioma is endophytic, exophytic, or sessile¹¹⁸. Secondary effects such as intraretinal and subretinal exudation are often observed surrounding the angioma, which may extend into the macula producing star exudates.

Of all the ancillary tests, fluorescein angiography is the most informative diagnostic tool because of the vascular nature of the tumor (Fig. 69.29). The angioma fills rapidly with the dye showing early circumscribed hyperfluorescence and delayed leakage. Prominent feeder arteriole and draining vein are also evident. Fluorescein angiography also helps in differentiating the feeder arteriole from the draining vein and is therefore important for treatment planning. Juxtapapillary retinal capillary angioma has similar angiographic features but lacks feeder and draining vessels¹²³. Optical coherent tomography of the macula helps in differentiating tractional maculopathy from exudative maculopathy in association with juxtapapillary tumors.

Fig. 69.29 Small retinal capillary angioma observed on surveillance examination in a patient with VHL disease (A). The angioma could be visualized with fluorescein angiography (B). Appearance immediately after laser photocoagulation (C). Four weeks later, the angioma is partially regressed and surrounded by a chorioretinal scar (D).

Patients with a solitary tumor and a negative family history should usually undergo systemic evaluation or genetic testing to exclude VHL¹²⁴. Those with definite or possible VHL should have a systemic evaluation for central nervous system hemangioblastomas, renal carcinomas, pheochromocytoma, deafness, and other abnormalities¹²⁵.

Ocular treatment

Small posterior retinal angiomas are treated by laser photocoagulation (see Fig. 69.29C)¹²⁶. Larger tumors up to 2 mm in thickness usually respond to cryotherapy, which may need to be repeated^120,127. Large peripheral tumors may respond to brachytherapy¹²⁸. More recently, photodynamic therapy has been reported to induce occlusion of juxtapapillary and peripheral tumors^122,129. Systemic or intravitreal treatments with anti-VEGF agents do not shrink the tumor, although there may be beneficial effects of resolution of the SRF in some cases¹³⁰. Tumor removal with a vitreous cutter is possible but may be followed by severe proliferative vitreoretinopathy. Vitreoretinal surgery is therefore limited to releasing any retinal traction once regression of the tumor has been achieved.

Postoperative care

Patients require close surveillance to ensure that any intraocular and systemic tumors are promptly detected and treated. The reader is referred elsewhere for an appropriate protocol.

Postoperative complications

The main complications are incomplete tumor response to treatment and aggravation of any cicatricial effects. The cumulative lifetime risk of significant permanent vision loss is estimated at 60%, and about 20% of patients have vision worse than 20/100 in at least one eye¹³¹.

Assessment of treatment

Treatment is assessed by the visual outcome, tumor regression, and resolution of tumor induced exudation.

Introduction

The current WHO classification of lymphomas categorizes the various subtypes according to clinical, histomorphological, immunophenotypical and genotypical features¹³². Intraocular lymphomas can be classified according to whether they are retinal or uveal, and primary or secondary¹³³. Ocular adnexal lymphomas can be clinically staged according to their location and extent, using the tumor, node, metastasis (TNM/AJCC) system¹³⁴.

Clinical features

Retinal lymphomas

Most retinal lymphomas present after the age of 60 years, usually as chronic uveitis unresponsive to steroid therapy^133,135,136. Creamy-white subretinal tumor deposits are usually present (Fig. 69.30A). The large majority are high-grade B-cell lymphomas, which can be subtyped as diffuse large B-cell lymphomas (DLBCL) (Fig. 69.30B). Before or after the appearance of ocular disease, about 70–80% of patients show central nervous system involvement, usually with a fatal outcome.

Fig. 69.30 Retinal lymphoma. (A) Ophthalmoscopic appearance of vitreoretinal lymphoma, demonstrating the typical yellow-white subretinal infiltrates and retinal pigment epithelial changes and focal involvement of the vitreous. (B) Large atypical blasts with folded and pleomorphic nuclei in a vitreous biopsy of a patient with vitreoretinal lymphoma (May Grunewald, Giemsa stain, ×60 objective).

