Chapter Publication Title: Finger’s Essential Ophthalmic Oncology

Functional Ophthalmic Oncology Anatomy

Anatomic and tumor-specific factors play dominant roles in clinical decision-making. Select examples include eyelid tumor position directing the postresection method of repair (see Chapter 37), orbital optic nerve sheath obstruction requiring slotted plaques (see Chapter 18) to completely cover juxtapapillary intraocular tumors, and the shape of the orbit affecting the orbitotomy approach. In consideration of the basic anatomy of the eyeball, the adnexa, and the orbit, this chapter highlights select salient anatomical features that affect tumor growth, metastasis (regional or distant), diagnosis, and management.

Overview of Ophthalmic Clinical Examination

The breadth of pathology within the scope of ocular oncology spans all ocular, orbital, and adnexal structures. As such, the clinical assessment of patients must be accordingly comprehensive and tailored for the detection and surveillance of neoplastic processes. While the essential modalities of standard ophthalmic examination are utilized in the practice of ocular oncology, a nuanced perspective is necessary to optimize management for this subset of patients. In this chapter, we present the systematic approach to clinical examination employed at The New York Eye Cancer Center as a basis for the assessment of patients in ophthalmic oncology practice.

Multimodality Imaging of Intraocular Tumors

Ophthalmology and ophthalmic oncology are blessed with excellent intraocular imaging modalities.1-4 Traditionally, we had slit-lamp examination, gonioscopy, and direct and indirect ophthalmoscopy (see Chapter 3). However, these techniques did not provide a recorded image and thus required both observational and recol-lection skills utilized over relatively short observational periods. Clearly, what we observe and recollect is processed to determine the diagnosis and condition of the eye. It is no wonder that ophthalmology quickly added photographic imaging to anterior and posterior segment examinations.
Photography not only provided a “snapshot” of the patient’s condition at a specific time but also allowed specialists to take more time to observe the ocular condition without the previously required cooperation of the patient. Such “snapshot” photographic images document the patient’s condition at one specific time, allowing for side-by-side comparisons with future or past images to assess change. For example, in ophthalmic oncology, we may use side-by-side imaging to monitor for tumor growth, increased SRF, or the presence of radiation side effects. Then, more complex ophthalmic imaging systems evolved. Angiographic (e.g., fluorescein [FA], indocyanine green [ICGA]) imaging is utilized to assess differences in tumor circulation, patterns of regression, and treatment-related side effects.5,6 Ultrasound imaging allows eye specialists to “see” within eyes with opaque media, evaluate mass lesions for internal reflectivity, and measure tumors prior to treatment. In addition, ultrasonography offers a method to measure intraocular neoplasms as well as reveal their internal reflectivity and interstitial extent. Three-dimensional ultrasound made a brief appearance in ophthalmology and offered interactive computerized reconstructions also like computerized radiographic imaging (e.g., MRI and CT). More recently, optical coherence tomography (OCT) with and without angiography uses laser-based imaging to create 2-D slices and 3-D reconstructions such as those previously limited to computerized radiographic imaging.7
However, multimodality imaging is what eye cancer specialists use to achieve a clinical diagnosis so accurate it is often used instead of pathology. For example, it is the low-lying, yellow tumor with scalloped edges combined with slow fluorescein uptake and internal acoustic reflectivity so high that it shadows the orbit which makes the clinical diagnosis of choroidal osteoma. Herein, we describe the use of ophthalmic imaging techniques to diagnose intraocular tumors. The process of diagnosis is dependent upon visible tumor characteristics as well as those that can only be uncovered with multiple ophthalmic imaging techniques (Mind map 4-1 and 4-2).

