896 Journal of the College of Physicians and Surgeons Pakistan 2016, Vol. 26 (11): 896-899 INTRODUCTION The priorities in managing a child with retinoblastoma are saving the patient’s life, globe salvation and preservation of vision. 1,2 Tumor regression patterns in retinoblastoma seen after conservative management include type 0 (no remnant), type l (calcified remnant), type ll (non-calcified remnant), type lll (partially calcified remnant), and type lV (flat scar). These regression patterns following external beam radiotherapy were initially described by Dunphy. 3 A better prediction of treatment success is seen in International Classification of Retinoblastoma (ICRB) staging system which is applicable to current therapies. 4 According to ICRB group A, tumors include small intra- retinal tumors away from foveola and disc, all tumors 3 mm or smaller in greatest dimension, confined to the retina and all tumors that are located farther than 3 mm from the foveola and 1.5 mm from the optic disc. Included in group B, are all remaining discrete tumors confined to the retina, all other tumors confined to the retina not in group A, and tumor-associated sub-retinal fluid less than 3 mm from the tumor with no sub-retinal seedings. Group C tumors include discrete local disease with minimal sub-retinal or vitreous seeding, tumor(s) that are discrete, sub-retinal fluid, present or past, without seeding involving up to one-fourth of the retina, local fine vitreous seeding may be present close to discrete tumor and local sub-retinal seeding less than 3 mm (2 DD) from the tumor. Group D tumors are diffuse disease with significant vitreous or sub-retinal seeding, tumor(s) may be massive or diffuse, sub-retinal fluid present or past without seeding, involving up to total retinal detachment. Diffuse or massive vitreous disease may include “greasy” seeds or avascular tumor masses, diffuse sub-retinal seeding may include sub-retinal plaques or tumor nodules. Group E tumors involve presence of any one or more of the following poor prognosis features: Tumor touching the lens, tumor anterior to anterior vitreous face involving ciliary body or anterior segment, diffuse infiltrating retinoblastoma, neovascular glaucoma, opaque media from hemorrhage, tumor necrosis with aseptic orbital cellulitis and phthisis bulbi. 4,5 The rationale of the present study was to observe the different types of tumor regression patterns in different ICRB groups of retinoblastoma after completion of laser treatment and systemic chemotherapy. The aim of the study was to document the most common pattern of tumor regression in pediatric eyes with retinoblastoma after completion of treatment. ORIGINAL ARTICLE Tumor Regression Patterns in Retinoblastoma Saemah Nuzhat Zafar, Sorath Noorani Siddiqui and Naima Zaheer ABSTRACT Objective: To observe the types of tumor regression after treatment, and identify the common pattern of regression in our patients. Study Design: Descriptive study. Place and Duration of Study: Department of Pediatric Ophthalmology and Strabismus, Al-Shifa Trust Eye Hospital, Rawalpindi, Pakistan, from October 2011 to October 2014. Methodology: Children with unilateral and bilateral retinoblastoma were included in the study. Patients were referred to Pakistan Institute of Medical Sciences, Islamabad, for chemotherapy. After every cycle of chemotherapy, dilated fundus examination under anesthesia was performed to record response of the treatment. Regression patterns were recorded on RetCam II. Results: Seventy-four tumors were included in the study. Out of 74 tumors, 3 were ICRB group A tumors, 43 were ICRB group B tumors, 14 tumors belonged to ICRB group C, and remaining 14 were ICRB group D tumors. Type IV regression was seen in 39.1% (n=29) tumors, type II in 29.7% (n=22), type III in 25.6% (n=19), and type I in 5.4% (n=4). All group A tumors (100%) showed type IV regression. Seventeen (39.5%) group B tumors showed type IV regression. In group C, 5 tumors (35.7%) showed type II regression and 5 tumors (35.7%) showed type IV regression. In group D, 6 tumors (42.9%) regressed to type II non-calcified remnants. Conclusion: The response and success of the focal and systemic treatment, as judged by the appearance of different patterns of tumor regression, varies with the ICRB grouping of the tumor. Key Words: Retinoblastoma. Chemotherapy. Sporadic retinoblastoma. Hereditary retinoblastoma. Department of Pediatric Ophthalmology, Al-Shifa Trust Eye Hospital, Rawalpindi. Correspondence: Dr. Sorath Noorani Siddiqui, Associate Professor and Consultant Pediatric Ophthalmologist, Pakistan Institute of Ophthalmology, Head, Department of Pediatric Ophthalmology and Strabismus, Al-Shifa Trust Eye Hospital, Rawalpindi, Pakistan. E-mail: [email protected] Received: November 18, 2015; Accepted: November 09, 2016.
