9.3  Ophthalmology Consultation

and Treatment Decisions SOP

9.3.1  Objectives

Personal and family history; thorough ocular examination to exclude differential diagnoses [5]; delineate diagnostic tests; estimate the extent of disease; generate a treatment plan.

9.3.2  Applicability

Retinoblastoma consultant, team of caregivers, oncologist, retinal specialist, pediatric ophthalmologist.

9.3.3  Scope

First consultation, diagnosis, preliminary treatment planning.

Fig. 9.4  Coats’ disease presented with “yellowish” leukocoria, in contrast to the white of retinoblastoma, due to localized retinal detachment and characteristic exudates from abnormal blood vessels in the supero-temporal quadrant (not shown)

a

•Retinoblastoma is the most urgent diagnosis that is lifeand vision-threatening when children present with leukocoria (Figs. 9.1a and 9.2a), strabismus, and/or retinal lesions.

•Differential diagnoses:

−−Rubella or toxoplasmosis: suggested by maternal immunization or illness in early pregnancy.

−−Leukoma: suggested by forceps damage of the cornea at delivery.

−−Retinopathy of prematurity: suggested by prematurity, low birth weight, and oxygen usage.

−−Toxocariasis: suggested by exposure to kittens or puppies.

−−Coats’ disease (Fig. 9.4), medulloepthelioma: suggested by unusual retinal detachment or tumor-like masses.

−−Persistent hyperplastic primary vitreous (PHPV) (Fig. 9.5): suggested by small eye and retrolental white mass.

Fig. 9.5  In a newborn infant, posterior hyperplastic primary vitreous (PHPV) presented as leukocoria in association with a posterior cataract in a small eye. The retinal lesion appeared elevated covering the optic nerve and connecting with the lens through a stalk (images generously provided by Dr. Andrew Q. McCormick, British Columbia Children Hospital, Vancouver, Canada)

−−Tuberous Sclerosis (Fig. 9.6): suggested by retinoblastoma-like, but uncalcified, retinal white lesions.

9.3.5  Procedures

•Visual acuity, evaluated according to the child’s age and cooperation: Small babies or infants, by observation and description of fixation patterns (central-steady-maintained/resisting occlusion/fix-

ation and following/nystagmus); children over 3 years, by HOTV matching test or logMAR testing. Poor vision may be due to tumor macular involvement, exudative retinal detachment, central nervous system involvement by extension into optic nerve and tract, or the rare trilateral retinoblastoma and extraocular disease.

•Red reflexes, ocular movements, alignment (Hirsch­ berg/cover test), and pupillary responses: presence and characteristics may be affected by the extent of tumor.

•Preoperative B-scan ultrasound (Figs. 9.1b and 9.2b): detects calcification diagnostic of retinoblastoma.

•Head and orbit computerized tomography (CT scan): detects calcification diagnostic of retinoblastoma (Fig. 9.2c, d); avoid, if possible, in cases of

confirmed or suspected germline RB1 mutation to reduce exposure to radiation that may predispose to secondary cancers.

•Head, orbit, and spine magnetic resonance imaging (MRI): at staging, particularly, for bilateral cases with higher risk of trilateral disease; for suspected choroid, sclera, or extraocular orbital disease; tumor extension in optic nerve beyond lamina cribrosa; pineal gland enlargement or suprasellar mass (the rare trilateral retinoblastoma) (Fig. 9.7a, e); craniospinal leptomenigeal disease.

•Total body MRI: screening for suspected bone marrow or systemic disease in retinoblastoma at higher risk for metastases.

•Pediatric Oncology consultation: overall coordination and management of the child with cancer.

•Surgery consultation: concurrent placement of a central venous line at the first examination under anesthesia (EUA) if chemotherapy is anticipated.

•Neurosurgery consultation: concurrent placement of an Ommaya reservoir for intrathecal chemotherapy­ for confirmed central nervous system involvement.

Fig. 9.7  (a) Trilateral retinoblastoma with a large suprasellar and hypothalamic mass in a 2 months-old-baby girl shown on MRI [14]. She presented with poor fixation, no light perception, and roving eye movements since birth. (b, c) RetCam® images showing bilateral involvement with two tumors in each eye. The intracranial mass was biopsied prior to the diagnosis of retinoblastoma. She was treated with systemic and intrathecal chemotherapy with (d) resolution of the tumor to a small dense focus,

with recovery of fixation and visual function. (e, f) All the retinal tumors responded to systemic chemotherapy and focal laser. The tumor near the optic nerve in the left eye was treated with more laser until it was a flat scar. However, after marrow-ablative chemotherapy and autologous stem cell bone marrow rescue, disease recurred along the initial needle biopsy and the child died (images by Dr. Shuan Dai and Carmelina Trimboli)

•Social work consultation: overall psychological and logistics support of the family with a child with cancer.

•The first EUA: staging and treatment decisions:

−−Corneal diameters, intraocular pressure, and anterior segment evaluation to determine if anterior disease is present.

−−Slit lamp examination identifies corneal edema from secondary glaucoma; shallow anterior chamber from a retrolental mass; tumor cells, hypopyon, or rubeosis in severe disease; cataract.

−−Fundus examination must be done through welldilated pupils to determine the severity of diagnosis and the extent of disease. Scleral indentation is used to visualize the vitreous and the whole retina, including 360° of the ora serrata with the indirect ophthalmoscope.