Uveal lymphomas

Primary choroidal lymphomas are relatively rare, presenting after the age of 50 years with unilateral loss of vision. Ophthalmoscopy shows a diffuse, pink, choroidal tumor (Fig. 69.31A), which on echography has a low internal acoustic reflectivity. Extraocular extension can occur near the optic nerve and/or sub-conjunctivally near the limbus (Fig. 69.31B). These are mostly low grade, extranodal marginal zone lymphomas (EMZL) with a good survival prognosis (Fig. 69.31C)¹³³. Secondary choroidal lymphomas are usually of the non-Hodgkin’s type, representing an ocular involvement of a systemic lymphoma. They present as multiple, unilateral or bilateral, creamy-white lesions (Fig. 69.31D). The behavior of the ocular deposits usually reflects the malignancy of the underlying systemic disease.

Fig. 69.31 Uveal lymphoma. (A) Fundus photograph of primary uveal lymphoma, showing loss of visible choroidal vessels. (B) Ultrasound scan showing low intensity choroidal tumor with extraocular spread. (C) Light micrograph with Ki-67 stain, showing small lymphocytes with dense nucleus and low proliferation rate. (D) Fundus photograph of secondary high grade, non-Hodgkin’s lymphoma, showing multiple cream-colored uveal tumors coalescing at the posterior pole.

Iridal lymphomas are exceedingly rare, presenting with unilateral pain, redness, and pseudohypopyon. They can be of T- or B-cell type, and tend to ultimately disseminate systemically, resulting in a poor prognosis for survival. Only one case of ciliary body lymphoma has been described and this was of low grade, B-cell type¹³³.

Ocular adnexal lymphomas

These tumors originate in conjunctiva, eyelids, lacrimal gland, and drainage system as well as other orbital tissues (Fig. 69.32A). Two-thirds of these lymphomas are low grade B-cell lymphomas, and can be subtyped as extranodal marginal zone B-cell lymphomas (EMZL) of the MALT type (i.e. mucosa-associated lymphoid tissue) (Fig. 69.32B)^137,138 and these occur as localized disease. Although various micro-organisms and chromosomal abnormalities have been linked to the ocular adnexal EMZL, their pathogenesis remains uncertain. High grade B-cell lymphomas, such as DLBCL and mantle cell lymphoma, can occur as primary or secondary tumors in the ocular adnexa, and tend to show more aggressive clinical courses.

Fig. 69.32 (A) Typical appearance of conjunctival lymphoma, with ‘salmon-pink’ tumor involving the caruncle and plica. (B) Hematoxylin and eosin stained micrography of a conjunctival biopsy showing a diffuse infiltration by small, atypical lymphocytes with occasional scattered blasts. Infiltration of the overlying conjunctival epithelium (i.e. ‘lymphoepithelial lesion’) is characteristic of ‘MALT’ lymphomas.

Ophthalmic assessment

All patients require full ophthalmic examination. If any form of intraocular lymphoma is suspected, then echography or other ocular imaging is required. In the case of retinal lymphoma, vitreous biopsy should also be performed, ideally also sampling a representative subretinal deposit. Steroid therapy should be discontinued several days before biopsy to increase cellular yield and to avoid false negative results¹³⁹. For uveal lymphoma, biopsy of the affected choroid, ciliary body, or iris should be performed.

Patients with suspected or definite ocular adnexal lymphoma require: examination of the entire conjunctival surface; exophthalmometry; color vision testing; ocular motility measurements; and orbital imaging, such as echography and magnetic resonance imaging. Incisional biopsy should be performed for histological assessment and lymphoma subtyping.

Systemic assessment

Any systemic disease is detected and staged by obtaining a full history and performing a complete medical examination, full hematological investigations, and imaging of chest, abdomen, and pelvis by computerized tomography (CT), magnetic resonance imaging (MRI), and/or positron emission tomography (PET). Brain scans are indicated for patients with retinal lymphoma, and scans of the orbit and sinuses are required for patients with ocular adnexal lymphoma. If possible, suspected lymph node or extranodal involvement should be confirmed histopathologically (e.g. by fine-needle aspiration biopsy or incisional biopsy). Bone marrow biopsy is required in the staging of all patients.

