clinical predictors of high risk histopathology in retinoblastoma

Pediatr Blood Cancer 2012;58:356–361

Clinical Predictors of High Risk Histopathology in Retinoblastoma

Seema Kashyap, MD,1,3,7 Rachna Meel, MS,2,3,7* Neelam Pushker, MD,2,3,7 Seema Sen, MD,1,3,7

Sameer Bakhshi, MD,4,5,7 Vishnubhatla Sreenivas, PhD,6,7 Sumita Sethi, MS,2,3,7

Bhavna Chawla, MS,2,3,7 and Supriyo Ghose, MD2,3,7

INTRODUCTION

Retinoblastoma is the most common primary intraocular ma-

lignancy of childhood. Introduction of chemotherapy in treatment

of retinoblastoma has dramatically improved the ocular salvage

rates for groups A, B, and C retinoblastoma (International Clas-

sification for Retinoblastoma [1]). However, enucleation remains

the choice of treatment for eyes with group E retinoblastoma in

view of risk of distant metastasis. Enucleation is also carried out

for unilateral group D retinoblastoma, where globe salvage rate

remains dismal. Several studies have shown that the presence of

certain histopathological features in the enucleated eyes is asso-

ciated with higher risk of systemic metastasis and/or local recur-

rence [2–4]. Prophylactic treatment with chemotherapy or

chemotherapy and radiotherapy, in these cases reduces the likeli-

hood of local recurrence and distant metastasis [5,6].

Previously published studies from developing countries have

shown a higher incidence of histopathological high risk factors

(HRF) in eyes enucleated for retinoblastoma [7,8]. Some clinical

features have shown to be associated with the presence of high

risk factors [3,4,9,10]. These clinical features may predict the

occurrence of HRF and therefore the need for further treatment,

especially in cases where a complete histopathology report is not

available. Herein, we report clinical and histopathology features

in eyes primarily enucleated for retinoblastoma at our center; and

evaluate the clinical features at the time of enucleation for possi-

ble association with the occurrence of any one HRF, concurrent

multiple HRF, and each individual HRF, respectively.

METHODS

We retrospectively analyzed all cases of retinoblastoma that

were primarily enucleated at our center between May 2004 and

June 2009. Institutional Review Board (IRB) approval was

obtained for this study. Those cases who had received chemother-

apy and/or radiotherapy preceding enucleation were excluded

from the study.

Clinical Data

Medical records of these cases were reviewed and demograph-

ic data including age at presentation, sex, and laterality were

recorded. Clinical data that was noted consisted of duration of

symptoms/lag period (time between first symptom and com-

mencement of treatment); first symptom and clinical features at

presentation such as glaucoma (intraocular pressure (IOP)

>21 mm), presence of neovascularization of iris (NVI), buphthal-

mos, hyphema, pseudohypopyon, cataract, staphyloma (thinning

and ectasia of sclera), phthisis bulbi, and orbital cellulitis.

Histopathology Data

Histopathology slides were reviewed in all cases. Tumor dif-

ferentiation (well-differentiated tumor—more than 50% rosettes

seen; poorly differentiated tumor—less than 50% rosettes seen)

(Supplemental Fig. 1A,B) and the presence of necrosis was noted;

further, amount of necrosis was graded on a scale of 0–2 (0—no

necrosis; 1—necrosis involving 50% of tumor or less; 2—massive

necrosis that is necrosis involving more than 50% of tumor). The

Background. Previous studies show that clinical features at pre-sentation, in retinoblastoma patients, like glaucoma and neovascu-larization of iris are associated with a higher incidence of high riskhistopathology findings (HRF) in enucleated eyes. Herein, we ana-lyze association between clinical features at time of enucleationand occurrence of HRF including invasion of anterior chamber,iris, ciliary body, choroid (massive), sclera, extrascleral tissue, opticnerve beyond lamina cribrosa, and optic nerve cut end, in a largeseries of eyes enucleated for retinoblastoma. Procedure. We retro-spectively studied demographic, clinical, and histopathology find-ings in all retinoblastoma patients who underwent primaryenucleation at our center, over a 5 years duration. Statistical analy-sis was done to find any association between clinical features atpresentation and the presence of HRF. Results. Three hundredtwenty-six eyes were studied. Median age of presentation was 2