−−Fundus drawings provide an overall record of the retinal tumors.

−−Wide-angle fundus photography most commonly uses the RetCam® (Clarity Medical Systems), a

standard tool worldwide to document the extent of retinoblastoma (Figs. 9.2e, 9.3b–g, 9.4–9.6, 9.7b, c, f, g, 9.8a). These images provide wide-field imaging of the retina and anterior segment, and angle; may identify small, flat tumors missed by indirect ophthalmoscopy; control of focus is useful to identify and document vitreous seeds; facilitates accurate retinal drawings; allows comparison of tumor activity between sessions during and after treatment, and between different centers.

−−RetCam® fluorescein angiography enhances effective management by intraoperative “real-time” fluorescein angiography (Fig. 9.8); provides additional information on tumor activity after focal or systemic therapy; tumor vascularity suggests residual activity and recurrences within laser scars earlier than detected by indirect ophthalmoscopy; facilitates distinction of tumor activity and nontumor ischemic retinal vascular changes.

−−Intraoperative two-dimensional B-scan ultrasound is useful to detect calcification diagnostic

Fig. 9.8  (a) Intraoperative fundus photograph of superior and parapapillary retinoblastoma scars in a patient who previously received systemic chemotherapy in addition to several sessions of focal treatment. In both the scars, areas of suspected tumor activity were identified. (b) Intravenous fluorescein angiogram demonstrated abnormal blood vessels of the active parapapillary tumor, but absence of tumor activity in the superior tumor,

suggesting­ gliosis. The patient received additional treatment for the parapapillary tumor only. (c) Fundus photograph of the same eye 2 years after additional focal and systemic chemotherapy, showing inactive scars. (d) Fluorescein angiogram confirms the absence of activity. Patient remains stable at 4 years of follow-up (images Carmelina Trimboli)

of retinoblastoma, monitor the dimensions of tumors following treatment, particularly when visualization is difficult or impossible because of media opacity.

−−Ultrasound biomicroscopy (UBM) is a useful tool in assessing anterior involvement and extension that provides information of possible tumor between the ora serrata and iris, which is impossible to assess by indirect ophthalmoscopy and RetCam®.

−−Bone marrow aspirations and/or biopsies to screen for metastatic disease include baseline prior to systemic chemotherapy to detect intrinsic bone marrow abnormality. These tests are necessary only in the presence of adverse ocular factors (anterior segment disease involving anterior chamber, iris, ciliary body, and lens, and extension beyond ora serrata), or histopathological factors (anterior segment, choroid, and sclera invasion) suggesting risk for systemic metastases.

−−Lumbar puncture (LP) for cerebrospinal fluid cytopathologic examination is indicated when

tumors obstruct the view of the optic nerve, and when there are adverse risk factors (rubeosis, glaucoma, hypopyon, anterior disease, disruption in the sclera) or histopathological risk factors suggesting a higher risk for central nervous system metastases (prelaminar or postlaminar tumor extension into the optic nerve). LP is not necessary in the absence of such adverse ocular factors.

−−Tumor biopsy is contraindicated for intraocular tumor because it would greatly increase the risk for systemic metastasis. Biopsy is indicated for suspected orbital or systemic tumor extension and for intracranial tumor extension if ocular findings and cerebrospinal fluid cytology are not conclusive.

−−Cancer Staging: The International Intraocular Retinoblastoma Classification (IIRC) (Table 9.2) scores for intraocular disease and the Tumor- Node-Metastasis (TNM) Classification scores of each child for the extent of intraand extraocular disease [8] (Table 9.3). Proper staging is key to

All tumors 3 mm (two disc diameter, DD), or smaller, in greatest dimension, confined to the retina

All tumors located farther than 3 mm from the fovea and 1.5 mm from the optic disc

£3 mm height

Farther than 1.5 mm from the fovea or optic nerve

Tumor or tumors that are discrete

Subretinal fluid, present or past, without subretinal seeding, greater than 5 mm from the tumor edge

Local subretinal seeding, present or past, less than 5 mm from the tumor Local fine vitreous seeding close to discrete tumor

Minimal tumor spread to vitreous and/or subretinal space tumor fills less than 2/3 of eye

Tumor or tumors may be massive or diffuse

Subretinal fluid, present or past, without subretinal seeding, causing total retinal detachment

Diffuse subretinal seeding, present or past, may include subretinal plaques or tumor nodules

Diffuse or massive vitreous disease may include “greasy” seeds or avascular tumor masses

(T2b) massive tumor spread to vitreous and/ or subretinal space (T3a) fills more than 2/3 of eye

an optimal treatment plan. Each eye is scored by IIRC and the T1 and T2 for the extent of intraocular disease, intended to relate to prognosis as the basis for therapeutic recommendations. The prognostic relevance of the IIRC is being evaluated in comparison to the Reese–Ellsworth Classification in an International Collaborative Survey including data on more than 2,000 eyes from more than 20 world retinoblastoma centers.

−−Invasion of the ocular coats (T3) and extraocular tumor (T4) are also scored after enucleation for pathological risk factors. Node, N0 (no nodal involvement), N1 (regional preauricular, submandibular, and/or cervical nodal involvement), N2 (distant nodal involvement) and Metastasis, M0 (no metastasis), M1 (central nervous system, bone marrow, bone, and/or other metastasis) reflect general cancer staging applied to extraocular retinoblastoma.