Laboratory techniques

The surgeon should liaise closely with the pathologist, to ensure that the specimen is transported to the laboratory in the correct medium and container and without delay¹³⁹. A fixative such as buffered formalin is required for tissue specimens, if they are unlikely to reach the laboratory in less than one hour. In contrast, cytological specimens (i.e. vitreous or aqueous taps) should be sent either fresh or in soft fixatives such as Cytolyte or HOPE fixation¹³⁹. Cytomorphological analysis is performed to determine the grade of malignancy of ocular lymphomas, and to exclude any microorganisms. Immunohistochemistry and/or flow cytometry differentiate reactive from neoplastic lymphocytes and identify the subtype of lymphoma¹³⁹. The polymerase chain reaction (PCR) directed against the immunoglobulin heavy chain gene or the TCR-receptor determines whether the lymphocytes are monoclonal or polyclonal¹³⁹. Levels of interleukins 6 and 10 in vitreous help determine whether infiltrates are likely to be inflammatory or neoplastic¹⁴⁰.

Fundamental principles of treatment

The treatment of a lymphoma depends on whether it is localized or widespread, and of low grade or high grade malignancy.

Low grade lymphomas, if localized, are treated by excision or radiotherapy followed by surveillance, since most patients do not require further therapy. Widespread, low grade lymphomas tend to be indolent but responsive to treatment. Patients are therefore treated symptomatically, by systemic chemotherapy if there are generalized symptoms or by radiotherapy for localized symptoms. Relapses tend to occur, necessitating repeated treatment, which may need to be more progressively more aggressive if resistance increases.

High grade lymphomas (e.g. DLBCL) are more life threatening but also more curable. They are treated with systemic therapy, using a combination of rituximab, cyclophosphamide, oncovin (vincristine), and prednisolone (R-CHOP). Localized disease may also require radiotherapy or intralesional injection of interferon.

Treatment

The first line of therapy for most ocular adnexal lymphomas is low dose radiotherapy with or without systemic chemotherapy, depending on the lymphoma stage¹⁴¹. The role of radiotherapy for retinal lymphoma is controversial, as a result of associated morbidities (see below). The current key chemotherapeutic agent in retinal and cerebral lymphoma is methotrexate, administered either intraocularly or intrathecally; possible new regimens could also include high dose cytarabine as this appears to be particularly effective¹⁴². Isolated (recurrent) retinal lymphoma may be treated with either intravitreal methotrexate or rituximab¹⁴³.

Complications

Follow-up

Patients with retinal lymphoma are at high risk of developing CNS disease within a few years whether or not there is intraocular tumor recurrence. Ocular treatment is therefore symptomatic, whereas systemic management is usually undertaken by an oncologist with expertise in lymphomas. Although ocular adnexal lymphomas are of low grade type, they undergo high grade transformation in about 10% of cases. Recurrence of ocular adnexal lymphomas in other extranodal sites occurs in one-third of patients, and systemic dissemination in up to 25%¹³⁹. Long-term follow-up is therefore, required.

Evaluation of treatment

Ocular treatment is evaluated in terms of local tumor control, visual acuity, and comfort. The impact of ocular treatment on survival is uncertain.

Introduction

Conjunctival melanoma is rare¹⁴⁴. Treatment depends on the tumor’s size and location and the presence or absence of diffuse intraepithelial disease. It is believed that local recurrence after initial treatment increases the likelihood of metastatic death.

Preoperative assessment

It is essential to examine the entire conjunctiva and palpate the regional lymph nodes. Ocular assessment involves determining the extent of any tumors and pigmented areas in each conjunctival region (i.e. limbus, bulbar conjunctiva, fornix, etc.) recording circumferential spread in clock hours or minutes in each involved region¹⁴⁵. Tumor dimensions are also recorded in millimeters. If possible, the tumor thickness is measured with high frequency echography.

The scope of confocal microscopy is still undefined. Some authors recommend sentinel node biopsy for high risk cases¹⁴⁹.

Systemic examination and imaging are guided by the likelihood of tumor dissemination. Examination of the entire skin surface has been recommended, because of reported associations with the dysplastic nevus syndrome and cutaneous melanoma.

Staging can be performed according to the latest edition of the tumor, node, metastasis (TNM/AJCC) clinical staging system¹⁵⁰.