years. Glaucoma was the most common clinical finding at presen-tation apart from leucocoria. Out of 326 enucleated eyes, 28 (8.6%)had extrascleral and/or optic nerve transection invasion. Amongremaining 298 eyes, with completely resected tumor, 115 (38.6%)had massive choroidal invasion, 54 (17%) had retrolaminar opticnerve invasion, and 24 (7%), 29 (9%), and 23(7%) had anteriorchamber, iris, and ciliary body invasion, respectively. Age morethan 2 years, lag period more than 3 months, hyphema, pseudohy-popyon, staphyloma, and orbital cellulitis were associated withoccurrence of three or more HRF on univariate analysis. Conclu-sions. Clinical variables including older age, longer lag period,hyphema, pseudohypopyon, staphyloma, and orbital cellulitiswere strongly associated with occurrence of HRF in this study.Pediatr Blood Cancer 2012;58:356–361.� 2011 Wiley Periodicals, Inc.

Key words: clinical predictors; high risk histopathology; retinoblastoma

Additional Supporting Information may be found in the online version

of this article.

1Ocular Pathology Services; 2Oculoplastics & Orbit Services;3Dr. Rajendra Prasad Centre for Ophthalmic Sciences; 4Department

of Medical Oncology; 5Dr. B.R. Ambedkar International Rotary

Cancer Hospital; 6Department of Biostatistics; 7All India Institute

of Medical Sciences, New Delhi, India

Conflict of interest: Nothing to declare.

*Correspondence to: Dr. Rachna Meel, MS, Senior Research Associ-

ate, Oculoplastic and Oncology Services, Dr. Rajendra Prasad Centre

for Ophthalmic Sciences, All India Institute of Medical Sciences,

New Delhi 110029, India. E-mail: [email protected]

Received 7 January 2011; Accepted 20 May 2011

� 2011 Wiley Periodicals, Inc.DOI 10.1002/pbc.23239Published online 30 June 2011 in Wiley Online Library(wileyonlinelibrary.com).

slides were assessed for the presence of HRF that merit adjuvant

treatment, that is, invasion of anterior chamber, iris, ciliary body,

choroid (massive) (Supplemental Fig. 1C), sclera, extrascleral

tissue, optic nerve beyond lamina cribrosa (Supplemental Fig.

1D), and optic nerve cut end. Additionally, extrascleral and optic

nerve cut end involvement was classified as microscopic residual

disease. Focal and massive choroidal invasion was defined as

per the consensus meeting of the International Retinoblastoma

Staging Working Group [11]. Prelaminar optic nerve invasion

and focal choroidal invasion were also noted but were not consid-

ered as histopathologic HRF in our study. At our center, all

cases with the presence of one or more of the following histo-

pathologic high risk factors: invasion of anterior chamber, iris,

ciliary body, choroid (massive), sclera, and optic nerve beyond

lamina cribrosa are treated with six cycles of prophylactic

chemotherapy consisting of carboplatin: 560 mg/m2 on day 1,

etoposide: 150 mg/m2 on days 1 and 2, and vincristine:

1.5 mg/m2 on day 1 of each cycle; while microscopic residual

disease is treated with 12 cycles of adjuvant chemotherapy and

radiotherapy.

Statistical Analysis

Age at presentation (more than 2 years), laterality, duration of

symptoms (more than 3 months), clinical features at presentation,

degree of tumor necrosis, and tumor differentiation (well differ-

entiated vs. poorly differentiated) were analyzed to determine if

they could predict the occurrence of microscopic residual disease

or histopathological HRF that require further treatment. Chi-

square test was used and odds ratio along with 95% confidence

interval (CI) were calculated for each characteristic. Binary logis-

tic regression was used to identify independent clinical predictors

(multivariate analysis) of HRF. Further eyes with at least one high

risk factor, more than two and more than three high risk factors,

respectively, were compared with eyes with no high risk factors to

evaluate features that could predict multiple high risk factors.

A P-value of less than 0.05 was considered to be statistically

significant. All analysis was implemented on SPSS.

RESULTS

Basic Demographics and Clinical Features

Three hundred twenty-six eyes were enucleated for retinoblas-

toma during the study period. The median age of presentation was

2 years (mean: 2.73 years, range 0.8–23 years). There were 215

(66%) male and 111 (34%) female patients. One hundred thirteen

cases (35%) were bilateral and 213 (65%) were unilateral. The

median age at presentation for unilateral retinoblastoma was 2.5

years (mean: 3.15 years) while that for bilateral retinoblastoma

was 1.5 years (mean: 1.87 years). The first symptom noted by the

parents was white reflex in 258/326 (79%) cases, squint in 39/326

(12%), decreased vision in 25/326 (7.7%), and pain in 13/326

(4%) cases in decreasing order of frequency.