Tumor Regression Patterns in Retinoblastoma
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896 Journal of the College of Physicians and Surgeons Pakistan 2016, Vol. 26 (11): 896-899
INTRODUCTION The priorities in managing a child with retinoblastoma are saving the patient’s life, globe salvation and preservation of vision.1,2 Tumor regression patterns in retinoblastoma seen after conservative management include type 0 (no remnant), type l (calcified remnant), type ll (non-calcified remnant), type lll (partially calcified remnant), and type lV (flat scar). These regression patterns following external beam radiotherapy were initially described by Dunphy.3
A better prediction of treatment success is seen in International Classification of Retinoblastoma (ICRB) staging system which is applicable to current therapies.4 According to ICRB group A, tumors include small intra- retinal tumors away from foveola and disc, all tumors 3 mm or smaller in greatest dimension, confined to the retina and all tumors that are located farther than 3 mm from the foveola and 1.5 mm from the optic disc. Included in group B, are all remaining discrete tumors confined to the retina, all other tumors confined to the
retina not in group A, and tumor-associated sub-retinal fluid less than 3 mm from the tumor with no sub-retinal seedings. Group C tumors include discrete local disease with minimal sub-retinal or vitreous seeding, tumor(s) that are discrete, sub-retinal fluid, present or past, without seeding involving up to one-fourth of the retina, local fine vitreous seeding may be present close to discrete tumor and local sub-retinal seeding less than 3 mm (2 DD) from the tumor. Group D tumors are diffuse disease with significant vitreous or sub-retinal seeding, tumor(s) may be massive or diffuse, sub-retinal fluid present or past without seeding, involving up to total retinal detachment. Diffuse or massive vitreous disease may include “greasy” seeds or avascular tumor masses, diffuse sub-retinal seeding may include sub-retinal plaques or tumor nodules. Group E tumors involve presence of any one or more of the following poor prognosis features: Tumor touching the lens, tumor anterior to anterior vitreous face involving ciliary body or anterior segment, diffuse infiltrating retinoblastoma, neovascular glaucoma, opaque media from hemorrhage, tumor necrosis with aseptic orbital cellulitis and phthisis bulbi.4,5
The rationale of the present study was to observe the different types of tumor regression patterns in different ICRB groups of retinoblastoma after completion of laser treatment and systemic chemotherapy.
The aim of the study was to document the most common pattern of tumor regression in pediatric eyes with retinoblastoma after completion of treatment.
ORIGINAL ARTICLE
Tumor Regression Patterns in Retinoblastoma Saemah Nuzhat Zafar, Sorath Noorani Siddiqui and Naima Zaheer
ABSTRACT Objective: To observe the types of tumor regression after treatment, and identify the common pattern of regression in our patients. Study Design: Descriptive study. Place and Duration of Study: Department of Pediatric Ophthalmology and Strabismus, Al-Shifa Trust Eye Hospital, Rawalpindi, Pakistan, from October 2011 to October 2014. Methodology: Children with unilateral and bilateral retinoblastoma were included in the study. Patients were referred to Pakistan Institute of Medical Sciences, Islamabad, for chemotherapy. After every cycle of chemotherapy, dilated fundus examination under anesthesia was performed to record response of the treatment. Regression patterns were recorded on RetCam II. Results: Seventy-four tumors were included in the study. Out of 74 tumors, 3 were ICRB group A tumors, 43 were ICRB group B tumors, 14 tumors belonged to ICRB group C, and remaining 14 were ICRB group D tumors. Type IV regression was seen in 39.1% (n=29) tumors, type II in 29.7% (n=22), type III in 25.6% (n=19), and type I in 5.4% (n=4). All group A tumors (100%) showed type IV regression. Seventeen (39.5%) group B tumors showed type IV regression. In group C, 5 tumors (35.7%) showed type II regression and 5 tumors (35.7%) showed type IV regression. In group D, 6 tumors (42.9%) regressed to type II non-calcified remnants. Conclusion: The response and success of the focal and systemic treatment, as judged by the appearance of different patterns of tumor regression, varies with the ICRB grouping of the tumor.