Anesthesia

General anesthesia is preferred because it avoids the need for local injections, which may make the surgery more difficult.

Therapeutic techniques

Treatment of invasive melanoma

With a bulbar tumor, a line of diathermy burns is placed around the tumor, about 1–2 mm from the tumor margins, along the intended line of conjunctival incision (Fig. 69.33). The corneal epithelium adjacent to any tumor is devitalized with alcohol and scraped towards the main tumor with a Bard–Parker scalpel. The conjunctiva and the underlying episclera are divided with scissors along the line of the diathermy burns and separated from the sclera with the scalpel. If possible, Bowman’s layer is preserved, to prevent deep corneal invasion. Any deep tumor extensions in sclera are diathermied. The tumor is excised en bloc using a no-touch technique. Hemostasis is strictly maintained by meticulous diathermy. The specimen is placed onto paper and into fixative. Any suspicious areas of residual intra-scleral tumor are treated with diathermy or cryotherapy. Some would perform a lamellar scleral excision¹⁵¹. Using fresh instruments, the conjunctiva is undermined and closed with interrupted sutures. Extensive wounds are allowed to heal by second intention or closed with an amniotic membrane graft.

Fig. 69.33 Authors’ method of treating bulbar conjunctival melanoma. Adjunctive radiotherapy is administered in all patients with invasive melanoma irrespective of histological appearances suggesting clearance.

With invasive melanoma, adjunctive brachytherapy can be administered, delivering 100 Gy to a depth of 1 mm using a strontium applicator, ruthenium plaque, or another device, such as an unshielded iodine plaque. If such brachytherapy is not possible, for example with caruncular tumors, then external beam radiotherapy or proton beam radiotherapy can be used (Fig. 69.34)¹⁵². We delay adjunctive radiotherapy until the conjunctiva has healed, usually about 2 weeks after the surgical excision. There is no consensus over whether adjunctive radiotherapy should be given to all patients with invasive melanoma or only if histology suggests incomplete surgical clearance.

Fig. 69.34 A 54-year-old woman was referred with a fungating conjunctival melanoma of the right eye. The tumor involved the caruncle and eyelids and was associated with diffuse intraepithelial spread (A). The patient was treated by excision of the nodular part of the tumor followed by proton beam radiotherapy and topical mitomycin C therapy. Local tumor control was achieved (B). However, the patient subsequently developed fatal metastatic disease.

Cryotherapy is widely used as adjunctive therapy¹⁵¹. Our impression is that it is less reliable than radiotherapy and more likely to cause complications, at least with bulbar tumors.

Diffuse intraepithelial disease is treated with topical chemotherapy using an agent such as mitomycin C; opinions differ as to the ideal concentration (0.02% or 0.04%) and dosage schedule.

Exenteration may be necessary if local tumor control cannot be achieved by radiotherapy or other methods.

Complications

Several published series report high rates of local tumor recurrence^147,153,154. Presumably, such recurrences have occurred despite measures such as adjunctive cryotherapy and histological assessment of surgical clearance. We therefore administer adjunctive radiotherapy after all excisions for invasive melanoma, rarely if ever seeing any recurrent disease within the irradiated field¹⁵⁵. Residual and recurrent melanomas threaten invasion of the eye and orbit as well as seeding and metastasis. There is some evidence that such seeding can be iatrogenic, caused by incisional biopsy, incomplete tumor excision, or carriage of cells by surgical instruments.

Epibulbar cryotherapy can cause uveitis, macular edema, and hypotony¹⁵⁵. Adjunctive radiotherapy may delay conjunctival healing and can cause necrosis of any exposed sclera. Excision near extraocular muscles can cause ocular motility problems. Extensive excision of the fornices can result in symblepharon and eyelid malposition¹⁵⁵. Topical chemotherapy can cause punctal stenosis and limbal stem cell failure.

Postoperative care

Lifelong monitoring is indicated and may involve repeat conjunctival micro-biopsies in some cases, particularly if there is recurrent or increasing conjunctival melanosis.

Assessment of treatment

Indicators of the success of treatment include: local tumor control, ocular comfort, cosmetic deformity, and visual acuity¹⁵⁵.

