Ординатура / Офтальмология / Английские материалы / Tumors of the Eye and Ocular Adnexa_Char_2001

260 TUMORS OF THE EYE AND OCULAR ADNEXA

Figure 12–15. Axial computed tomography demonstrating intraocular opacification without calcification in biopsy-proven toxocariasis.

and midline intracranial tumors (Figure 12–16). With modern spiral/helical CT units, most children can be rapidly evaluated without anesthesia.43

Ultrasonography is useful as a noninvasive diagnostic test that can be performed in the office. For retinoblastoma, the A-scan mode reveals highly reflective internal echoes and orbital shadowing due

to calcium (Figure 12–17). B-scan also shows highly reflective internal signals and orbital shadowing (Figure 12–18). In addition B-scan reveals the topology of the lesion and is helpful in identifying simulating lesions such as PHPV, in which the presence of a retrolental plaque, persistent hyaloidal structures, and absence of a retinal tumor could be diagnostic. Ultrasonography is not as sensitive as CT for detecting calcium or for evaluating the optic nerve, and its utility is highly dependent on the examiner’s skill.

Magnetic resonance imaging (MRI) is not as sensitive as CT for detecting calcium in the initial diagnosis of retinoblastoma. However, MRI is superior for evaluating optic nerve invasion and midline intracranial tumors.

Fluorescein angiography is rarely needed in the evaluation of patients with suspected retinoblastoma. However, this modality may occasionally be useful in ruling out simulating lesions. For example, the characteristic retinal telangiectatic changes of Coats’ disease are unambiguously demonstrated with this modality.44

Intraocular fine-needle aspiration biopsy (FNAB) for cytologic examination is avoided, whenever possible, in suspected retinoblastomas, due to concern about extraocular tumor spread.45 However, intraocular FNAB may rarely be necessary in a difficult diagnostic situation in which all noninvasive approaches have failed to achieve the diagnosis (Figure 12–19).46 To minimize the risk of extraocular spread, such biopsies are usually performed through peripheral clear cornea and should be performed by an experienced ocular oncologist.

SYSTEMIC SCREENING

Systemic evaluation for metastatic disease and for second primary cancers is an important component in the overall management of patients with retinoblastoma.

Metastatic Disease

The most common sites of extraocular spread from retinoblastoma include the central nervous system, orbit, bone marrow, and viscera (especially the liver and kidney).47 Early detection of metastatic spread is critical in order to institute prompt therapy. However, since the incidence of extraocular spread is low in the developed countries (due to early diagnosis and treatment), metastatic testing is not routinely performed in most centers in the United States.48,49 The presence of clinical or pathologic risk factors for metastasis should prompt an appropriate work-up. If optic nerve invasion is suspected on ophthalmologic examination or imaging studies or if neurologic signs are found on physical examination, lumbar puncture and MRI are indicated.50 In addition, bone marrow biopsy and bone scan may be indicated when extensive choroidal invasion is present.51

Second Primary Tumors

With modern diagnostic and therapeutic capabilities, survival for retinoblastoma patients is over 90 percent in the developed countries.3 Therefore, second primary tumors are now the most common cause of mortality in germline retinoblastoma patients.52 The germline Rb gene mutation in these patients predisposes them to cancers throughout life, including midline intracranial tumors, osteosarcomas, soft tissue sarcomas, melanomas, brain tumors, and other neo- plasms.14,29,53–56 Second tumors can occur even in patients who do not receive radiotherapy, but the risk is much higher within the field of radiation.57,58 As retinoblastoma survivors live longer, the occurrence of second tumors continues to increase. One study reported a 25 percent rate of second tumors at 40 years after diagnosis.57 In general, a cancer cell emerges when multiple mutations accumulate in regulatory genes, such as Rb and p53. The distinctive spectrum of second tumors that occur in retinoblastoma survivors (generally of nonepithelial origin) may

Figure 12–18. B-scan ultrasonography in retinoblastoma showing highly reflective internal signals and marked orbital shadowing.

reflect a particular susceptibility to loss of Rb in these tumors. Since germline retinoblastoma patients already carry one Rb mutation in most or all cells of the body, they require fewer additional mutations for cancer to develop. Accumulation of these additional mutations is more likely when the patient has been treated with radiotherapy and some forms of chemotherapy that damage DNA.