Minimally Invasive Ocular Tissue Biopsy

Tissue biopsy is necessary for the management of patients with ocular cancers and benign growths. It is used to determine the diagnosis, assess tumor biology, and plan treatment strategies. The goals of a biopsy are to safely obtain a sample of tissue by minimizing cosmetic and functional risk. However, tumor location and presumptive clinical diagnosis affect both approach and technique (see Chapter 6). The pathologist’s preference is to receive an ample amount of tissue, enabling a comprehensive assessment of tumor cytology, tissue architecture, and invasion into neighboring normal tissues. A larger tissue sample allows for immunopathology, electron micrography, and/or molecular/genetic studies (as needed).
However, the current trend in ocular tumor tissue biopsy techniques shows a preference for smaller incisions and less invasive surgical procedures. For instance, in numerous non-ocular surgical scenarios, the adoption of smaller incisions has resulted in reduced complications and faster recovery rates.1 This evolution has been aided by the development of small endoscopic cameras, monitors, and micro-instrumentation. Likewise, ophthalmic pathologists face the challenge of diagnosing from increasingly smaller tissue samples and cells. Herein, we explore relatively recent and less invasive methods, such as exfoliative techniques, fine-needle aspiration biopsy (FNAB), aspiration-cutter techniques (Finger’s iridectomy technique [FIT], Finger’s aspiration cutter technique [FACT]), and liquid biopsy approaches.
The process of biopsy, whether involving large, small, or microincisions, begins with the patient’s history and clinical examination. When a patient’s medical history indicates multiorgan metastatic disease, confirmation may only necessitate a small tissue sample or cell specimen. Similarly, in cases of ocular surface squamous neoplasia, an exfoliative biopsy can distinguish between normal and dysplastic cells, enabling precise topical chemotherapy. The prebiopsy examination plays a crucial role in determining the appropriate handling and transport medium, as well as the specific studies to be conducted. We highly recommend that the eye cancer specialist consult with the ophthalmic pathologist to discuss the presumed diagnosis before proceeding with the biopsy surgery.
Incisional, excisional, shave, and punch biopsies com¬monly used for eyelid and adnexal tumors are described in Chapter 6. However, in the case of eyelid tumors, the minimally invasive biopsy techniques (MIBT) discussed in this chapter have played a relatively minor role. Conversely, MIBT has found extensive use in biopsies of the cornea, conjunctiva, anterior chamber, iris, ciliary body, vitreous, retina, choroid, and orbit. These innovative techniques allow for cytologic analysis of individual cells, small clumps, or microscopic masses, along with histopathology, immunopathology, DNA, and molecular analysis.

Pathological Evaluation of Orbital and Periorbital Tumors

Space-occupying mass lesions in the orbit and peri-orbit are rather uncommon but can be a diagnostic challenge for ophthalmologists and orbital surgeons. In some patients, the combination of clinical presentation and imaging is sufficient to reach a diagnosis; however, many others require morphologic evaluation. The histo-pathologic specification can only be definite by biopsy. The etymologic origin of “biopsy” stems from the Greek words “bios,” meaning “life,” and “opsis,” meaning “sight or view,” together crudely meaning, “to view life.” Plainly, the examination of “live tissue.” Tissue acquisition can be performed via excisional, incisional, core, fine-needle aspiration (FNAB), aspiration-cutter, intraoperative biopsy with frozen-section (FS), or Mohs methods. Occasionally, sentinel node biopsy is utilized for staging purposes of certain orbital tumors.1-3
Most anterior and well-delineated orbital masses can be sampled with any approach: incisional, core, or FNAB. The terms “incisional” and “excisional” are sometimes used interchangeably, but in actuality, “incisional” biopsy refers to cutting into a lesion to sample a portion of tissue solely for the purpose of obtaining a tissue sample, while “excisional” biopsy, implies removal of the tumor and some surrounding normal tissue.1 Naturally, the excised tissue provides more material for histopathologic examination. While incisional biopsy can also obtain a sufficient quantity of tissue for lesions in the anterior orbit, incising tissue acquisition in the posterior orbit can be complex, increasing the risk of complications. In addition, posterior orbital surgery typically requires general anesthesia to facilitate a higher diagnostic yield. Lastly, aspiration is the least invasive technique, and expectedly, offers the least amount of material.4

Patient Counseling in Ocular Oncology

Patient counseling is one of the most important aspects of ocular oncology (Mind map 7-1). It starts with devel-oping a rapport with the patient and continues as an element of teaching about their medical problem. It affects future recovery, psychological stability, and follow-up compliance. Patient counseling helps patients develop realistic expectations for disease outcomes and has a lasting impact on the patient’s quality of life and perception of their care. The patient’s recollections of your counseling process will remain with them for the rest of their lives. This chapter teaches the basic concepts of patient and family counseling for ophthalmic oncology. For this purpose, we utilize the most common primary intraocular tumors: RB in children and choroidal melanoma in adults.