Key Words: Retinoblastoma. Chemotherapy. Sporadic retinoblastoma. Hereditary retinoblastoma.
Department of Pediatric Ophthalmology, Al-Shifa Trust Eye Hospital, Rawalpindi.
Correspondence: Dr. Sorath Noorani Siddiqui, Associate Professor and Consultant Pediatric Ophthalmologist, Pakistan Institute of Ophthalmology, Head, Department of Pediatric Ophthalmology and Strabismus, Al-Shifa Trust Eye Hospital, Rawalpindi, Pakistan. E-mail: [email protected]
Received: November 18, 2015; Accepted: November 09, 2016.
METHODOLOGY This study was conducted in the Department of Pediatric Ophthalmology and Strabismus, Al-Shifa Trust Eye Hospital, Rawalpindi, from October 2011 to October 2014. Approval for the study was obtained from Institutional Review Board. Informed consent was obtained from the parents of the patients. The participants did not receive a stipend. Authors did not have financial or proprietary interest in any material or method mentioned. Children with sporadic or hereditary retinoblastoma, unilateral or bilateral retinoblastoma were included to observe the regression of retinoblastoma after focal consolidating measures and systemic intravenous chemotherapy. Children with group E ICRB retinoblastoma and with intracranial spread were excluded. The tumors which did not show regression after treatment were also excluded from the study.
Diode laser was applied using Iridis Machine (Quantel medical). For intravenous chemotherapy, patients were referred to oncologist. Standard protocol using Carboplatin, Etoposide and Vincristine was followed. After every cycle of chemotherapy, examination under anesthesia was scheduled to record the response of the treatment. After dilation of pupils, indirect ophthalmoscopy was performed in each patient to monitor changes in the appearance of tumor. At the end of chemotherapy cycles and adjuvant focal treatment, final pattern of tumor regression was recorded. Regression patterns type 0 (no remnant), type I (calcified remnant), type II (non- calcified remnant), type III (partially calcified remnant), and type IV (flat scar) were recorded on RetCam II.
The variables of the current study were groups A, B, C, D of international classification of retinoblastoma (ICRB) and type I - IV regression patterns of tumors. Descriptive statistics using SPSS (IBM, USA) version 17 were applied to calculate frequencies and percentages of ICRB tumor groups and type I - IV regression patterns of tumors.
RESULTS Seventy-four tumors in 30 eyes of 28 patients were included in the study. Mean age of these children was 1.66 ±1.65 years. Girls and boys were 39.3% (11) and 60.7% (17), respectively. Twenty-six children (92.9%) had bilateral and 2 (7.1%) had unilateral retinoblastoma.
Overall, 74 tumors were included in the study. ICRB was used to classify these tumors. ICRB group B was observed as the most common tumor type. Out of 74 tumors, 3 (4.05%) were ICRB group A tumors and 43 (58.10%) were ICRB group B tumors. Fourteen (18.81%) tumors belonged to ICRB group C and remaining 14 (18.81%) were ICRB group D tumors.
Type IV regression appeared as most common pattern of retinoblastoma regression after completion of focal treatment and systemic chemotherapy. Overall, 39.1% (n=29) tumors showed type IV regression (Figure 1), followed by type II regression pattern seen in 29.7% (n=22, Figure 2), type III regression in 25.6% (n=19, Figure 3), and type I regression pattern was observed in 5.4% (n=4, Figure 4). All group A tumors (100%) showed type IV regression. Most group B tumors (n=17, 39.5%) showed type IV regression. Out of 14 ICRB group C tumors, 5 tumors (35.7%) showed type II regression and 5 tumors (35.7%) showed type IV regression. In cases of group D, 6 tumors (42.9%) regressed to type II non- calcified remnants. Table I shows ICRB groups of retinoblastoma and different patterns of tumor regression in all 74 tumors.
