Treatment

A major advance in the treatment of retinoblastoma is intravitreal chemotherapy for eyes with vitreous seeds, which respond poorly to other forms of therapy [51]. This has greatly improved chances of ocular conservation in patients with advanced disease. Tumor seeding into extraocular tissues is prevented by a variety of measures, such as using fine needle to inject the drug into the eye and administering cryotherapy to the injection site on withdrawing the needle from the eye. A system for classifying vitreous seeds has been developed (i.e., dust, spheres, clouds), which helps to predict the efficacy of intra-vitreal chemotherapy [51]. There has also been progress in intra-arterial chemotherapy, with improvements in technique and the use of drugs other than melphalan, such as topotecan [52]. There is ongoing debate as to how intra-arterial and systemic therapy compare with respect to preventing pineoblastoma and metastatic disease.

Classification

There are several classification systems for retinoblastoma, the Reese-Ellsworth method having become less relevant since external beam radiotherapy was superseded by chemotherapy. The most widely used is the International Retinoblastoma Classification (IRC), which categorizes retinoblastomas according to size, extent, proximity to disc and fovea, seeding and secondary effects; however, different versions of the IRC exist [53]. The TNM staging system has recently undergone several refinements, one of which defines heritability of the disease. A limitation of current staging systems is that they classify whole eyes and not individual tumors in eyes harboring multiple lesions. There is a need for improved documentation so that classification systems can evolve in response to advances in imaging and treatment [54].

Genetic Analysis

Advances in genetic techniques makes it possible to identify RB1 mutations that were previously undetectable [55]. This improved sensitivity has enhanced the detection of mosicism. A relatively recent discovery is that some retinoblastomas develop with high levels of MYC amplification in the absence of detectable RB1, these tumors occurring unilaterally and tending to be highly aggressive, presenting at a median age of 4 months [56].

Survival

Pineoblastoma is the most common cause of death in the first decade of life in countries with high-quality care. Survival rates have improved greatly with the development of aggressive treatment protocols if started early so that patients with germline retinoblastoma now undergo screening with 6-monthly brain MRI until the age of around 5 years. In later life, mortality occurs because of osteosarcomas and other second malignant neoplasms, especially in patients who have received external beam radiotherapy, which is why this modality has been abandoned. Early results suggest that proton beam radiotherapy does not cause second malignant neoplasms, but further studies are needed [57].

There is a need for greater efforts to detect second cancers earlier. There is also a need for improved awareness of the late physical and emotional effects of retinoblastoma and its treatment so that these problems can be addressed in a timely manner.

Diagnosis

The diagnosis of choroidal metastases has become easier with optical coherence tomography, which shows the surface of these tumors to have a characteristic ‘lumpy-bumpy’ appearance (Fig. 10.4) [59]. Diagnosis has also been enhanced by improvements in tumor biopsy and immunohistochemistry. In some centers, biopsy is performed without delay, to confirm the diagnosis and to seek clues to the location of the primary tumor, if this is not already known [60]. In other centers, intraocular tumor biopsy is performed only as a last resort, if systemic investigations are uninformative.

Treatment

Previously, patients underwent immediate radiotherapy whereas now there is now a growing tendency to administer this form of treatment only if systemic therapy fails to control the ocular tumor [61].

Terminology

This terms ‘vitreoretinal lymphoma’ and ‘retinal lymphoma’ have replaced ‘primary intraocular lymphoma (PIOL)’, because intraocular lymphomas comprise both retinal lymphomas, which are aggressive and highly lethal because of CNS involvement, as well as indolent uveal lymphomas, which are associated with a very good survival probability [65]. Retinal lymphoma is becoming more common.

Investigation

Ocular assessment has improved thanks to optical coherence tomography, which demonstrates lymphoma deposits between the retinal pigment epithelium and Bruch’s membrane [66]. Another useful development is fundus autofluorescence imaging, with hyper-autofluorescence indicating active disease and hypo-autofluorescence corresponding to areas of inactive RPE atrophy (Fig. 10.5) [67]. Vitreous biopsy often fails to detect lymphoma cells, because these are so fragile, but diagnosis can still be achieved by detecting immunoglobulin heavy chain rearrangements, measuring interleukin-10 protein levels, detecting myeloid differentiation primary response 88 (MYD88) L265P mutation and measuring levels of particular microRNAs [68, 69]. It can be difficult to differentiate lymphoma from uveitis, but this task has become easier with the development of metagenomic deep sequencing, which detects any non-human DNA, also identifying the species of any infectious organism [70].

Treatment

In many centers, the standard treatment for retinal lymphoma consists of ocular radiotherapy or intra-vitreal methotrexate and/or rituximab injections [71]. Encouraging results have recently been reported with intravitreal melphalan injections, which need to be administered less frequently than methotrexate [72]. Although ocular therapy suppresses the intraocular disease, it does not prevent mortality from central nervous system disease. Some studies have concluded that systemic therapy does not prolong survival [73]; however, the author and associates have achieved encouraging ocular and systemic outcomes with systemic chemotherapy combined with maintenance therapy using immunomodulators. These include lenalidomide, which is effective only in activated B-cell (ABC) lymphoma subtype, and CC-122, which also induces regression of the germinal center B-cell lymphoma subtype [74, 75]. The author and associates have found that systemic therapy is relatively ineffective for vitreous infiltrates unless combined with ‘therapeutic vitrectomy’ [76].

Grading and Staging

As with other ocular tumors, such as uveal melanoma and retinoblastoma, the Tumor, Node, Metastasis (TNM) staging of conjunctival melanomas has been refined. One significant improvement is the incorporation of in-situ melanoma in this classification (Tis). A scoring system has been developed to grade conjunctival melanocytic intra-epithelial neoplasia (otherwise known as primary acquired melanosis [PAM] with atypia) more objectively according to the density of melanoma cells in the epithelium and the degree of cellular atypia [78]. Sentinel lymph node biopsy is reported to improve prognostication but has yet to be accepted widely [79].

Treatment

Many centers continue to treat invasive conjunctival melanoma by excision with wide margins, adjunctive cryotherapy, and amniotic membrane grafting [80]; however, the author prefers excision with narrow safety margins and wound closure by primary intention without grafting, administering adjunctive radiotherapy and, in patients with diffuse intra-epithelial disease, adjunctive mitomycin C drops [81]. The author has found that comfort and compliance are improved by prescribing this topical chemotherapy for only 1 week per month for 4 months, instead of two 14-day courses over 6 weeks, as originally recommended. Successful treatment with interferon alpha-2a has also been reported [82, 83].

BRAF mutation is found in about 40% of conjunctival melanomas, many of which are responsive to systemic treatment with a BRAF inhibitor, such as vemurafenib (Zelboraf) [84, 85]. As with cutaneous melanoma, metastases from conjunctival melanoma can respond to systemic treatment with immune checkpoint inhibitors [86, 87].

Investigation

The development of optical coherence tomography has made it easier to differentiate CISN/CCIN from other conditions; however, most surgeons continue to perform biopsy to establish the diagnosis [89].

Treatment

Invasive conjunctival carcinomas are treated by excision, with adjunctive cryotherapy or radiotherapy. In many centers, the preferred treatment for primary or secondary in-situ disease is topical interferon, administered 4 times per day continuously for 3–6 months [90]. The author has achieved good results with 5-FU drops, administered four times daily for only 4 days a month for 4 months [91]. The 5-FU drops are less expensive than interferon and do not require refrigeration.