The midline intracranial tumors were once called pinealoblastomas due to their proximity to this structure but are now more properly called primitive neuroectodermal tumors (PNETs). Even though they are histopathologically similar to retinoblastoma and are caused by mutations in the Rb gene, PNETs are thought to be distinct second neoplasms rather than intracranial spread from the eye tumor.59 They probably arise from a germinal layer of primitive subependymal neuroblasts and have been observed in transgenic mouse models of hereditary retinoblas-

PNETs occur in about 6 to 10 percent of

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germline retinoblastoma patients and are more common in patients with a positive family history.52,61 The presence of a PNET portends an extremely poor prognosis, and the few patients who have been successfully treated had their PNETs detected before the appearance of clinical symptoms.62 Therefore, screening for early detection is essential for patients

A

B

C

Figure 12–19. A, Child with leukocoria in which a solid intraocular tumor was not seen. B, Computed tomography failed to demonstrate intraocular calcium. C, Cytologic examination of fine-needle aspiration biopsy shows small, round, malignant cells forming rosettes, consistent with retinoblastoma.

with known or suspected germline disease. CT can detect many of these lesions, since most have calcification.63 However, MRI has certain advantages in providing higher-resolution images of intracranial structures. Therefore, many centers will initially screen both the eyes and the brain with CT at the initial evaluation, whereas subsequent screenings are performed with MRI every 6 to 12 months, until the child is around 5 years old.

Children with germline retinoblastoma continue to be predisposed to second primary cancers throughout life, and the ophthalmologist will to inform the primary-care physician of the spectrum of susceptible cancers.

GENETIC TESTING AND COUNSELING

There are several situations in which genetic testing can be helpful in retinoblastoma. First, in adults with a history of retinoblastoma, it is desirable to determine the genetic status of their children as soon as possible in order to initiate appropriate clinical surveillance and therapy. With chorionic villus sampling, the child’s DNA can be analyzed in utero. Second, in children who present with unilateral retinoblastoma and no family history, it is important to determine the germline status. These children have an age-dependent risk that they will develop new tumors in the other eye. In addition, they have a 15 percent chance of carrying a germline mutation despite unilateral involvement.

There are several approaches to genetic testing, depending on the clinical setting. In about 7 percent of retinoblastoma patients, there is a positive family history, which may allow an accurate estimation of risk by performing linkage analysis to study restriction fragment length polymorphisms around the Rb locus.64,65 More commonly, however, direct identification of the causative mutation must be performed. Due to the large size of the Rb gene, lack of mutational hot spots and heterogeneity of mutation types, a systematic screening approach is required.66,67 Cytogenetic analysis is relatively low in resolution and can only detect large chromosomal alterations at chromosome 13q14 in 7 to 8 percent of patients.68 Southern blot and other techniques for detecting abnormalities in DNA fragment size at the Rb locus are relatively rapid and

can detect re-arrangements in about 16 percent of hereditary retinoblastoma patients.69 More sophisticated molecular techniques that can detect smaller mutations have also been employed, including sin- gle-strand conformation polymorphism analysis (SSCP), heteroduplex analysis, multiplex fragment length analysis, alteration of restriction fragment length polymorphisms (RFLP), and direct sequencing.70,71 These techniques can detect small insertions and deletions, or even single base-pair changes, but they are expensive and time consuming, especially if the mutation must be found in peripheral blood leukocytes that also carry a normal Rb allele. In most retinoblastomas, the first Rb allele is inactivated by mutation, whereas the second allele is lost by mitotic nondysjunction or recombination which results in “loss of heterozygosity.”72 Thus, identifying a mutation is technically easier in tumor tissue, since no normal Rb gene is present to interfere with genetic analysis. Therefore, when an eye is enucleated in a patient with unilateral tumor, analysis of tumor tissue may reveal a mutation, and analysis of a blood sample can be performed to determine if this mutation is in the germline. Even with such a multifaceted screening approach, however, current techniques fail to identify the mutation in 17 to 20 percent of patients.70 Thus, further research is needed to develop more rapid, inexpensive, and clinically useful genetic testing strategies.66 Several centers offering clinical genetic testing for retinoblastoma can be contacted through the website www.genetests.com.