The median duration from the first symptom till the time of

presentation to our center (lag period) was 2.25 months (mean:

4.93 months; range: 0.25–65 months). At the time of presentation

at our center the clinical evaluation revealed glaucoma and NVI to

be the most common clinical findings apart from leucocoria

(Table I).

Histopathology Features

Histopathology details were available for all 326 enucleated

globes. The tumor was poorly differentiated in 252/326 (77.3%)

cases and showed massive necrosis in 117/326 (35.9%) cases

(Table I). A well-differentiated tumor was observed in 51/159

(32.1%) children less than 2 years as compared to 16/160

(10%) in those more than 2 years of age (P < 0.001). Extensive

necrosis was seen in 98/252 (38.9%) poorly differentiated tumors

and in 15/67 (22.4%) well-differentiated tumors (P ¼ 0.014).

Out of 326 eyes enucleated for retinoblastoma, 298 (91.4%)

had completely resected retinoblastoma while 28 (8.6%) had mi-

croscopic residual disease. Among cases with completely resected

tumor, 115/298 (38.6%) involved the retina and vitreous alone;

83/298 (27.8%) had either focal choroidal invasion or pre-lami-

nar/laminar optic nerve invasion or both; and 100/298 (33.5%)

eyes had one or more histopathological HRF Massive choroidal

invasion was the most frequently observed histopathologic high

risk factor (Table I). Among the 28 cases with microscopic resid-

ual disease, 17 (60.7%) involved cut end of optic nerve, while 10

(35.7%) had extrascleral soft tissue invasion, and 1 (3.6%) case

had both optic nerve cut end and extrascleral soft tissue invasion.

Overall, 128/326 (39.26%) (100 cases with HRF and 28 with

microscopic residual disease) patients received further treatment

with chemotherapy or chemotherapy and radiotherapy. Out of

TABLE I. Clinical Features at Presentation and Histopathology

Details of 326 Eyes Enucleated for Retinoblastoma

n (%)

Clinical features at presentation

Hyphema 16 (5%)

Pseudohypopyon 17 (5%)

Neovascularization of iris 39 (12%)

Cataract 9 (2.8%)

Buphthalmos 29 (9%)

Staphyloma 10 (3%)

Elevated IOP 87 (27%)

Orbital cellulitis 20 (6%)

Phthisis bulbi 21 (6.4%)

Histopathology findings

Tumor differentiation

No viable tumor cells 7 (2.1%)

Well differentiated 67 (20.6%)

Poorly differentiated 252 (77.3%)

Necrosis

None 150 (46%)

Small areas (<50%) 59 (18%)

Massive (>50%) 117 (35.9%)

Invasion of anterior chamber 24 (7%)

Invasion of Iris 29 (9%)

Invasion of ciliary body 23 (7%)

Invasion of choroid

Focal 68 (21%)

Massive 71 (22%)

Invasion of sclera 28 (9%)

Invasion of optic nerve

Pre-laminar 23 (23%)

Post-laminar 54 (17%)

Invasion of optic nerve cut end 18 (5.5%)

Extrascleral soft tissue invasion 11 (3.4%)

Predictors of Pathology in Retinoblastoma 357

Pediatr Blood Cancer DOI 10.1002/pbc

TABLE

II.Predictors

forAtLeast

1,AtLeast

2,andAtLeast

3HistopathologicalHighRiskFactors

Clinical

predictor

n(326)

No.HRF

(198)

AtleastoneHRFa

Twoormore

HRFa

Threeormore

HRFa

HRFþ

(n¼

128)

P

OR

(95%CI)

HRFþ

(n¼

74)

P

OR

(95%CI)

HRFþ

(n¼

40)

P

OR

(95%CI)

Age �2

years

165

56.06

42.19

0.02

141.89

0.04

135.00

0.02

1

>2years

161

43.94

57.81

1.75(1.12–2.74)

58.11

1.77(1.03–3.04)

65.00

2.37(1.17–4.81)

Duration

�3months

196

67.18

52.00

0.01

147.95

0.01

142.50

0.004

1

>3months

124

32.82

48.00

1.90(1.20–2.99)

52.05

2.22(1.29–3.84)

57.50

2.77(1.38–5.55)

Well-differentiated

tumor

67

28.27

10.16

<0.001

14.05

<0.001

10.00

<0.001

—

Poorlydifferentiated

tumor

252

71.73

89.84

3.50(1.81–6.71)

95.95

9.32(2.82–10.89)

