Uveal melanoma (UM) has a propensity for metastasis which results in high mortality.1,2 As metastases are rarely detectable at the time of diagnosis, great efforts have been directed toward accurate prognostication and identifying high-risk factors for metastasis.3-5 One can differentiate between clinical, histopathologic, and genetic prognostic factors.6 However, this chapter reveals the breadth of parameters that must be taken into account when trying to predict a patient’s prognosis.7 These include, but are not limited to, the age of the patient, tumor-specific factors, patient comorbidities, the effectiveness of local treatment, and a plethora of tumor-associated mutations and aberrations, all of which influence the risk for metastatic disease.6,8,9
Chapter Publication Title: Finger’s Essential Ophthalmic Oncology
Screening for Uveal Melanoma Metastasis
Metastasis is the leading cause of death amongst patients, diagnosed with uveal melanoma (UM).1-3 Depending on, the AJCC cT category and method of detection, overall, 1.9% (cT1–cT4) and up to 20% of select cT4 patients, have demonstrable metastatic disease at the time of ocular, diagnosis.4,5 However, even after local treatment, a, tumor-size-based risk of metastasis (mean 50%, range, 10%–90%) exists within 10 years (Fig. 27-1).4,6-8 This is, attributed to the slow growth of previously seeded metastatic, tumor cells, which are undetectable to all existing, screening methods. It is widely accepted that subclinical, metastases remain occult for years until they grow, to a certain size to become radiologically detectable.9,10, Therefore, multiple research studies have focused on, extending life for patients with metastatic UM utilizing, early detection as to allow time for palliative and sometimes, curative treatment.2,9,11, The hunt for metastatic UM starts at initial diagnostic, staging. Large multicenter international studies have, revealed that clinical characteristics (e.g., ciliary body, origin, presence of extrascleral extension, greater tumor, thickness, and largest basal diameter) are associated with, a greater risk for metastases at initial presentation.2,4-6,9, The most common metastatic sites at presentation are, the liver (91%), lung (16%), bone (9%), brain (6%), skin, (4%), and others (5%).4,5,7,12 In that multiorgan disease has, been identified in over 80% of patients with metastatic, disease, this data supports multiorgan screening (Figs., 27-2 and 27-3).4,5,7,9,12 In addition, multiple centers have, reported that UM patients are at risk for second nonocular, primary cancers, suggesting a genetic predisposition, to cancer (Fig. 27-2)., Genetic studies support mutations in BAP1, GNAQ,, GNA11, LZTS1 (8p22), DDEF1 (8q24.21), PTP4A3, (8q24.3), TCEB1 (8q21.11), EIF1AX, and SF3B1 (see, Abbreviations section) as predisposing factors for UM, metastasis (see Chapter 26).2,13 Structurally, monosomy, 3, 1p loss, 1q gain, 6q loss, 6p gain, 8p loss, and 8q gain, are common chromosomal abnormalities in UM.14-19, The data suggests that both AJCC cT-category, genetic, information, and the patient’s health status may be selectively, employed to modify the intensity or periodicity, of post-treatment systemic surveillance (Mind map, 27-1).4,6,9,14,18-22, However, to date, no consensus guidelines have been, established for methods of diagnosis, surveillance, or, treatment for metastatic UM. In 1985, the COMS methods, for metastatic surveillance included a combination of, physical examination for hepatomegaly, enlarged lymph, nodes, and subcutaneous nodules, as well as ancillary, chest X-rays (CXR) and liver function tests (LFT). These, methods were specific but not sensitive, thus typically, diagnosing only late-stage disease.20,21, In the modern era, a shift toward radiographic systemic, screening has allowed metastatic screening to, be more sensitive and specific for early asymptomatic, metastasis.5,23 Today, we rely more heavily on PET/CT,, abdominal CT or MRI, CXR, or abdominal-hepatic, ultrasound (USG).4,5,23-26 Of these radiographic methods,, only whole-body, PET/CT offers radiographic screening, that can reveal both hepatic and extrahepatic UM, metastasis.4,5 PET/CT has also been found to reveal second, nonocular primary cancers and help differentiate, melanoma from uveal metastasis in this population.5,25,27, Clearly, hematologic surveys now play a less prominent, role. In general, current options for surveillance of metastatic, UM include physical examination, hematologic, screening, and radiographic imaging (Table 27-1).
