Aims To correlate the clinical and histopathological findings of eyes primarily enucleated for advanced intraocular retinoblastoma.
Methods In a retrospective study, the authors identified patients primarily enucleated for advanced intraocular retinoblastoma. The authors retrieved patient demographics, clinical findings, subsequent treatments and outcomes, and reviewed the histopathology of each eye for invasion of the anterior chamber, iris, ciliary body, choroid, sclera and optic nerve, and extraocular extension. The authors used the Fisher exact, exact Jonkheere–Terpstra, exact Wilcoxon rank sum and Kruskal–Wallis statistical tests (p<0.05) to study associations between clinical and histopathological findings.
Results The authors identified 67 eyes of 67 patients (33 males) primarily enucleated for retinoblastoma between March 1997 and January 2008. Corneal diameter, intraocular pressure and Reese–Ellsworth Classification had no significant association with invasive disease. The International Classification, however, was associated with optic nerve (p=0.026), choroid (p<0.001), ciliary body (p=0.002), iris (p=0.002), anterior chamber (p=0.025) and scleral (p<0.001) invasion. Eyes classified as International Classification Group E were more likely to have invasion of these sites and have more severe optic-nerve invasion.
Conclusions Corneal diameter, intraocular pressure and Reese–Ellsworth Classification do not correlate with histopathological evidence of invasive retinoblastoma. Eyes classified as International Classification Group E are more likely to have elevated intraocular pressure, invasion of the anterior chamber, uveal tract, optic nerve and sclera. The findings warrant primary enucleation with meticulous histopathological examination of such eyes prior to any adjuvant therapy.
- Retin oblastoma
- adjuvant therapy
- International Classification
- treatment surgery
- child health (paediatrics)
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- Retin oblastoma
- adjuvant therapy
- International Classification
- treatment surgery
- child health (paediatrics)
Retinoblastoma is the most common primary intraocular malignancy of childhood.1 The treatment of retinoblastoma is individualised and generally based upon the age of the child, laterality (unilateral vs bilateral) and extent of disease. Unilateral retinoblastoma accounts for approximately 60% of the disease and is diagnosed at a mean age of 24 months. Typically, there is advanced intraocular disease at diagnosis (Reese–Ellsworth Classification Group V and International Classification Groups D or E) with limited hope of visual rehabilitation. In such cases, enucleation remains the standard of care.
Additional treatments such as adjuvant chemotherapy and external beam radiation are prescribed based on the presence of high-risk pathological features, which have been described, and debated, in the literature.2–12 Uniform consensus as to what constitutes high-risk pathology has not been reached. At our institution, we have defined high-risk pathology as any of the following features: tumour invasion of the anterior chamber, iris, ciliary body, choroid (massive), sclera and postlaminar portion of the optic nerve, as well as extraocular extension. The Children's Oncology Group has adopted similar criteria for an ongoing Phase III study for patients with and without high-risk pathological features following primary enucleation.13
Recently, some investigators have proposed neoadjuvant chemotherapy prior to enucleation based solely on clinical findings.14 15 These eyes have extensive disease with raised intraocular pressures, and may exhibit buphthalmos. Neoadjuvant therapy, however, alters histopathology and may needlessly commit a child to unnecessary treatment with its associated toxicity. Histological findings after chemotherapy include evidence of tumour regression with or without viable-appearing retinoblastoma cells, glial proliferations and retinoma-like features. Prolonged treatment and coexisting ocular morbidities (glaucoma, vitreous haemorrhage, retinal detachment and cataracts) are predictive of extraretinal extension.16 17 Thus, to better define the relationship between clinical and histopathological findings, we undertook a retrospective clinicopathological correlation of eyes primarily enucleated for advanced intraocular retinoblastoma at our institution.
After obtaining approval from the institutional review board, we retrospectively reviewed our Health Insurance Portability and Accountability Act of 1996 compliant database to identify those patients primarily enucleated for retinoblastoma between March 1997 and January 2008. The following data were retrieved from the patients' medical records: sex, age at diagnosis, laterality of disease, corneal diameter, intraocular pressure, Reese–Ellsworth Classification, International Classification, subsequent treatments and outcomes. For the purposes of our study, the clinical International Classification system was used.18
All enucleated eyes had been fixed in formalin, and submitted for routine histopathological processing with H&E stain. Calottes were removed from the globe (horizontal, vertical or oblique) in such a manner as to ensure maximum tumour volume in the pupil–optic nerve section. Calottes and pupil–optic nerve sections were submitted for processing. We reviewed the histopathology of the enucleated eyes for tumour differentiation (rosette formation or none), predominant growth pattern (endophytic, exophytic, or combined), optic-nerve invasion (none, prelaminar, laminar, and postlaminar), choroid involvement (none, focal or massive deep) ciliary-body involvement, iris involvement, anterior-chamber involvement, scleral involvement, calcification, neovascular glaucoma, exudative retinal detachment, vitreous seeds, subretinal seeds and extraocular extension. In this study, we defined invasion of the anterior chamber, iris, choroid (massive), sclera, postlaminar optic nerve and/or extraocular extension to be high-risk histopathological features. Our definition of massive choroidal involvement was in keeping with the International Retinoblastoma Staging Working Group: full-thickness replacement of the choroid by tumour with basal diameter greater than 3 mm.19 Ciliary-body involvement was defined as cohesive invasion of cells beneath the epithelium. Iris involvement was defined as a grouping of cells on the iris surface or within its stroma. Anterior-chamber involvement was defined as a cohesive grouping of cells between the cornea and anterior lens capsule not attributable to processing artefact. Sclera involvement was defined as invasion of inner scleral lamella or emissary canal. Examples of these can be seen in figure 1A–E.