100.00

Non-m

assivenecrosis

209

70.71

53.91

<0.001

151.35

0.004

157.50

0.13

1

Massivenecrosis

117

29.29

46.09

2.06(1.30–3.29)

48.65

2.28(1.32–3.96)

42.50

1.78(0.89–3.58)

Hyphem

a

Absent

310

97.47

91.41

0.02

189.19

0.01

185.00

0.004

1

Present

16

2.53

8.59

3.63(1.23–10.71)

10.81

4.69(1.47–14.8)

15.00

6.81(1.97–23.58)

Pseudohypopyon

Absent

309

96.97

91.41

0.04

186.49

0.002

180.00

<0.001

1

Present

17

3.03

8.59

3.01(1.08–8.35)

13.51

5.00(1.74–14.3)

20.00

8.00(2.60–24.59)

NVI Absent

287

88.89

86.72

0.60

186.49

0.67

192.50

0.78

1

Present

39

11.11

13.28

1.22(0.62–2.41)

13.51

1.25(0.56–2.78)

7.50

0.65(0.18–2.28)

Cataract

Absent

317

98.48

95.31

0.16

194.59

0.09

195.00

0.20

1

Present

91.52

4.69

3.20(0.78–13.02)

5.41

3.71(0.81–17.01)

5.00

3.42(0.55–21.17)

Buphthalmos

Absent

297

93.43

87.50

0.08

189.19

0.31

192.50

0.74

1

Present

29

6.57

12.50

2.03(0.94–4.38)

10.81

1.72(0.68–4.34)

7.50

1.15(0.31–4.25)

Staphyloma

Absent

316

100.00

92.19

<0.001

—90.54

<0.001

—87.50

<0.001

—

Present

10

0.00

7.81

9.46

12.50

Glaucoma

Absent

239

78.79

64.84

0.01

164.86

0.03

167.50

0.15

1

Present

87

21.21

35.16

2.01(1.22–3.31)

35.14

2.01(1.12–3.62)

32.50

1.79(0.85–3.76)

Orbital

cellulitis

Absent

306

97.47

88.28

<0.001

182.43

<0.001

177.50

<0.001

1

Present

20

2.53

11.72

5.12(1.81–14.48)

17.57

8.20(2.82–24.00)

22.50

11.21(3.52–35.64)

Phthisisbulbi

Absent

305

93.94

92.97

0.82

191.89

0.59

190.00

0.32

1

Present

21

6.06

7.03

1.17(0.48–2.87)

8.11

1.37(0.49–3.79)

10.00

1.72(0.53–6.64)

NVI,neovascularization;HRF,histopathological

highrisk

factor;CI,confidence

interval.aAscompared

witheyes

withnohighrisk

factors.

358 Kashyap et al.


TABLE III. Predictors of Individual Histopathological High Risk Factors (Univariate Analysis)

Clinical predictor

Anterior chamber invasion Iris invasion Ciliary body invasion

Massive choroidal

invasion

No

(302)

Yes

(24) P

OR

(95%CI)

No

(297)

Yes

(29) P

OR

(95%CI)

No

(303)

Yes

(23) P

OR

(95%CI)

No

(255)

Yes

(71) P

OR

(95%CI)

Age

�2 years 50.7 50.0 0.99 1 50.5 51.7 0.99 1 50.8 47.8 0.83 1 52.2 45.1 0.35 1

>2 years 49.3 50.0 1.0 (0.5–2.4) 49.5 48.3 0.9 (0.4–2.0) 49.2 52.2 1.1 (0.5–2.6) 47.8 54.9 1.3 (0.8–2.3)

Duration

� 3 mos 62.5 45.8 0.13 1 63.7 35.7 0.01 1 63.6 30.4 0.003 1 63.6 52.9 0.13 1

> 3 mos 39.5 54.2 1.9 (0.8–4.5) 36.3 64.3 3.2 (1.4–7.1) 36.4 69.6 4.0 (1.6–10.0) 36.4 47.1 1.6 (0.9–2.7)

Well diff. tumor 22.2 0.0 0.004 — 22.4 6.9 — 22.6 0.0 0.01 — 23.8 11.3 0.02 1

Poorly diff. tumor 75.5 100.0 77.6 93.1 0.06 77.4 100.0 76.2 88.7 2.5 (1.1–5.4)

Massive nec.