Genetic counseling requires an understanding of the autosomal-dominant inheritance and the implications for the patient, parents, siblings, and offspring.73 The penetrance (i.e., the percentage of individuals with an inherited mutant Rb gene mutation who develop clinical manifestations of the disease) is normally about 85 to 90 percent. Each offspring of a germline retinoblastoma survivor has a 40 to 45 percent chance of developing retinoblastoma. If there is no family history and the germline status is unknown, the parents of a single child with retinoblastoma have a 1 to 6 percent chance that future children will develop the disease. If the parents then have a second affected child, one of the parents must then have a germline mutation, and all future children have a 40 to 45 percent risk. A patient with unilateral retinoblas-

toma has a 15 percent risk of a germline mutation, so their chance of having an affected child is about 7 percent. When there is a positive family history, normal siblings of an affected patient have a 1 to 6 percent chance of transmitting the disease to their children, since the parent could be a gene carrier.

The genetic counselor must also be familiar with the concept of low penetrance. In retinoblastoma, the penetrance is normally very high, but in a few families, the penetrance may be as low as 30 to 50 percent. Thus, low penetrance should be suspected when more than one individual in a family is affected but there is not a clear autosomal-dominant pattern. The molecular basis for most cases of low penetrance has been elucidated.74 In some families, there is a mutation in the promoter region of the Rb gene which causes a reduced amount of the Rb protein to be produced, whereas in other families a mutation within the coding sequence of the Rb gene results in a partial loss of Rb function.75,76 Many of these mutations have been identified and can be detected by genetic testing.

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22.Harbour JW, Luo RX, Dei Sante A, et al. Cdk phosphorylation triggers sequential intramolecular interactions that progressively block Rb functions as cells move through G1. Cell 1999;98:859–69.

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30.Moll AC, Imhof SM, Bouter LM, Tan KE. Second primary tumors in patients with retinoblastoma. A review of the literature. Ophthalmic Genet 1994;18: 27–34.

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33.Allderdice PW, Davis JG, Miller OJ, et al. The 13qdeletion syndrome. Am J Hum Genet 1969;21: 499–512.

34.Abramson DH, Gamell LS, Ellsworth RM, et al. Unilateral retinoblastoma: new intraocular tumours after treatment. Br J Ophthalmol 1994;78:698–701.

35.Abramson DH, Gombos DS. The topography of bilateral retinoblastoma lesions. Retina 1996;16:232–9.

36.Morgan G. Diffuse infiltrating retinoblastoma. Br J Ophthalmol 1997;55:600–6.

37.Nicholson DH, Norton EWD. Diffuse infiltrating retinoblastoma. Trans Am Ophthalmol Soc 1980; 78:265–89.

38.Gallie BL, Ellsworth RM, Abramson DH, Phillips RA. Retinoma: spontaneous regression of retinoblastoma or benign manifestation of the mutation? Br J Cancer 1982;45:513–21.

39.Margo C, Hidayat A, Kopelman J. Retinocytoma: a benign variant of retinoblastoma. Arch Ophthalmol 1983;101:1519–31.

40.Felgberg NT, Shields JA, Federman JL. Antibody to Toxocara canis in the aqueous humor. Arch Ophthalmol 1981;99:1563–4.

41.Shields JA. Ocular toxocariasis: a review. Surv Ophthalmol 1984;28:361–81.

42.Char DH, Hedges TRD, Norman D. Retinoblastoma. CT diagnosis. Ophthalmology 1984;91:1347–50.