Fisher exact tests were used to study associations between invasion (anterior chamber, iris, ciliary body, choroid, sclera and optic nerve) and disease classification (Reese–Ellsworth and International). Exact Jonkheere–Terpstra tests were used to study associations of invasion (anterior chamber, iris, ciliary body, choroid, sclera and optic nerve) with disease classification (variables were considered to be ordinal). Exact Wilcoxon rank sum tests or Kruskal–Wallis tests were used to examine associations between continuous variables (corneal diameter and intraocular pressure) with invasion (anterior chamber, iris, ciliary body, choroid, sclera and optic nerve) and disease classifications. Significance was determined by p<0.05, and no adjustments were made for multiple comparisons in this exploratory study.
Patients, clinical findings and histopathology
We identified 67 patients (33 males) who underwent primary enucleation for retinoblastoma between March 1997 and January 2008 (table 1). Of the 67 patients, 62 had unilateral retinoblastoma. The median age at diagnosis was 24 months (range 1.5–189.6 months). Adjuvant therapy was recommended for 17 patients (14 unilateral, three bilateral) with high-risk histopathology; however, one patient declined adjuvant therapy. For the three patients with bilateral retinoblastomas, their chemotherapy regimen was intensified due to high-risk histopathology in the enucleated eye. For the purposes of our study, intensification of the prescribed chemotherapy was considered adjuvant therapy. Prior to receiving adjuvant therapy, patients underwent enucleation, bone marrow biopsy/aspirate, lumbar puncture and bone scan. One patient with unilateral disease required external beam radiation for extraocular extension. Two patients, both with eyes in Groups Vb and E, who had been treated with adjuvant therapy, developed metastatic disease and died. The median follow-up was 39 months (range 1–129 months). No patients were lost to follow-up.
Table 2 shows the clinical findings of the 67 enucleated eyes. All eyes were classified as Reese–Ellsworth Group V, 19 Group Va and 48 Group Vb. Using the clinical International Classification, 47 eyes were classified as Group D and 20 as Group E. There was no evidence of any association between the Reese–Ellsworth and the International Classification (p=0.39). Four of the 19 Reese–Ellsworth Va eyes were group E (21%), compared with 16 of the 48 Vb eyes (33%). Corneal diameters were available for 61 eyes; the median corneal diameter was 12 mm (range 9–14 mm). Intraocular pressures were recorded for 63 eyes; the median intraocular pressure was 22 mm Hg (range 9–64 mm Hg).
Histopathological findings for the 67 eyes are shown in table 3. In brief, all tumours had some calcification, and most were poorly differentiated (n=49). The predominant growth patterns were equally distributed. Seventeen eyes had at least one high-risk histopathological feature, most notably massive choroidal invasion (n=17) and postlaminar optic-nerve invasion (n=8). One eye had extraocular extension. The majority of eyes (n=54) had histopathological evidence of an exudative retinal detachment, while nearly half (n=32) had neovascularisation of the iris.
Correlation of clinical and high-risk histopathological features
Corneal diameter and intraocular pressure with classification
Table 4 shows descriptive statistics for corneal diameter and intraocular pressure by Reese–Ellsworth and International Classifications. Eyes classified as Group E by the International Classification had a higher (p=0.002) intraocular pressure than Group D eyes (median pressures of 35 and 20 mm Hg, respectively). The mean corneal diameter for Group E eyes was slightly larger (12.04 mm) compared with Group D eyes (11.65 mm); however, median values were the same (12 mm) for both groups, and there was no evidence of a statistically significant association (p=0.085). There was no evidence that the Reese–Ellsworth Classification (Groups Va and Vb) was associated with either corneal diameter (p=0.21) or intraocular pressure (p=0.70).