Treatment of Choroidal Melanoma
Uveal melanoma (UM) management is based on tumor, characteristics, prognostic factors, local availability of, treatment modalities, and patient preference.1 A detailed, discussion between the physician and the patient helps, navigate the complex shared decision-making process, (see Chapter 7). Herein, we discuss UM treatment, options (Mind map 28-1).
Melanocytoma of the Uvea and Optic Nerve
Melanocytomas (magnocellular nevi) are deeply pigmented, melanocytic nevi. They can occur in the eye,, central nervous system (CNS), and rarely in the skin., Melanocytomas of the CNS occur in the meninges and, spinal cord, and may be rarely associated with intraocular, melanocytomas.1 Ocular melanocytomas have been, reported to arise in the iris, ciliary body, choroid, optic, disc, sclera, and orbit.1-4, Rarely symptomatic, isolated cases of painful melanocytoma, involving the ciliary body and iris root are likely, associated with secondary pigment-dispersion glaucoma.5,6, Local growth and large lesions cause symptoms and vision, loss. Though there are no reported cases of systemic metastasis,, malignant transformation has been documented.7, Enucleated eye specimens have shown malignant transformation, of the magnocellular nevus with mitoses,, neovascularization, and exudative retinal detachment.
Vascular Tumors of the Retina, Uvea, and Optic Disc
Vascular neoplasms of the retina, optic disc, and choroid, are benign tumors that can be either congenital or, acquired (Table 30-1). Many have significant systemic, associations (e.g., neuro-oculo-cutaneous syndromes), that require multidisciplinary management. Vascular, neoplasia can be occult or present with mass- or, exudation-related vision loss, visual field defects,, metamorphopsia, and retinal detachment. Their variable, presentations underscore the importance of early, screening and prompt management, particularly in symptomatic, patients. There are various treatment modalities,, the choice of which can be challenging. In this chapter, we cover the most common vascular tumors of the eye.
Tumors of the Retinal Pigment Epithelium
Retinal pigment epithelial tumors are both congenital, and acquired. The most common are created by laser,, cryotherapy, infection, inflammation, trauma, neovascularization,, and long-standing SRF. However, there exist, other forms, such as congenital hypertrophy of the RPE, (CHRPE), acquired hamartomas, as well as adenomas, and adenocarcinoma (Mind map 31-1). It is important, for the eye cancer specialist to be familiar with retinal, pigment epithelial tumors, as they need to be differentiated, from choroidal melanoma.1, CHRPE, or “bear tracks”, are typically discovered in children, and young adults as multifocal, flat, inactive, and, grouped pigmented fundus lesions. They are associated, with familial adenomatous polyposis (FAP), suggesting, their treatment must be coordinated with a gastroenterologist, (see Chapter 10).2,3 Hamartomas of the RPE can, be subdivided into simple acquired hypertrophic or idiopathic, RPE hamartomas, to more complex combined, hamartomas of the retina and RPE, and unilateral RPE, dysgenesis.4,5, Retinal pigment epithelial dysplasias include idiopathic, RPE hyperplasia, adenoma, and adenocarcinoma, and, are described later in this chapter. These 3 entities are, clinically and histopathologically challenging to distinguish, and likely represent stages along a continuous, spectrum (Mind map 31-1).6
Scleral Toxicity and Repair
The sclera is the outermost coat of the eyeball and provides structural support and protection for intraocular structures. In contrast to the other coats, the sclera is hypovascular, hypocellular, and composed of dense con-nective tissue. Histologically, it consists of interwoven collagen fibrils and a dense extracellular matrix. Scleral rigidity is imparted by glycation-induced cross-linking of collagen fibrils.1 Despite a low metabolic activity, the sclera undergoes remodeling throughout life. For example, fibroblastic activity and increased scleral thickness have been reported in response to thermal stimuli.2 Scleral metabolism plays an integral role in emmetropization by precisely regulating the growth of the extracellular matrix, suggesting that the sclera is metabolically active.3 Although sparsely populated, scleral fibroblasts can be activated to proliferate after injury, pathology, or infection.4
Treatment of benign and malignant intraocular (e.g., uveal, retinal, neural) tumors as well as extraocular (e.g., ocular surface and orbital) often require episcleral or trans-scleral modalities. Therefore, scleral toxicity can be an adverse effect, manifesting as scleral thinning or scleral melt. In addition, these tumors can directly invade and thus weaken the sclera in select cases. Resultant scleral thinning can lead to perforation and expulsion of intraocular contents. Early diagnosis and appropriate management can prevent the consequences of scleral toxicity.