43.O’Brien JM, Char DH, Tucker N, et al. Efficacy of unanesthetized spiral computed tomography scanning in initial evaluation of childhood leukocoria. Ophthalmology 1995;102:1345–50.

44.Ohnishi Y, Yamana Y, Minei M. Application of fluorescein angiography in retinoblastoma. Am J Ophthalmol 1982;93:578–88.

45.Karcioglu ZA, Gordon RA, Karcioglu GL. Tumor seeding in ocular fine needle aspiration biopsy. Ophthalmology 1985;92:1763–7.

46.Char DH, Miller TR. Fine needle biopsy in retinoblastoma. Am J Ophthalmol 1984;97:686–90.

47.MacKay CJ, Abramson DH, Ellsworth RM. Metastatic patterns of retinoblastoma. Arch Ophthalmol 1984; 102:391–6.

48.Mohney BG, Robertson DM. Ancillary testing for metastasis in patients with newly diagnosed retinoblastoma. Am J Ophthalmol 1994;118:707–11.

49.Pratt CB, Meyer D, Chenaille P, Crom DB. The use of bone marrow aspirations and lumbar punctures at the time of diagnosis of retinoblastoma. J Clin Oncol 1989;7:140–3.

50.Moscinski LC, Pendergrass TW, Weiss A, et al. Recommendations for the use of routine bone marrow aspiration and lumbar punctures in the follow-up of patients with retinoblastoma. J Pediatr Hematol Oncol 1996;18:130–4.

51.Karcioglu ZA, Al-Mefser SA, Abboud E, et al. Workup for metastatic retinoblastoma. A review of 261 patients. Ophthalmology 1997;104:307–12.

52.Moll AC, Imhof SM, Bouter LM, et al. Second primary tumors in patients with hereditary retinoblastoma: a register-based follow-up study, 1945-1994. Int J Cancer 1996;67:515–9.

53.Albert DM, McGhee CN, Seddon JM, Weichselbaum RR. Development of additional primary tumors after 62 years in the first patient with retinoblastoma cured by radiation therapy. Am J Ophthalmol 1984;97:189–96.

54.Font RL, Jurco SD, Brechner RJ. Postradiation leiomyosarcoma of the orbit complicating bilateral retinoblastoma. Arch Ophthalmol 1983;101:1557–61.

55.Helton KJ, Fletcher BD, Kun LE, et al. Bone tumors other than osteosarcoma after retinoblastoma. Cancer 1993;71:2847–53.

56.Nuutinen J, Karja J, Sainio P. Epithelial second malignant tumours in retinoblastoma survivors. A review and report of a case. Acta Ophthalmol (Copenh) 1982;60:133–40.

57.Eng C, Li FP, Abramson DH, et al. Mortality from second tumors among long-term survivors of retinoblastoma. J Natl Cancer Inst 1993;85:1121–8.

58.Roarty JD, McLean IW, Zimmerman LE. Incidence of second neoplasms in patients with bilateral retinoblastoma. Ophthalmology 1988;95:1583–7.

59.Onadim Z, Woolford AJ, Kingston JE, Hungerford JL. The RB1 gene mutation in a child with ectopic intracranial retinoblastoma. Br J Cancer 1997;76: 1405–9.

60.Marcus DM, Lasudry JG, Carpenter JL, et al. Trilateral tumors in four different lines of transgenic mice expressing SV40 T-antigen. Invest Ophthalmol Vis Sci 1996;37:392–6.

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come: a decade of experience. Int J Radiat Oncol Biol Phys 1994;29:729–33.

62.Paulino AC. Trilateral retinoblastoma: is the location of the intracranial tumor important? Cancer 1999;86: 135–41.

63.Bagley LJ, Hurst RW, Zimmerman RA, et al. Imaging in the trilateral retinoblastoma syndrome. Neuroradiology 1996;38:166–70.

64.Cavenee WK, Murphree AL, Shull MM, et al. Prediction of familial predisposition to retinoblastoma. N Engl J Med 1986;314:1201–7.