Introduction

Ocular surface squamous neoplasia (OSSN) is a spectrum of malignancies of the conjunctiva, limbus, and cornea that includes epithelial dysplasia, carcinoma in situ, and invasive squamous cell carcinoma (SCC).^156,157

The most important causes are ultraviolet radiation¹⁵⁸, human papilloma virus (HPV), and acquired immunodeficiency syndrome (AIDS)¹⁵⁹.

Timely diagnosis and treatment of SCC can prevent the rare intraocular or orbital extension and the very rare metastatic spread of this neoplasm.

Clinical features and diagnosis

OSSN lesions are usually interpalpebral and mostly at the limbus, although they may be found in or extend to any part of the conjunctiva and cornea. Corneal involvement is usually secondary. OSSN may appear gelatinous, papilliform, or leukoplakic. It may be nodular, especially when invasive, or diffuse, mimicking chronic conjunctivitis^156,157. OSSN may be pigmented. Visual acuity is not affected unless the tumor involves central cornea. In most cases the history is of several months.

Clinically, it may be difficult to distinguish between conjunctival epithelial dysplasia, carcinoma in situ (Fig. 69.35), invasive SCC (Fig. 69.36), pinguecula, pterygium, and squamous papilloma. The definitive diagnosis is histological.

Fig. 69.35 Right eye with conjunctival carcinoma in situ involving the temporal bulbar conjunctiva, the limbus, and the superotemporal cornea.

Fig. 69.36 Left eye with a large keratinized mass of invasive carcinoma involving the lower bulbar conjunctiva, limbus, and cornea.

Preoperative diagnostic cytology is useful when planning surgery, helping to avoid excessive excision in benign lesions and prevent incomplete excision of malignant tumors. Exfoliative cytology and impression cytology are popular but only sample superficial conjunctiva, so that invasion cannot be assessed¹⁶⁰.

Only histopathologic evaluation of the excised lesion allows differentiation between the three lesions within the spectrum of OSSN^156,157. It is important to distinguish non-invasive dysplastic epithelial lesions and carcinoma in situ from invasive SCC, which breaches the basement membrane and invades the subepithelial tissues. Most conjunctival SCC are well differentiated. However, there are three aggressive types of invasive conjunctival SCC: spindle cell squamous carcinoma, mucoepidermoid carcinoma, and adenoid squamous cell carcinoma.

Treatment

The goal of treatment of OSSN is the total eradication of all disease. Most OSSN lesions can be excised with clear margins. However, incisional biopsy is performed for extensive OSSN lesions when planning surgical excision and/or adjuvant treatment such as cryotherapy, brachytherapy, or topical chemotherapy.

Preoperative assessment

A detailed examination of the entire ocular surface is essential. This should be done using the slit lamp and must include the upper and lower fornices and palpebral conjunctiva. The findings should be photographed and drawn in detail. Fluorescein and Rose Bengal stains can assist diagnosis, highlighting the papillary or granular surface of the OSSN and delineating the lesion’s borders. Scleral invasion is suspected if the affected conjunctiva cannot be moved with a cotton bud. Ultrasound biomicroscopy can sometimes demonstrate the depth of invasion. Preauricular and submandibular nodes should be palpated. In advanced tumors, systemic assessment should be performed. The role of sentinel lymph node biopsy is uncertain.

Anesthesia

With most patients, adequate anesthesia is achieved with drops and a subconjunctival injection of 1% lidocaine with or without epinephrine, which elevates the conjunctiva with the lesion, facilitating excision. In patients with extensive disease, retrobulbar anesthesia with or without sedation can be used. General anesthesia is required for children and uncooperative adults, or if very extensive surgery is anticipated.

Surgical techniques

Surgical success depends on adequate clearance of the lateral and deep margins. This requires safety margins of 2–3 mm, with some authors even advocating 4–5 mm¹⁶¹. It is important not to touch the affected conjunctiva and to use fresh instruments for closure, to prevent iatrogenic seeding of tumor cells to healthy tissue.