� 64.2 62.5 0.83 1 66.0 44.8 0.03 1 64.4 60.9 0.82 1 67.5 52.1 0.03 1

þ 35.8 37.5 1.1 (0.5–2.5) 34.0 55.2 2.4 (1.1–5.2) 35.6 39.1 1.2 (0.5–2.8) 32.5 47.9 1.9 (1.1–3.3)

Hyphema

� 96.7 75.0 <0.001 1 97.0 75.9 <0.001 1 97.0 69.6 <0.001 1 94.9 95.8 0.99 1

þ 3.3 25.0 9.7 (3.2–29.8) 3.0 24.1 10.2 (3.5–29.9) 3.0 30.4 14.3 (4.7–43.3) 5.1 4.2 0.8 (0.2–2.9)

Pseudohypop

� 95.7 83.3 0.03 1 96.6 75.9 <0.001 1 96.4 73.9 <0.001 1 95.7 91.5 0.22 1

þ 4.3 16.7 4.5 (1.3–14.9) 3.4 24.1 9.1 (3.2–26.3) 3.6 26.1 9.4 (3.1–28.4) 4.3 8.5 2.1 (0.7–5.7)

NVI

� 87.7 91.7 0.75 1 87.9 89.7 0.99 1 87.8 91.3 0.99 1 88.6 85.9 0.54 1

þ 12.3 8.3 0.7 (0.2–2.9) 12.1 10.3 0.8 (0.2–2.9) 12.2 8.7 0.7 (0.2–3.0) 11.4 14.1 1.3 (0.6–2.8)

Cataract

� 97.7 91.7 0.14 1 97.0 100.0 0.99 — 97.0 100.0 0.99 — 98.8 91.5 0.004 1

þ 2.3 8.3 3.8 (0.8–19.6) 3.0 0.0 3.0 0.0 1.2 8.5 7.8 (1.9–31.8)

Buphthalmos

� 90.4 100.0 0.15 — 90.2 100.0 0.09 — 91.1 91.3 0.99 1 93.3 83.1 0.02 1

þ 9.6 0.0 9.8 0.0 8.9 8.7 0.9 (0.2–4.4) 6.7 16.9 2.8 (1.3–6.3)

Staphyloma

� 97.7 87.5 0.03 1 97.3 93.1 0.22 1 97.4 91.3 0.15 1 98.4 91.5 0.01 1

þ 2.3 12.5 6.0 (1.5–24.9) 2.7 6.9 2.7 (0.5–13.2) 2.6 8.7 3.5 (0.7–17.6) 1.6 8.5 5.8 (1.6–21.1)

Glaucoma

� 75.2 50.0 0.01 1 75.1 55.2 0.03 1 74.6 56.5 0.08 1 73.7 71.8 0.76 1

þ 24.8 50.0 3.0 (1.3–7.0) 24.9 44.8 2.5 (1.1–5.3) 25.4 43.5 2.3 (0.9–5.4) 26.3 28.2 1.1 (0.6–1.9)

Orbital cellulitis

� 94.7 83.3 0.05 1 96.6 65.5 <0.001 1 95.7 69.6 <0.001 1 95.3 88.7 0.05 1

þ 5.3 16.7 3.6 (1.1–11.7) 3.4 34.5 15.1 (5.6–40.7) 4.3 30.4 9.8 (3.4–27.8) 4.7 11.3 2.6 (1.0–6.6)

Phthisis bulbi

� 93.7 91.7 0.66 1 93.6 93.1 0.99 1 93.7 91.3 0.65 1 93.7 93.0 0.79 1

þ 6.3 8.3 1.4 (0.3–6.2) 6.4 6.9 1.1 (0.2–4.9) 6.3 8.7 1.4 (0.3–6.5) 6.3 7.0 1.1 (0.4–3.2)

Clinical predictor

Scleral invasion Post-laminar ON invasion ON cut end invasion Extrascleral invasion

No

(298)

Yes

(28) P

OR

(95%CI)

No

(272)

Yes

(54) P

OR

(95%CI)

No

(308)

Yes

(18) P

OR

(95%CI)

No

(315)

Yes

(11) P

OR

(95%CI)

Age

�2 years 50.3 53.6 0.84 1 54.0 33.3 0.01 1 52.6 16.7 0.003 1 50.5 54.5 0.99 1

>2 years 49.7 46.4 0.9 (0.4–1.9) 46.0 66.7 2.4 (1.3–4.3) 47.4 83.3 5.6 (1.6–19.6) 49.5 45.5 0.8 (0.3–2.8)

Duration

�3 mos 62.3 50.0 0.23 1 64.6 44.0 0.01 1 60.9 66.7 0.80 1 62.0 36.4 0.12 1

>3 mos 37.7 50.0 1.7 (0.8–3.6) 35.4 56.0 2.3 (1.3–4.2) 39.1 33.3 0.8 (0.3–2.1) 38.0 63.6 2.9 (0.8–10.0)

Well-diff. tumor 22.7 3.6 0.01 1 23.4 9.3 0.02 1 22.3 0.0 0.02 — 21.8 0.0 0.13 —

Poorly diff. tumor 77.3 96.4 7.9 (1.1–59.4) 76.6 90.7 2.9 (1.1–7.8) 77.7 100.0 78.2 100.0

Massive nec.