65.Wiggs J, Nordenskjold M, Yandell D, et al. Prediction of the risk of hereditary retinoblastoma, using DNA polymorphisms within the retinoblastoma gene. N Engl J Med 1988;318:151–7.

66.Harbour JW. Overview of RB gene mutations in patients with retinoblastoma. Implications for clinical genetic screening. Ophthalmology 1998;105:1442–7.

67.Lohmann DR, Brandt B, Oehlschlager U, et al. Molecular analysis and predictive testing in retinoblastoma. Ophthalmic Genet 1995;16:135–42.

68.Bunin GR, Emanuel BS, Meadows AT. Frequency of 13q abnormalities among 203 patients with retinoblastoma. J Natl Cancer Inst 1989;81:370–4.

69.Kloss K, Wahrisch P, Greger V. Characterization of deletions at the retinoblastoma locus in patients with bilateral retinoblastoma. Am J Med Genet 1991;39:196–200.

70.Lohmann DR, Brandt B, Hopping W, et al. Distinct RB1 gene mutations with low penetrance in hereditary retinoblastoma. Hum Genet 1994;94:349–54.

71.Mastrangelo D, Squitieri N, Bruni S, et al. The polymerase chain reaction (PCR) in the routine genetic characterization of retinoblastoma: a tool for the clinical laboratory. Surv Ophthalmol 1997;41:331–40.

72.Cavenee WK, Dryja TP, Phillips RA, et al. Expression of recessive alleles by chromosomal mechanisms in retinoblastoma. Nature 1983;305:779–84.

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74.Otterson GA, Chen WD, Coxon AB, et al. Incomplete penetrance of familial retinoblastoma linked to germ-line mutations that result in partial loss of RB function. Proc Natl Acad Sci USA 1997;94: 12036–40.

75.Cowell JK, Bia B, Akoulitchev A. A novel mutation in the promotor region in a family with a mild form of retinoblastoma indicates the location of a new regulatory domain for the RB1 gene. Oncogene 1996; 12:431–6.

76.Lohmann DR, Brandt B, Hopping W, et al. Distinct RB1 gene mutations with low penetrance in hereditary retinoblastoma. Hum Genet 1994;94:349–54.

J. WILLIAM HARBOUR, MD

Prior to the 20th century, mortality from retinoblastoma approached 100 percent because of delayed diagnosis and ineffective treatments. However, there is now a 95 percent survival rate due to earlier diagnosis and improved treatments. For years, the mainstay of treatment was enucleation. External beam radiotherapy was introduced early in the 20th century. More recently, there has been a resurgent interest in chemotherapy as a means of avoiding some complications of radiation. With a growing number of treatment options, it is increasingly important for the ocular oncologist taking care of retinoblastoma patients to have a thorough knowledge of the risks, benefits, and indications for each modality.

TREATMENT CONSIDERATIONS

The evaluation and treatment of patients with retinoblastoma should be carried out in specialized centers with ophthalmic, pediatric, and radiation oncologists, who have considerable experience with retinoblastoma.

Previously, enucleation was recommended for all unilateral tumors and the worst eye of patients with bilateral tumors. This dictum is no longer appropriate in many settings, since effective alternative therapies are available. However, enucleation is still the best option for many very large tumors. Radiation has been a mainstay of therapy for many years but should be avoided whenever other modalities can yield similar or superior results, since the long-term complications of radiation are becoming increasingly apparent. Systemic chemotherapy, combined with local therapies, has recently re-emerged as a viable treatment option that may replace radiation in many settings. However, the long-term complications of chemotherapy are still undetermined.