Corneal diameter and intraocular pressure with histopathology
Table 5 shows descriptive statistics for corneal diameter and intraocular pressure as they related to high-risk histopathological features. No significant associations were observed. Median intraocular pressure, however, did increase (p=0.002) with extent of optic-nerve invasion (17 mm Hg for eyes with no optic-nerve involvement compared with 31 mm Hg for eyes with postlaminar invasion). Though not statistically significant (p=0.081), eyes with scleral invasion tended to have higher median intraocular pressures (29 mm Hg with vs 22 mm Hg without).
Reese–Ellsworth and International Classification with histopathology
The correlation of the Reese–Ellsworth and the International Classification with high-risk histopathological features can be seen in table 4. There was evidence that International Classification was associated with optic-nerve invasion (p=0.026) as well as choroidal (p<0.001), ciliary body (p=0.002), iris (p=0.002), anterior chamber (p=0.025) and scleral invasion (p<0.001). Eyes classified as Group E were more likely to have invasion of these sites and have more severe optic-nerve invasion; seven (35%) Group E eyes had postlaminar optic-nerve invasion compared with three (6%) Group D eyes. Of the Group E eyes, 11 (55%) had massive choroid invasion compared with six (13%) of the Group D eyes. Although invasion was more often seen in eyes classified as Reese–Ellsworth Group Vb than Group Va, differences were not statistically significant. Only invasion of the sclera approached statistical significance as 10 (21%) Group Vb eyes had scleral invasion compared with none of the Group Va eyes (p=0.052). When invasion of the choroid was categorised as none versus focal/massive, the difference was statistically significant. Sixteen (84%) of the Group Va eyes had some choroidal invasion compared with 25 (52%) of the Group Vb eyes (p=0.025).
Correlation of adjuvant treatment with Reese–Ellsworth and International Classifications
Of the 16 patients requiring adjuvant therapy, 10 had eyes classified as International Classification Group E, while six had eyes classified as Group D (p=0.005). Using the Reese–Ellsworth Classification, two patients had Group Va eyes, while 14 had Group Vb eyes (p=0.120). The Group E classification proved predictive of the need for adjuvant therapy, as 50% of patients with Group E eyes were so treated following enucleation.
We examined the histopathology of 67 eyes primarily enucleated for retinoblastoma and correlated high-risk histopathological features with clinical findings (corneal diameter, intraocular pressure, Reese–Ellsworth Classification and International Classification) in hopes of better defining the role of neoadjuvant chemotherapy prior to planned enucleation. All eyes examined had advanced intraocular disease at diagnosis and were classified as either Reese–Ellsworth Group Va or Vb and International Group D or E.
First, we studied the association of clinical findings among each other. We found no association between the Reese–Ellsworth and International Classification assigned to a given eye. This was not surprising, as the classifications are based on both different clinical findings and treatment modalities. Reese and Ellsworth based their classification on tumour(s) size, tumour(s) location, the presence of vitreous seeding and response to external beam radiation.1 Large, anterior tumours with vitreous seeding had a worse prognosis, Groups Va and Vb. The International Classification was put forth to better define the relationship between tumour(s) size, subretinal fluid, vitreous or subretinal seeding and response to chemotherapy.18 20 Eyes with diffuse vitreous or subretinal seeding are classified as Group D, while Group E is reserved for those eyes with tumours filling the vitreous cavity, neovascular glaucoma, anterior-chamber involvement, extensive necrosis, phthisis or otherwise deemed non-salvageable.
The association of corneal diameters and intraocular pressure with both the Reese–Ellsworth and International Classification was also studied. Corneal diameter was not significantly associated with either classification, even though eyes with worse groupings (Vb and E) had higher mean corneal diameters. Intraocular pressure was associated with the International Classification but not the Reese–Ellsworth Classification. Group E eyes had a significantly higher intraocular pressure than Group D eyes. This was as expected, since Group E includes those eyes with neovascular glaucoma, and Reese–Ellsworth does not make this distinction. The association between corneal diameter and intraocular pressure was not studied.
We then studied the association between clinical and histopathological findings. Corneal diameter was not associated with the presence of high-risk histopathological features. Our ability to detect significant differences may have been limited by the small range of corneal diameter (9–14 mm) and the limited number of eyes with high-risk histopathological features (n=17). We also found no association between intraocular pressure and high-risk histopathology. However, we did find a trend of higher mean intraocular pressure and greater extent of optic-nerve invasion. Eyes with postlaminar involvement had a higher intraocular pressure than those with laminar, prelaminar and no optic-nerve invasion. This is in keeping with previously published series that found higher intraocular pressures predictive of more extensive optic-nerve involvement.21
We found no association between Reese–Ellsworth Classification and the presence of high-risk histopathology for the sites examined: anterior chamber, iris, ciliary body, choroid, sclera and optic nerve. In contrast, there was a significant association between the International Classification and high-risk histopathology for all sites examined, with Group E eyes having more invasive disease than their Group D counterparts. Our findings would suggest that the clinical International Classification, in addition to predicting response to chemotherapy, also predicts the likelihood of high-risk histopathological features; 10 of the 20 Group E eyes studied had high-risk histopathology compared with seven of the 47 Group D eyes (p=0.005).
