Hematologic malignancies are generally categorized by, their cell of origin. Most commonly, leukemias arise from, early myeloid or lymphoid progenitors (blasts), whereas, lymphomas are derived from mature lymphocytes or, their progenitors. As a result, leukemias are characterized, by infiltration of the bone marrow and peripheral blood, with malignant cells, whereas lymphomas are diagnosed, from biopsies of solid lymphoid tissues., Ophthalmic manifestations of hematologic malignancies, can arise via direct and indirect mechanisms, with the, former due to infiltration of neoplastic cells and the latter, resulting from downstream hematologic alterations, (anemia, hyperviscosity, and/or thrombocytopenia)., This chapter reviews the ophthalmic manifestations of, vitreoretinal lymphoma (VRL), choroidal lymphoma, (CL), and leukemia, and discuss an approach to diagnosing, and managing each condition (Mind map 34-1).
Archives: Chapters
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).
Metastatic Cancer to the Eye, Lids, and Orbit
Though innumerable scientific articles start with “the most common intraocular malignancy is choroidal melanoma,” choroidal metastases are much more common.1 Uveal metastases are seen histologically at postmortem in up to 12.6% of patients dying from metastatic cancer.2 However, clinically observable metastatic disease has been noted in only 2%–7% of patients with dissem-inated disease.3-5 Similarly, orbital metastases have been found in up to 5% of patients with systemic malignancy.6,7 This disparity is likely due to the patients being asymptomatic, having little time to live, or a combination of both.5,8 Further, systemic treatment may render the ocular metastasis occult, leaving the patient and oncologist unaware of its existence. , However, the life expectancy for patients with metastatic disease from cancers that commonly spread to the eye has improved over time, particularly in the case of breast cancer.9,10 This longevity has resulted in increased numbers of patients needing ocular treatment to prevent vision loss and ensure their quality of life.11,12 Further, ocular metastases may be the first presentation of systemic disease. One study found that uveal metastases from lung carcinoma (47%), pancreatic cancer (37%), and lung carcinoid (33%) often preceded the systemic diagnosis; by contrast, 94% of patients with breast metastases had a history of the disease.13 Other studies have reported similar results.9,14,15 Similarly, 15% of patients with orbital metastases do not have a cancer diagnosis at presentation.7 Some ocular metastases may, albeit rarely, occur after a tumor has been in remission for years (reported up to 43 years later), which may be a diagnostic shock.16-18 The ocular presentation of metastatic disease is also changing. For instance, because the eye is a relatively immunologically privileged site, vitreous metastases of cutaneous melanoma (Fig. 35-1) are increasingly common in patients on checkpoint inhibitors and who are otherwise in remission.19,20 Prior to this therapy, vitreous involvement was seen only in 18% of eye, lid, or orbital cutaneous melanoma metastases.21 , Further, there has been an evolution of local therapies. The goal of local treatment is to retain vision. Thus, observation for response to systemic therapy may work but risks vision loss in cases where the reattachment of the macula is delayed. Treatments to decrease exudative retinal detachments include laser (e.g., PDT), intravitreal anti-VEGF injections, and steroid implants.22 Larger tumors may be treated with EBRT and smaller extramacular tumors with plaque brachytherapy. However, both forms of radiation carry dose-dependent risks of long-term side effects in longer-lived patients.23 Finger has used anti-VEGF drugs as a bridge therapy to more definitive EBRT irradiation.
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.
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.
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
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
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.