Age is a key consideration in treatment of these special patients. Patients with bilateral tumors present earlier than those with unilateral tumors.1 Children age < 1 year are at considerably higher risk of serious radiation complications than older children.2 Younger patients are more likely to develop new tumors in the same or other eye.3 The topographic pattern of tumor development is also age dependent, with macular tumors occurring earlier and peripheral tumors occurring later.4

Laterality is another important treatment consideration. Patients with unilateral tumors and no family history usually have at presentation a large tumor that often precludes ocular salvage. In this setting, one must weigh the modest benefit of salvaging an eye with extremely limited vision against the risks of treatment complications and failure. In a minority of cases (20 to 30%), a sporadic unilateral tumor may be amenable to ocular salvage therapy. While the same principles apply to bilateral tumors, one may be more compelled to attempt ocular salvage when vision is threatened in both eyes.

Location, size, and number of tumors are additional treatment considerations. When the fovea or papillomacular bundle are involved, one may wish to avoid locally destructive therapies, whereas these therapies can be highly effective for small equatorial or anterior tumors. When tumors occupy over 50 percent of the retina and intraocular volume, ocular salvage becomes less likely.

TREATMENT MODALITIES

Enucleation

Until recently, the vast majority of unilaterally affected eyes were removed.5,6 Enucleation is still

the treatment of choice in many cases but has become less common with earlier diagnosis and better alternative therapies.7 In general, enucleation is indicated for large tumors that occupy > 50 percent of the intraocular volume (Figure 13–1). Additional indications include anterior segment tumor extension, neovascular glaucoma, and failure of conservative therapies, usually with extensive, diffuse, vitreous seeding.

The technique for enucleation in children with retinoblastoma is different from that for adults and should be performed by experienced surgeons. Children have smaller orbits than adults do, and standard adult instruments cannot be used. Adult enucleation scissors are often too large to fit in the posterior orbit, so instead, we use the smaller, minimally curved Stevens scissors. We also avoid the use of an optic nerve snare, since this technique creates crush artifact in the optic nerve stump, which is to be avoided, since histopathologic evaluation of the optic nerve is imperative for assessing tumor invasion. It is also imperative to obtain a long segment of the optic nerve, as leaving residual tumor in the optic nerve stump is a poor prognostic indicator.8,9 Our goal is a 10-mm segment because tumor invasion beyond this point is likely to have seeded the subarachnoid space. If an insufficient stump is obtained, an additional segment can be taken by using Soule retractors to visualize the orbital contents, grasping the nerve stump and cutting an additional segment (Figure 13–2). Use of anterior traction on the globe is critical for obtaining a long nerve segment, but we do not recommend placing traction sutures through the sclera, since this could lead to ocular penetration and extraocular tumor

Figure 13–1. Large unilateral exophytic retinoblastoma which is too large for vision-sparing therapy and is best treated by enucleation.

Figure 13–2. Visualization of optic nerve stump after enucleation, using Soule retractors for exposure.

extension. Instead, we cut the horizontal rectus muscles 3 to 4 mm away from the globe to leave long stumps for grasping with hemostats, which can then be used for traction while cutting the optic nerve. Hemostasis is obtained by compression of the orbit with a small test tube. The four rectus muscle stumps are secured to a hydroxyapatite implant wrapped in donor sclera or other materials.

Complications are uncommon but can include conjunctival breakdown and extrusion of the implant. This can be avoided by careful closure of Tenon’s layer with two layers of interrupted sutures and closure of the conjunctiva with a separate running suture (see Chapter 8). Orbital cellulitis and hemorrhage can also occur but are rare. The most serious enucleation complication is globe penetration, which could result in extraocular tumor extension.

External Beam Radiotherapy

External beam radiotherapy (EBRT) was first used to treat retinoblastoma in the United States in 1903, but the widespread use of this modality awaited the work of Reese and Martin in the 1930s.10 EBRT has subsequently become a mainstay of treatment, although the long-term risks of radiation have recently dampened enthusiasm for this modality. Because of these risks, there has been a recent shift to systemic chemotherapy (see below), although the scientific basis for this change is still not firm. It is important to keep in mind that much of the available information on radiation complications is derived from patients treated 30 or more years ago using high-dose orthovoltage therapy, whereas lower doses and megavoltage tech-

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niques are now used. Thus, the estimated radiation risks of current techniques have been considerably exaggerated.11 Also, it is now clear that most radiation complications are age dependent, occurring less frequently in children treated after age 12 months.2 Therefore, EBRT will likely continue to play an important role in the treatment of retinoblastoma, but its precise indications are in evolution.