This chapter discusses the various mechanisms of scleral toxicity, scleral complications of cancer therapy, indications, and techniques of scleral repair.
Diagnosis of Retinoblastoma
RB is a retinal developmental tumor and the most frequent, intraocular malignancy in chidlren.1,2 Though, others may have done so before, Dr. James Wardrop is, often credited for the first RB enucleations with curative, intent. However, only later did enucleation of early-stage, RB become the standard of care.3 Along with progress in, pathology and the advent of ophthalmoscopy, Virchow, and subsequently Flexner and Wintersteiner described, the tumor’s retinal origin and histopathologic characteristics., 4 However, it wasn’t until 1926 that the consensus, term “retinoblastoma” was accepted based on its cytological, origin from retinoblasts.5, The scientific advances and increased RB awareness in, the last few decades have resulted in early detection,, diagnosis, and protocol-based treatment. This, in turn,, improved RB patient survival and globe salvage, often, with the preservation of useful vision.6-8 However, there, exists a disparity in RB outcomes globally.9 In lower-resource, nations, birth rates and RB incidence are higher,, and it is made worse by a lack of access to RB care.10, Therefore, it is imperative to focus on raising awareness,, subspecialty eye cancer training, and thereby employment, of effective treatment strategies for children in, low- and middle-resource countries (see Chapter 9).8,11, In this chapter, we will discuss the epidemiology, clinical, presentation, and socioeconomic aspects of RB.
Overview of Ophthalmic Radiation Therapy
Radiation therapy is widely used for the treatment of intraocular and orbital tumors as well as inflammatory ocular diseases.1-3 Both implant brachytherapy and EBRT techniques are widely employed. For example, linear accelerator (LINAC)-based EBRT is widely used to treat metastatic uveal, orbital, and sinus tumors as it involves directing an external radiation beam source to the eye, eyelids, sinuses, and orbit. Should one or both eyes need be irradiated, LINAC-based EBRT can be delivered using an anterior unilateral approach as seen in Figure 1, or as 2 apposing, bilateral confrontational fields.4 In contrast, most patients with uveal melanoma are commonly treated with ophthalmic plaque brachytherapy. Here, disc-shaped radioactive devices are affixed to the sclera beneath the tumor volume within the eye (Fig. 17-2).
Orbital disease is most commonly treated with LINAC-derived EBRT, and less frequently with proton beam, stereotactic radiosurgery (SRS) and Gamma Knife®, and intensity-modulated radiation therapy (IMRT).2 Radiation can be used alone, after surgery, and with chemotherapy. In contrast, orbital brachytherapy involves surgical placement of radiation sources next to a tumor or within a targeted orbital volume. Typically considered the most conformal form of radiotherapy, brachytherapy relatively increases the radiation dose within the targeted volume while decreasing exposure to most normal tissues.
At The New York Eye Cancer Center, orbital high-dose rate brachytherapy is used to treat the resected tumor bed followed by an overlay of lower-dose EBRT to the entire orbit (Fig. 17-3).5-7 Called “brachy-boost”, this technique increases the dose to a targeted portion of the orbit.