Tumor regression patterns in retinoblastoma
Table I: Tumor regression patterns in different ICRB groups. ICRB groups and patterns of regression in retinoblastoma tumours (n=74 tumours).
ICRB Number of Pattern of regression
tumors Type I Type II Type III Type IV
Calcified tumor regression Non-calcified tumor regression Combination of type I and II Atrophic tumor regression
Cottage cheese appearance Fish flesh appearance Calcified and non-calcified Chorioretinal atrophic scar tumor regression
A 3 Frequency 3 (100%)
(Percent)
B 43 Frequency 1 (2.3%) 11 (25.6%) 14 (32.6%) 17 (39.5%)
(Percent)
C 14 Frequency 2 (14.3%) 5 (35.7%) 2 (14.3%) 5 (35.7%)
(Percent)
D 14 Frequency 1 (7.1%) 6 (42.9%) 3 (21.4%) 4 (28.6%)
(Percent)
Total 74 Frequency 4 (5.4%) 22 (29.7%) 19 (25.6%) 29 (39.1%)
(Percent)
Figure 1b: Regressed tumors with type IV pattern.
Journal of the College of Physicians and Surgeons Pakistan 2016, Vol. 26 (11): 896-899 897
DISCUSSION Retinoblastoma is a common intraocular malignancy in childhood which poses a major threat to patients' survival.6,7 Clinically, leukocoria is considered to be the commonest presentation.8,9 Intravenous chemotherapy is used worldwide and remains the most common treatment modality for retinoblastoma and prevention of systemic metastasis.10 Chemotherapy is usually combined with focal treatment for treating retino- blastoma. Commonly used focal treatment options include laser photocoagulation, trans-pupillary thermotherapy and cryotherapy.1 Visual prognosis after treatment with primary chemotherapy along with local treatment has been reported in a study.11 Shield recognized the effectiveness of intravenous chemo- therapy in the management of retinoblastoma.10 Shields reported increased tumor control with globe salvage from 30% to 70% after intravenous chemotherapy.1 In the last decade, the modality of intra-arterial chemotherapy has been investigated.12,13 Recently, intra-vitreal chemotherapy used for recurrent vitreous seeds has shown good results.14,15
Survival of retinoblastoma patients varies in different parts of the world. Literature shows that survival of
retinoblastoma patients is 30% in Africa, 60% in Asia, and 97% in North America.16 Treatment of retino- blastoma requires specialised skills. Treating physician needs to be familiar with diagnostic workup, staging of malignancy to provide appropriate treatment. Another clinical skill which plays a significant role in treating retinoblastoma is to clinically appreciate the response of tumor to systemic chemotherapy and focal treatment; which in turn, results into regression of tumor. The five regression patterns of retinoblastoma are based on clinical features observed on indirect ophthalmoscopy, including the presence and absence of calcium in the tumors.3
In this study, type IV was the most common regression pattern. This is similar to a larger study at Wills Eye Institute where type IV regression was the most frequently observed pattern in 57% of tumors.17 Type 0 regression was identified in 2%, type I in 13%, type II in 5%, and type III in 23% in their study. Immediately following 6 cycles of chemoreduction, types III (33%) and IV (32%) regression patterns were the most frequently observed by Palamer et al.17 Similar results were seen in a study where type III (n = 25), and type IV (n = 71) regressions were the most common patterns reported after chemoreduction.18 Ghassemi et al. reported type IV regression as the most common type seen 6 - 8 months following systemic chemoreduction and tumor consolidation (trans-pupillary thermotherapy [TTT] or cryotherapy.15 This observation is comparable to the present findings.