� 63.8 67.9 0.84 1 65.1 59.3 0.44 1 64.9 50.0 0.21 1 63.5 81.8 0.34 1

þ 36.2 32.1 0.8 (0.4–1.9) 34.9 40.7 1.3 (0.7–2.3) 35.1 50.0 1.9 (0.7–4.8) 36.5 18.2 0.4 (0.1–1.8)

Hyphema

� 95.0 96.4 0.99 1 95.6 92.6 0.32 1 95.5 88.9 0.22 1 94.9 100.0 0.99 —

þ 5.0 3.6 0.7 (0.1–5.5) 4.4 7.4 1.7 (0.5–5.6) 4.5 11.1 2.6 (0.6–12.6) 5.1 0.0

Pseudohypopyon

� 95.3 89.3 0.17 1 94.9 94.4 0.99 1 95.1 88.9 0.24 1 94.9 90.9 0.45 1

þ 4.7 10.7 2.4 (0.7–9.0) 5.1 5.6 1.1 (0.3–3.9) 4.9 11.1 2.4 (0.5–11.6) 5.1 5.9 1.9 (0.2–15.5)

NVI

� 87.6 92.9 0.55 1 88.6 85.2 0.50 1 88.0 88.9 0.99 1 88.3 81.8 0.63 1

þ 12.4 7.1 0.5 (0.1–2.4) 11.4 14.8 1.4 (0.6–3.1) 12.0 11.1 0.9 (0.2–4.1) 11.7 18.2 1.7 (0.4–8.0)

Cataract

� 97.0 100.0 0.99 — 97.1 98.1 0.99 1 97.7 88.9 0.08 1 97.1 100.0 0.99 —

þ 3.0 0.0 2.9 1.9 0.6 (0.1–5.1) 2.3 11.1 5.4 (1.0–27.9) 2.9 0.0

(Continued)



these 128 cases, 74 (58%) had 2 or more and 40 (31%) had 3 or

more HRF.

Correlation of Tumor Differentiation andNecrosis With HRF

On a univariate analysis, poorly differentiated tumor was as-

sociated with several histopathological HRF; however, on multi-

variate analysis it was associated with massive choroidal invasion

alone (Supplemental Table I). A poorly differentiated tumor had a

two and a half times higher risk of massive choroidal invasion

compared to a well-differentiated tumor (P ¼ 0.038). Similarly,

massive tumor necrosis was also associated with massive choroi-

dal invasion on multivariate analysis (P ¼ 0.015) (Supplemental

Table I). Poor differentiation of tumor was associated with simul-

taneous occurrence of three or more HRF (P < 0.001) while

massive necrosis was associated with the presence of two or

more HRF (P ¼ 0.004) (Table II).

Correlation of Clinical Features With HRF

The P-value, odds ratio, and 95%CI for various clinical pre-

dictors found to be significant on univariate analysis are shown in

Table III. Unilateral retinoblastoma was associated with a two

times higher risk of post-laminar optic nerve invasion as com-

pared to bilateral retinoblastoma (P ¼ 0.018).

Clinical features that emerged as independent variables for

predicting various HRF (on multivariate analysis) are shown in

Table IV. Older age at presentation, lag time greater than 3

months, and glaucoma were associated with post-laminar optic

nerve invasion; all three variables were associated with a two

times greater likelihood of post-laminar optic nerve invasion.

Independent variables associated with massive choroidal invasion

included cataract, staphyloma, and glaucoma (Table IV).

Age more than 2 years at presentation, duration of symptoms

longer than 3 months, hyphema, pseudohypopyon, staphyloma,

and orbital cellulitis were significant for predicting the presence

of three or more HRF (P < 0.05) (Table II).

DISCUSSION

Most studies reported in literature have evaluated the inci-

dence of various histopathological HRF in eyes enucleated for

retinoblastoma. Few authors have analyzed whether some clinical

features at presentation could predict high risk pathology and

found some statistically significant predictors like glaucoma and

NVI [3,4,9,10]. At our center, retinoblastoma patients often pres-

ent with an inadequate pathology report after undergoing enucle-

ation elsewhere and may not have any slides for review.