With the increased use of chemotherapy, indications for EBRT have become more limited, but there are still situations in which EBRT is superior to chemotherapy, such as when there is substantial vitreous seeding. Other indications vary from center to center but would include large bilateral tumors that have failed chemotherapy. Unilateral tumors will often have a better cosmetic result with enucleation in younger patients. In general, EBRT should be avoided when possible in children age < 12 months, in large tumors that occupy > 50 percent of the intraocular volume, and whenever other modalities are likely to provide similar tumor control.2

EBRT can be delivered by several techniques. Most American centers have had better local tumor control with a lateral port, lens-sparing technique, rather than an anterior whole-eye approach (Figure 13–3).12,13 However, the anterior retina is not adequately treated with lateral ports, so any tumors anterior to the equator need to be treated with local modalities prior to EBRT, and subsequently the

anterior retina must be monitored closely with indirect ophthalmoscopy with scleral depression. Radiation is typically delivered using a 4-MeV linear accelerator through lateral fields angled 5° posteriorly to avoid the contralateral lens. If there is a question of optic nerve involvement, the entire orbit is included in the radiation field. Daily fractions of 200 cGy are delivered to a total dose of about 45 Gy. Children are under anesthesia during the treatments.

The complications of EBRT can include lid injury, dry eye, cataract, glaucoma, uveitis, lacrimal gland damage, retinopathy, optic nerve damage, and vitreous hemorrhage, but these are not usually severe at the lower radiation doses used to treat retinoblastoma. The more concerning complications are orbital bone deformities (Figure 13–4) and second primary cancers in the field of radiation (Figure 13–5). The bone orbital deformities are especially disfiguring when treated before age 12 months but are less severe in older children. In germline patients, the risk of second primary cancers increases dramatically within the field of radiation. In one study, patients who did not receive radiation had a 6 percent rate of second tumors, while those receiving radiation had a 35 percent risk.14 Germline patients are more likely to die of a second cancer than of retinoblastoma itself. It should be re-emphasized, however, that much of our information on orbital bone deformities and second cancers is derived from children treated with older techniques. The risk of these complications is probably lower with modern lower doses, megavoltage equipment, limiting of daily fractionation to < 225 cGy, treatment planning with computed tomography (CT), and other advances.11,15 In addition, newer intensitymodulated conformal therapies should further decrease local complications.

The tumoricidal effect of radiation is largely due to destruction of the reproductive capacity of the neoplasm and subsequent induction of programmed cell death. This often occurs through activation of the p53 pathway by radiation-induced DNA damage.16 The visible changes in tumor appearance following EBRT have been well documented and have become the standard for evaluating tumor response following various therapies.17,18 Five major regression patterns have been described. Type I regression consists of white intratumoral excrescences which resemble cottage cheese (Figure 13–6). Type II is more difficult to distinguish from active tumor. It has been likened to “fish flesh” and looks like active tumor, except that there is a modest shrinkage (25 to 50%) from pretreatment size, and the tumor typically loses its pinkish color due to intratumoral capillaries (Figure 13–7). Type

III is a mixture of types I and II (Figure 13–8). Type IV is complete regression with a residual chorioretinal scar. Type 0 is complete disappearance of the tumor. There does not appear to be any correlation between regression pattern and local recurrence.19

Exudative retinal detachments usually disappear within 6 months after treatment. Persistent detachment beyond this point suggests either treatment failure or a retinal break. A rhegmatogenous detachment can be repaired once all tumors are well controlled.20,21 Exudative detachment can also be caused by heavy cryotherapy or laser treatment. A thin serous detachment overlying a regressed tumor does not necessarily indicate tumor activity. Tumor persistence or recurrence will usually be evident within 6 months of initial therapy, and it is rare to have reactivation more than a year after treat-