Pigmentation of the conjunctiva is common and may be, benign or malignant. The spectrum of conjunctival pigmented, tumors is broad, ranging from benign acquired, melanosis and conjunctival nevi to more sinister variants, such as melanoma in situ and invasive conjunctival, melanoma.1,2, Conjunctival melanomas can originate spontaneously, from a pre-existing nevus or from primary acquired, melanosis (PAM).33 It is important to note that the 8th, edition AJCC Cancer Staging Manual replaced the term, “primary acquired melanosis with atypia” with “melanoma, in situ.” This was because the former was easily, mistaken for being benign and the latter was consistent, with the nonocular epithelial melanoma nomenclature.1, Further, the AJCC-OOTF advises using PAM only as a, clinical description, as biopsy remains essential for its, differentiation from conjunctival melanoma in situ., Epidemiology of conjunctival melanoma suggests it, most commonly presents in one eye in middle-aged, fairskinned, individuals.3,4 While conjunctival melanoma can, occur in all races, it must be differentiated from naturally, occurring, bilateral, lifelong pigment on the conjunctiva,, termed racial or congenital melanosis.5 Conjunctival, melanomas are rare, comprising approximately 2% of, all ocular tumors and 5% of ocular melanomas.6,7 Nevertheless,, its incidence is increasing and is associated with, a considerable tumor-related risk of mortality.8, However, several pilot studies now suggest that systemic, and advanced local conjunctival melanoma may be treatable, with immunotherapy.9-11, This chapter aims to provide an in-depth understanding, of the varying presentations of pigmented conjunctival, tumors, their differentiation, and appropriate management, (Mind map 39-1). Given the reported recurrence, rates of 12% to 50% after treatment and an overall incidence, of metastasis reaching 26%, there is need for, life-long follow-up and improved treatment options.12,13
Chapter Keyword: metastasis
Approach to Diagnosis of Orbital Tumors
The orbit and ocular adnexa are susceptible to several, primary and secondary diseases affecting various tissue, types such as osseous, vascular, neural, muscular, and, glandular structures (see Chapters 44 and 45).1-3 These, include primary tumors, infections, and inflammations,, as well as secondary disease from the periorbital paranasal, sinuses, eyelids, and brain., Given the intricate anatomy of the orbit, it is no wonder, that most primary and secondary orbital diseases share, the common symptoms of proptosis, strabismus, and, optic nerve compression. Clearly, diagnosis of orbital, pathologies requires a meticulous approach, leading to, an assessment of urgency and often tissue diagnosis., A comprehensive assessment begins with a thorough, ophthalmic and systemic history, considering the chief, complaint(s), major ophthalmic symptoms, their onset,, and duration (see Chapter 3). This information, coupled, with a meticulous ophthalmic examination and, radiologic imaging, typically forms the bedrock for establishing, a presumptive diagnosis and course of medical or, surgical management.
Diagnosis and Management of Malignant Orbital Tumors
Given the confined space of the bony orbit, any neoplasm, of the orbit can present with a varying mixture of similar, signs and symptoms of globe displacement, eyelid, swelling, blepharoptosis, limitation in eye movement,, conjunctival chemosis, hyperemia, elevated intraocular, pressure, chorioretinal folds, and optic nerve compression, as well as other cranial neuropathies.1 Malignant, tumors grow rapidly, with symptoms developing over, months to weeks. Due to the rapid growth and tendency, to involve sensory nerves, pain is a more common (but, not necessary) feature of a malignant orbital tumor.2 On, imaging, malignant lesions tend to be infiltrative, not, respecting the natural boundaries of anatomic compartments, and causing bone erosion and destruction rather, than remodeling. These general rules have exceptions., Not all lesions can be classified into benign or malignant, based on clinical presentation and imaging findings;, therefore, most will require tissue biopsy.3 Treatment, is multidisciplinary, with oncology, radiation oncology,, and other specialties as needed. Staging orbital tumors, with the most recent AJCC TNM classification ensures, improved multidisciplinary communication and patient, care.4 The topics of orbital tumor classification and differential, diagnosis are covered elsewhere in this book (see, Chapters 42 and 43). In the current chapter, we focus, on the diagnosis and specific management of common, malignant orbital neoplasms.
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
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
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.
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.
Systemic Treatment of Uveal Melanoma: Insights and Emerging Strategies
Uveal melanoma (UM) is a relatively rare cancer, but is the most common primary intraocular malignancy (see Chapter 25) and comprises 5% of all melanoma diagnoses in the United States.1,2 UM arises from mel¬anocytes within the capillary-rich uveal tract, with the most frequent locations being the choroid (90%), ciliary body (6%), and iris (4%).3 Although UM occurs with an incidence of ~2,000 cases per year, it is an aggressive can¬cer.4,5 Screening with periodic, abdominal radiographic imaging, 25%–30% of patients are diagnosed with met¬astatic UM within 5 years (see Chapter 27). Exiting the eye by hematogenous spread, commonly reported met¬astatic sites include the liver (89%), lung (29%), and bone (17%).6 The latency between the treatment of the primary tumor and the emergence of metastases ranges from months to decades, underscoring the likelihood of early dissemination from the primary site and varia¬ble metastatic growth rates.7 Unfortunately, there is no standardized consensus and known effective treatment for advanced UM in the adjuvant or metastatic settings. The prognosis is poor once metastasis develops, with a median overall survival of 10.2 months.8 Long-term sur-vival is unusual except in rare patients with isolated liver metastases amenable to surgical resection. When availa¬ble and clinically appropriate, treatment within a clinical trial is recommended.
Although UM differs from cutaneous melanoma both clinically and biologically, treatment options for advanced stages have largely been adopted with much lower resultant response rates.9 Similarly, in that UM metastases are less responsive than cutaneous melanoma to both chemotherapy and immune checkpoint inhibi¬tors, several treatment modalities have been evaluated, including systemic chemotherapy, immunotherapy, and molecularly targeted agents for the MAPK pathway. As the most common initial site of metastasis is the liver, palliative management includes liver-directed thera¬pies such as bland embolization, chemoembolization, radioembolization, immunoembolization, and hepatic arterial infusion of chemotherapy. In this chapter, we review the molecular pathogenesis of UM, its progno¬sis, and advances in the management of metastatic UM (Mind map 14-1).