A Review of Intraocular and Orbital Tumor Registry Studies

“Do you speak ocular tumor?” Dr. Finger asked this question in his thought-provoking editorial for the journal Ophthalmology nearly 20 years ago.1 Since then, there have been numerous advances in diagnostic and thera-peutic modalities for eye cancers. However, this question is just as relevant as it was 2 decades ago. The extent of tumor at presentation, defined by cancer staging, is an essential factor that determines disease prognosis, guides treatment planning, helps plan and evaluate clinical trials, and aids in the exchange and comparison of information across treatment centers.1,2 At a multicenter or global level, a uniform cancer classification is critical for clearly conveying clinical experience to others without ambiguity. A standardized cancer staging system enhances communication amongst specialists involved in tumor care: eye cancer specialists, pediatric oncologists, radiologists, radiation therapists, ophthalmic pathologists, geneticists, and researchers. With this in mind, Dr. Finger led the pursuit to develop the most scientifically sound language to address eye cancers: the AJCC eye cancer staging system (Mind map 8-1).
The AJCC, in conjunction with its international counterpart, the Union for International Cancer Control (UICC), joined forces to develop a consensus staging system for cancers of the eye, lids, and orbit. Dr. Finger was selected to chair the 7th edition AJCC effort for ophthalmic oncology in 2003. His philosophy to approach this task was “what is made by the community will be used by the community” (see Chapter 1). Upon review of their research and clinical reputation, Dr. Finger rallied to bring the leading specialists in each tumor type to the discussion table and laid the foundations of the AJCC-OOTF.
The process involved the formation of expert clinical and pathology peer review. An initial group re-examined the literature for each type of eye cancer and synthesized an evidence-based medical consensus on paper. Another group of similar experts critically reviewed the staging proposal. Both teams reviewed the final draft. This process was conducted through monthly phone meetings and periodic in-person discussions over 4 years. The community’s efforts resulted in the 7th edition AJCC eye cancer staging system in 2009.3 As the AJCC staging system is periodically updated with newly available medical evidence, the 8th edition of AJCC staging was drafted with the participation of 58 specialists from 13 countries.4
Since its publication, this staging system has become universally accepted by tumor registries worldwide, prominent ophthalmology journals, and their associated societies. The widespread utilization of ophthalmic AJCC staging can be revealed by searching PubMed for the terms “AJCC” and “eye”. One of the major advantages of the AJCC TNM staging system is that it can be modified in response to newly acquired clinical and pathologic data, improved understanding of cancer biology, and other factors affecting prognosis. The evidence-based modifications are made meticulously, and the revision cycle usually spans 5–7 years. The intent is to provide ample time for implementing changes in clinical management and cancer registry operations.
Herein, we discuss the impact of AJCC staging by outlining how it has improved the abilities of eye cancer specialists and thus saved the lives of patients.

International Outreach: Improving Global Retinoblastoma Outcomes

RB is the most common primary intraocular malignancy of childhood, and > 8,000 children are diagnosed each year worldwide.1,2 In high-resource settings with infrastructure and support, the survival of children with RB can be nearly 100%.3,4 In contrast, in low- and middle-resource countries, eye cancer specialists and support are lacking, leading to survival rates approximating 10%.3-5 In that more than 80% of the children diagnosed with pediatric cancer live in low- and middle-resource countries, many more children are dying of RB than surviving.6-11 Given this disparity, it is important to identify what can be done to save the lives of RB children in low- and middle-resource countries.
That said, the World Health Organization (WHO) has identified RB as one of the most curable pediatric index cancers, stating a goal of at least 60% survival by 2030.12 This will require cooperation between ophthalmic and pediatric oncology. Governments and nongovernmental organizations will need to work towards allocating highly specific resources, education/training, and infrastructure. Thus, RB can serve as a model for other pediatric cancers by implementing effective education, training, and capacity-building initiatives that are scalable and adaptable. Many strategies are already known to be effective: multidisciplinary care teams, well-defined referral networks, resource-adapted treatment guidelines, as well as early programs to promote early detection and awareness.