Knowledge regarding clinical predictors for high risk pathology

would especially be useful in such a situation for deciding the

need for adjuvant therapy. We carried out a retrospective review

of 326 consecutively, primarily enucleated retinoblastoma eyes

and analyzed a number of demographic and clinical features at

presentation for possible association with the presence of high

risk pathology eligible for adjuvant therapy.

The incidence of various histopathological HRF in current

study was similar to previously published studies from India

[7,10]. A delay in presentation is a possible cause for the higher

incidence compared to that reported from Europe and North

America [2–4,7]. The mean age of diagnosis in western literature

is reported as 18 months; in contrast Indian studies have reported

a mean age of 23–34 months [7,10,12,13]. In the current study the

median age at diagnosis was 24 months.

Massive necrosis was found in 117/326 (35.9%) eyes. Exten-

sive necrosis of the tumor and intraocular structures has previous-

ly shown to be associated with increased risk retrolaminar optic

nerve and choroidal invasion [14]. In the current study, tumors

with massive necrosis had a two times higher risk for occurrence

of at least two high risk histopathologic features as compared to

tumors with none or lesser degree of necrosis. Specifically, mas-

sive necrosis was predictive of massive choroidal invasion on

multivariate analysis.

In an earlier study, published in literature, raised IOP and NVI

was reported to be predictive of choroidal invasion, while raised

IOPs, exophytic growth pattern, and tumor thickness more than

15 mm were able to predict optic nerve invasion [3,4]. In another

study, a significant association was reported between elevated IOP

and high risk histopathology in 182 enucleated eyes. No associa-

tion was reported between high risk histopathology and inflam-

matory eye which included eyes with hyphema, orbital cellulitis,

and infiltrative retinoblastoma [9]. A study from India reported

age >24 months and NVI to be statistically significant predictors

of high risk histopathology [10].

TABLE III. (Continued)

Clinical predictor

Scleral invasion Post-laminar ON invasion ON cut end invasion Extrascleral invasion

No

(298)

Yes

(28) P

OR

(95%CI)

No

(272)

Yes

(54) P

OR

(95%CI)

No

(308)

Yes

(18) P

OR

(95%CI)

No

(315)

Yes

(11) P

OR

(95%CI)

Buphthalmos

� 91.9 82.1 0.09 1 92.3 85.2 0.11 1 90.6 100.0 0.39 — 91.7 72.7 0.06 1

þ 8.1 17.9 2.5 (0.9–7.1) 7.7 14.8 2.1 (0.9–4.9) 9.4 0.0 8.3 27.3 4.2 (1.0–16.7)

Staphyloma

� 97.7 89.3 0.05 1 97.4 94.4 0.22 1 97.7 83.3 0.01 1 97.1 90.9 0.29 1

þ 2.3 10.7 4.9 (1.2–20.5) 2.6 5.6 2.2 (0.6–8.9) 2.3 16.7 8.6 (2.0–36.6) 2.9 9.1 3.4 (0.4–29.5)

Glaucoma

� 72.5 82.1 0.37 1 76.8 55.6 0.002 1 73.1 77.8 0.79 1 73.3 72.7 0.99 1

þ 27.5 17.9 0.6 (0.2–1.6) 23.2 44.4 2.7 (1.5–4.9) 26.9 22.2 0.8 (0.3–2.4) 26.7 27.3 1.0 (0.3–3.9)

Orbital cellulitis

� 95.3 78.6 0.004 1 93.4 96.3 0.55 1 94.8 77.8 0.02 1 94.0 90.9 0.51 1

þ 4.7 21.4 5.5 (1.9–15.8) 6.6 3.7 0.5 (0.1–2.4) 5.2 22.2 5.2 (1.5–17.7) 6.0 9.1 1.6 (0.2–12.8)

Phthisis bulbi

� 94.0 89.3 0.41 1 93.0 96.3 0.55 1 93.8 88.9 0.33 1 94.3 72.7 0.03 1

þ 6.0 10.7 1.9 (0.5–6.8) 7.0 3.7 0.5 (0.1–2.3) 6.2 11.1 1.9 (0.4–8.9) 5.7 27.3 6.2 (1.5–25.3)

mos, months; diff., differentiated; nec, necrosis; NVI, neovascularization of iris; þ, present; �, absent; CI, confidence interval; ON, optic nerve.