Superficial lesions can be excised with scissors; however, when the sclera is involved, it is necessary to perform a lamellar sclerectomy using a Beaver blade. Frozen sections and modified Mohs’ micrographic techniques have been used by some surgeons, but are not routine. For conjunctival tumors extending posteriorly, the appropriate rectus muscle can be hooked and isolated, to provide traction for better exposure and to avoid inadvertent muscle injury. With limited excisions, the surgical wound can be left without sutures to re-epithelialize. Large defects require suturing using 6/0 or 7/0 absorbable sutures, after undermining the surrounding conjunctiva¹⁶¹.

Corneal involvement is usually limited to the epithelium so that corneal epitheliectomy can be performed without disrupting the Bowman’s layer, which serves as a natural barrier to invasion. Absolute alcohol is applied with a cotton-tipped applicator, to facilitate removal of the epithelium in one piece and to denaturate the neoplastic cells. When the OSSN lesion invades the deeper layers of the cornea, lamellar keratectomy is performed^157,161.

When intraocular invasion occurs, local block excision with iridocyclochoroidectomy can be performed; however, this is rarely possible and most eyes with intraocular invasion of SCC require enucleation. Orbital invasion may necessitate exenteration.

Reconstruction of the ocular surface may be needed after large excisions, and the use of autologous conjunctival transplantation and autologous limbal transplants to restore corneal and limbal areas has been described. Others have used amniotic membrane transplantation for reconstruction after excision of large ocular surface neoplasia¹⁶².

Adjuvant therapy

After excision alone, recurrence of OSSN is common, with rates averaging 30%. The risk of recurrence is about 5% when the surgical margins are free, increasing to 53–69% when the surgical margins are involved^156,157. Treatment with multiple modalities has therefore been recommended.

Fraunfelder and others advocated the use of combined excision and cryotherapy using nitrous oxide and liquid nitrogen¹⁶³. The cryoprobe can be applied to the surgical margins and to the surgical bed to destroy any tumor cells and obliterate microcirculations. Such adjuvant cryotherapy decreases the recurrence rate to about 0–12.3%. Possible complications include iritis, increased or deceased intraocular pressure, inflammation, corneal edema and scarring, sector iris atrophy, ablation of the peripheral retina, ectropion, and superficial corneal vascularization.

Brachytherapy has been used for many years in treating OSSN, either as monotherapy or in combination with surgical excision. The most commonly used irradiation sources are beta emitters such as strontium-90 and ruthenium-106¹⁶⁴. Gamma irradiation has also been administered. Possible complications include post-irradiation inflammation, dry eye, cataract, conjunctival telangiectasis, scarring, symblepharon, scleral ulceration, and corneal perforation.

Since the 1990s topical chemotherapy using mitomycin C, 5-fluorouracil (5FU), and interferon alpha-2b have been used for treating intraepithelial conjunctival and corneal lesions¹⁶⁵. These agents have also been administered as adjuvant therapy, either after incomplete excision of conjunctival SCC¹⁶⁶ or preoperatively, to decrease the extent of the surgery, eliminating intraepithelial disease. The main adverse reactions to the topical chemotherapy include conjunctival hyperemia, pain, and a burning sensation, all of which are transient.

Treatment of conjunctival–corneal intraepithelial neoplasia

Conjunctival and corneal epithelial dysplasia and carcinoma in situ can be excised when the lesion is small. However, in recent years, good results have been reported with topical chemotherapy using mitomycin C 0.02% or 5FU 1% drops, or intralesional or topical recombinant interferon alpha-2b¹⁶⁵. Cryotherapy and brachytherapy are used for extensive or recurrent disease^163,164.

Postoperative care

Following surgery, the eye is treated with antibiotic and corticosteroid ointment and patched for 24 hours. Antibiotic and corticosteroid drops or ointment are administered for 1–3 weeks until re-epithelialization occurs. Histopathological assessment of the excised specimen is mandatory, to confirm the diagnosis and evaluate surgical clearance. As with other conjunctival malignancies, patients require life-long follow-up.

Postoperative complications

Complications after excision of OSSN are rare and include infection, bleeding, delayed epithelial healing, granulation tissue formation, epithelial cyst formation, conjunctival and corneal scarring, and restriction of eye movements. Complications after adjuvant treatments are mentioned above.

Assessment of treatment

The main indicators of treatment success are local tumor control, preservation of visual acuity, comfort, and cosmesis.