Iris neoplasms include nevi, melanocytomas, melanomas,, hamartomas (e.g., Lisch nodules), as well as cysts of the, iris stroma and pigment epithelium. Amelanotic tumors, are more likely vascular, epithelial, or metastatic.1,2 Most, can be distinguished by clinical examination, including, slit lamp, gonioscopic, ultrasound, optical coherence, tomography (OCT), and angiographic techniques.3, However, diagnosing small indeterminate lesions can be, difficult. They may require photographic documentation, for growth over several weeks, months, or even years as, well as for biopsy (see Chapter 5)., It is important to determine the entire anatomic extent, of the tumor, as tissue invasion and displacement can, help determine if a tumor is benign or malignant. For, example, this is particularly important for iris melanoma, extending into the ciliary body or a primary ciliary body, tumor extending into or through the iris root. For this, reason, slit-lamp imaging, gonio-photography, UBM,, and anterior segment OCT imaging as well as fluorescein, angiography (FA) help this determination. The usefulness, of CT and MRI has been described but is less helpful, in discriminating between different types of iris tumors.4, Treatments for any individual tumor depend highly on the, clinical or biopsy-proven diagnosis, size, and extent. Benign, lesions (e.g., nevi and small cysts) are typically observed, and may not require treatment. Because of their anterior, and clearly visible location, iris tumors—especially iris, melanomas—are treated when relatively small compared, to more posteriorly located uveal melanoma, yielding, more favorable prognoses. Treatment modalities typically, include surgical excision (sector iridectomy), radiation (e.g.,, charged particle, plaque brachytherapy), and enucleation.5-7
Chapter Publication Title: Finger’s Essential Ophthalmic Oncology
Diagnosis of Choroidal and Ciliary Body Melanoma
Extending from the optic disc to the pupillary margin,, the vascular uvea contains melanocytes that can transform, into what is the most common primary intraocular, malignancy in adults, uveal melanoma (UM).1-3 Further,, the uveal layer can be anterior to posteriorly divided into, iris, ciliary body, and choroidal portions. COMS examined, choroidal melanomas and found their average, presenting age to be 60 years; however, uveal melanomas, can occur as early as infancy.1,4,5, Younger patients with choroidal melanoma tend to, have a better prognosis, and it’s thought due to a better, immunological profile.1-3,6 UM incidence is nearly equally, distributed between males and females.1,7 The most common, location of the tumor is the choroid (85%–90%),, followed by the ciliary body (5%–8%) and iris (3%–, 5%).1,2 The annual age-adjusted incidence per million, population is 6.02 for non-Hispanic whites, 1.67 for Hispanics,, 0.38 for Asians, and 0.31 for blacks.8, UMs may arise de novo or from pre-existing uveal nevi., They are also more common in patients with outdoor, occupations, beneath Australia’s ozone hole, on the, sun-exposed lower half of the iris, and in arc welders., This suggests ultraviolet light exposure is a predisposing, factor. However, the etiologic risks of ultraviolet, light exposure have been disputed.9 In addition, several, geographical clusters of UM (primarily affecting, young patients) have been discovered with no identifiable, genetic or environmental factors (e.g., Huntersville,, NC, USA and Auburn, AL, USA).10, UM is not hereditary; however, there have been reports, of familial cases affecting several family members.11, Melanoma is typically a unilateral, unifocal disease, but, cases of primary bilateral or multifocal tumors have been, published.12,13 BAP1 tumor predisposition syndrome has, been associated with an increased risk of developing UM, (2.8% incidence) compared to 0.0061% in the general, population.14,15 Like most cancers, the development of, UM is likely multifactorial.
Prognostication in Uveal Melanoma
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
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.