360 Kashyap et al.


In the current study, besides the already described clinical

predictors, we additionally evaluated hyphema, pseudohypopyon,

orbital cellulitis, phthisis bulbi, staphyloma, and cataract as clini-

cal predictors of high risk pathology.

In our study 30.7% patients were eligible for prophylactic

chemotherapy and 8.6% patients were candidates for adjuvant

chemotherapy and radiotherapy. Therefore a total of 39% patients

who underwent primary enucleation required post-operative

treatment.

The clinical features like age more than 2 years, lag period

more than 3 months, hyphema, pseudohypopyon, staphyloma, and

orbital cellulitis were associated with the presence of three or

more HRF and can be considered most predictive of high risk

pathology. We hypothesize that some of these may be used as

indication for neoadjuvant chemotherapy, similar to the proposal

made by the authors of a previous study for use of neoadjuvant

chemotherapy in cases with raised IOP [6].

Unilateral retinoblastoma was associated with a greater risk of

retrolaminar optic nerve invasion compared to bilateral retinoblas-

toma, on a univariate analysis. This could probably be explained

by the fact that the unilateral cases had longer lag period (median,

3 months; mean, 5.15 months) compared to bilateral cases (medi-

an, 2 months; mean, 4.5 months). Despite the fact that clinical

predictors being evaluated were present only in a small (3–27%)

percentage of retinoblastoma patients, the associations found be-

tween the clinical predictors and HRF were statistically significant.

To conclude, our study evaluated clinical predictors of high

risk histopathology in eyes enucleated for retinoblastoma. This

study may help oncologists and ophthalmologists in deciding the

need for prophylactic chemotherapy in the absence of a histopa-

thology report. Older age at presentation, longer lag time, pres-

ence of hyphema, pseudohypopyon, staphyloma, and history of

orbital cellulitis may provide a valuable indication for considering

adjuvant therapy in such cases, especially in the less developed

world.

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3. Shields CL, Shields JA, Baez KA, et al. Choroidal invasion of retinoblastoma: Metastatic potential and

clinical risk factors. Br J Ophthalmol 1993;77:544–548.

4. Shields CL, Shields JA, Baez KA, et al. Optic nerve invasion of retinoblastoma. Metastatic potential

and clinical risk factors. Cancer 1994;73:692–698.

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ma. Arch Ophthalmol 2002;120:923–931.

6. Chantada GL, Casco F, Fandino AC, et al. Outcome of patients with retinoblastoma and postlaminar

optic nerve invasion. Ophthalmology 2007;114:2083–2089.

7. Biswas J, Das D, Krishnakumar S, et al. Histopathologic analysis of 232 eyes with retinoblastoma

conducted in an Indian tertiary-care ophthalmic center. J Pediatr Ophthalmol Strabismus 2003;40:265–

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retinoblastoma from a developing country. J Pediatr Ophthalmol Strabismus 2009;46:294–299.

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TABLE

IV.ClinicalPredictors

ofIndividualHistopathologicalHighRiskFactors

(Multivariable

Analysis;

OR

and95%

CI)

ACinvasion

Iris

invasion

Ciliary

body

invasion

MassiveCh

invasion

Scleral

invasion

Post-lam

inar

ONinvasion

ONcutend

invasion

Extrascleral

invasion

Age,>2years

——

——

—2.1

(1.1–3.9)

5.9

(1.5–22.4)

—

Duration,>3months

—3.2

(1.2–8.7)

4.8

(1.5–14.8)

——

2.1

(1.1–3.8)

——

Hyphem

a9.3

(2.8–31.0)

21.4

(5.6–81.3)

29.9

(7.5–118.5)

——

——

—

Pseudohypopyon

—7.6

(1.9–29.8)

6.9

(1.7–27.9)

——

——

—

Neovascularizationofiris

——

——

——

——

Cataract

——

—7.2

(1.7–31.1)

——

——

Buphthalmos

——

—2.9

(1.3–6.7)

——

—6.3

(1.4–27.7)

Staphyloma

——

—4.1

(1.0–16.3)

4.9

(1.2–21.4)

——

—

Glaucoma

2.6

(1.1–6.5)

——

——

2.4

(1.3–4.5)

——

Orbital

cellulitis

4.5

(1.2–16.5)

26.2

(8.0–85.0)

13.9

(4.0–48.3)

—5.5

(1.9–16.0)

—7.6

(1.9–30.2)

—

Phthisisbulbi

——

——

——

—9.0

(1.9–40.8)

AC,anteriorcham

ber;Ch,choroidal;ON,opticnerve.



clinical predictors of high risk histopathology in retinoblastoma

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