As stated previously, for the purposes of our study we used the clinical International Classification, and thus, we believe a comparison of clinical groupings and pathological findings is valid. The clinical observation of anterior-chamber invasion remains just that until confirmed by histology. Although one would expect a high degree of correlation between the two, it is not guaranteed. Furthermore, it should be emphasised that 50% of Group E eyes did not harbour high-risk histopathological features.
Based on these findings, the question arises as to whether it is reasonable to prescribe neoadjuvant chemotherapy for eyes classified as International Group E eyes. Proponents argue that such measures facilitate later enucleation in cases of buphthalmos and suspected optic-nerve invasion.14 15 However, as others and we have previously shown, the ability to reliably detect optic-nerve invasion on MRI remains in question.22–27 We acknowledge that 50% of Group E eyes in our study having high-risk histopathological features creates a strong argument for those who propose neoadjuvant therapy. We argue the opposite. First and foremost, 50% of the patients with Group E eyes did not have high-risk features that warranted adjuvant treatment. Neoadjuvant treatment would have needlessly exposed those children to the toxicities of chemotherapy. Furthermore, as neoadjuvant chemotherapy alters histopathology,20 21 the severity of invasive disease cannot be reliably assessed following enucleation. This would be expected, regardless of the means of delivery of the chemotherapeutic agents. Subsequently, patients may be under- or overtreated.
We prescribed adjuvant therapy based on the severity of disease, as did others.28–31 At our institution, patients with massive choroidal invasion (with or without postlaminar optic nerve extension not involving the surgical margin or the subarachnoid space, and with or without scleral invasion) receive six alternating cycles of carboplatin, vincristine and etoposide, with vincristine, cyclophosphamide and doxorubicin. Patients with extraocular extension, invasion of the subarachnoid space or involvement of the cut margin of the optic nerve receive four high-dose cycles of cisplatin, cyclophosphamide and etoposide.32 This criterion is similar to that of the Children's Oncology Group's ongoing Phase III study for patients with and without high-risk pathological features following primary enucleation using adjuvant vincristine, carboplatin and etoposide.13
Although we believe definitive treatment should be prescribed on histopathological findings at the time of primary enucleation, we acknowledge possible caveats for exclusion. These scenarios include when the operating surgeon does not feel they can resect the disease with primary enucleation due to gross extraocular extension or extreme buphthalmos. Such advanced presentations are less common in developed countries. Ophthalmologists in developing countries may defer to chemotherapy to facilitate later enucleation, thereby decreasing the risk of inadvertent globe perforation or rupture. However, Group E eyes amenable to primary enucleation are best managed without neoadjuvant chemotherapy, as we found that only 50% of such eyes had high-risk histopathological features.
We acknowledge our study has limitations. We limited our reported clinical findings to corneal diameter and intraocular pressure because we believe other clinical features are contained within the Reese–Ellsworth and International Classifications. For example, anterior-chamber invasion indicates a Group E eye by the International Classification and implies a Group Vb the Reese–Ellsworth Classification, as vitreous seeding would most often account for anterior-chamber involvement. Additionally, there are differing iterations of the International Classification. We limited our study to that version focussing on clinical features alone.18 Despite these limitations, we believe our study remains pertinent to the management of retinoblastoma.
In summary, corneal diameter, intraocular pressure and Reese–Ellsworth Classification did not correlate with histopathological evidence of invasive retinoblastoma. Eyes classified as International Classification Group E were more likely to have invasion of the uveal tract, optic nerve and sclera, and as such, these patients were more likely to require adjuvant therapy. However, we believe recommendations for the use of neoadjuvant chemotherapy in patients with Group E eyes must be made cautiously. Although such patients are more likely to require adjuvant therapy, not all will (50% in our study). We believe definitive treatment should still be made on the basis of histopathological findings. Our findings warrant meticulous histopathological examination of such eyes.
Presented at the Annual Meeting of the Association for Research in Vision and Ophthalmology, Fort Lauderdale, Florida, 4 May 2009
Funding For financial support, we thank Research to Prevent Blindness, New York, and the St Giles Foundation, New York.
Competing interests None.
Ethics approval Ethics approval was provided by the University of Tennessee Health Science Center and St Jude Children's Research Hospital.
Provenance and peer review Not commissioned; externally peer reviewed.
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