This chapter explores the unique challenges associated with irradiation of the eye, lids, and orbit. It includes basic radiobiology, doses, indications, and results of treatment. We discuss the tolerances of normal ocular and orbital tissues. Herein, we review the literature to offer a unique perspective of the world’s experience with ocular and orbital radiation therapy.
Ocular and orbital anatomy, as well as tissue radiosensitivity, provide unique challenges for radiation-based patient care. By definition, the eye globe is bounded by the sclera and cornea, within which there exist tissues that contain melanocytes, retinal, and epithelial cells, amongst others. Each gives rise to unique tumors with different radiosensitivities. Most orbital tumors occur between the eyeball and bony orbital walls, within which there exist even more varieties of progenitor cells and their related tumors. Orbital tumors may also extend either into or from the eye, orbit orbital bone, brain, and sinuses. As a result, radiation delivery systems (teletherapy or brachytherapy)—each with unique characteristics—are carefully selected to deliver tailored dose distributions within the eye and orbit. To better understand the differences between these radiation modalities, this chapter reviews their inherent differences and why each is typically selected.
While any radiation modality can sterilize a cancer, the location and intensity of side effects or normal tissue tolerances typically govern the physician’s choice of method. However, individual tissue tolerances and
thus the incidence of radiation side effects are variable. For example, the sclera, cornea, bones, ocular muscles, optic nerve, and orbital fat can tolerate relatively high doses, whereas the lens, eyelashes, retina, and lacrimal system are more radiosensitive.2 Therefore, side effects of ocular and orbital irradiation commonly include dry eye, eyelash loss, cataracts, neovascular glaucoma, radiation retinopathy (see Chapter 22), and optic neuropathy as opposed to osteonecrosis, strabismus, or enophthalmos.1,2 Depending on the tissue and its function, each ophthalmic side effect results in either cosmetic or functional morbidities. In practice, modality selection and treatment plans are typically created to avoid the retina, lacrimal system, and natural lens.2,8-10 In addition, there exists an oncogenic risk associated with ionizing radiation as most commonly seen in children.11-16
It is important to note that the incidence of side effects is proportional to the volume of irradiated tissue. Therefore, any technique that reduces the irradiated volume, conforms to the tumor, and reduces organ dose will be beneficial. Despite the risks of side effects, radiation therapy has become an essential tool used by eye cancer specialists to provide local control of benign and malignant ocular and orbital diseases. The clinical benefits of improving survival and preserving vision have clearly outweighed the radiation risks. Herein, we review how radiotherapy has played an integral role in the treatment of benign and malignant ocular tumors.
Treatment of Retinoblastoma
The aims of RB treatment in order of priority are to save, life, the eye, and vision. Early detection, prompt treatment,, and advanced treatment modalities have improved, survival leading to increased interest in globe salvage., All patients should be initially staged using the 8th edition, AJCC TNMH staging of RB as shown in Table 33-1.1, Many centers use the International Intraocular RB Classification, (IIRC) in addition to the AJCC.2 Staging can help, determine the type of treatment required and has been, shown to accurately predict both mortality from metastatic, disease and globe salvage rates.3,4 Table 33-1 includes, a column showing how the IIRC classification compares, to AJCC staging, as many studies discussed in this chapter, use the older, less robust classification. In contrast to IIRC, and other RB classification systems, the 8th edition AJCC, RB staging system is the only comprehensive classification, that addresses intraocular, orbital, and metastatic RB,, predicts metastatic death and local treatment outcomes,, accounts for sporadic and germline RB, and has been periodically, updated with new medical evidence.3,4, Treatment modalities have evolved from external radiation, in the 1960s, to systemic chemotherapy with sequentially, aggressive local treatments (SALT) in the 1990s.5 The, last decade has witnessed a growing interest in therapies, where treatment is delivered through regional arteries or, directly into the globe. In high resource countries, where, patients present early and more treatment options are readily, available, there exists a 3%–5% risk of metastasis-related, mortality.6-8 In contrast, children with RB from middle- and, lower-resource countries have a 10.3-fold and 9.3 to 10-fold, higher risk of metastasis-related mortality, respectively.9