Type lll and type lV regressions may show tumor recurrence.18 Such correlation between regression patterns and their significance needs longer-term follow- up. The presented patients are being monitored for any recurrence of the tumors or new tumors by regular examination under anesthesia (EUA). It is important to note any tumor recurrence in cases of type lll and type lV regressions, during ongoing chemotherapy and after completion of all cycles of chemotherapy. EUA was carried out at the study centre after every chemotherapy cycle and focal laser treatment as required. Stable regression patterns in a study were observed to be types 0, l and lV.17 The same study also reported that most of the evolution in regression pattern occurred in the first 6 months after termination of chemoreduction (CRD).17
The 'retinocytoma', like non-calcified regression seen histopathlogically after CRD, were most likely type II and type III.19 These benign cellular elements seen in type II and III may cause a gradual change in the appearance of the scar, which however, is not found in regression type 0, l and IV.17 It is essential for the treating physician to be familiar with the various regression patterns of the tumor during and after the completion of chemotherapy.
Saemah Nuzhat Zafar, Sorath Noorani Siddiqui and Naima Zaheer
898 Journal of the College of Physicians and Surgeons Pakistan 2016, Vol. 26 (11): 896-899
Figure 2a: Fundus photograph showing a macular tumor at presentation.
Figure 2b: Regressed tumor with type II pattern.
Figure 3a: Fundus photograph showing 3 large tumors.
Figure 3b: Regressed tumors with type III pattern.
Figure 4a: Fundus photograph showing a large tumor at presentation.
Figure 4b: Regressed tumor with type I pattern.
Tumor regression patterns in retinoblastoma
Journal of the College of Physicians and Surgeons Pakistan 2016, Vol. 26 (11): 896-899 899
CONCLUSION The response and success of the focal and systemic treatment is judged by the patterns of tumor regression on clinical examination, which vary in different groups. Some patterns may require regular surveillance.
REFERENCES 1. Shields CL, Shields JA. Retinoblastoma management:
advances in enucleation, intravenous chemoreduction, and intra-arterial chemotherapy. Curr Opin Ophthalmol 2010; 21:203-12.
2. Shields CL, Kaliki S, Rojanaporn D, Al-Dahmash S, Bianciotto CG, Shields JA. Intravenous and intra-arterial chemotherapy for retinoblastoma: What have we learned. Curr Opin Ophthalmol 2012; 23:202-9.
3. Ghassemi F, Rahmanikhah E, Roohipoor R, Karkhaneh R, Faegh A. Regression patterns in treated retinoblastoma with chemotherapy plus focal adjuvant therapy. Pediatr Blood Cancer 2013; 60:599-604.
4. Shields CL, Mashayekhi A, Au AK. The international classification of retinoblastoma predicts chemoreduction success. Ophthalmology 2006; 113:2276-80.
5. Murphree L. Staging and grouping of retinoblastoma. In: Singh A, Damato B, editors. Clinical Ophthalmic Oncology. Philadelphia: Saunders Elsevier 2007; p.422-7.
6. Ramasubramanian A, Shields CL. Epidemiology and magnitude of the problem. In: Ramasubramanian A, Shields CL, editors. Retinoblastoma. New Delhi: Jaypee Brothers Medical Publishers 2012; p.10-5.
7. Shields JA, Shields CL. Retinoblastoma. In: Shields JA, Shields CL, editors. Intraocular tumors. An atlas and textbook. 2nd ed. Philadelphia, PA: Lippincott Williams Wilkins 2008; p.293-365.
8. Islam F, Zafar SN, Siddiqui SN, Khan A. Clinical course of retinoblastoma. J Coll Physicians Surg Pak 2013; 23:566-9.
9. Zhao J, Li S, Shi J, Wang N. Clinical presentation and group
classification of newly diagnosed intraocular retinoblastoma in China. Br J Ophthalmol 2011; 95:1072-6.
10. Shields CL, Fulco EM, Arias JD, Alarcon C, Pellegrini M, Rishi P, et al. Retinoblastoma frontiers with intravenous, intra- arterial, periocular, and intravitreal chemotherapy. Eye (Lond). 2013; 27:253-64.
11. Kim JM, Kim JH, Kim SJ, Park KD, Shin HY, Ahn HS, et al. Visual prognosis of retinoblastoma in the posterior pole treated with primary chemotherapy plus local treatment. Korean J Ophthalmol 2010; 24347-52.
12. Vajzovic LM, Murray TG, Aziz-Sultan MA, Schefler AC, Wolfe SQ, Hess D, et al. Supraselective intra-arterial chemotherapy: evaluation of treatment-related complications in advanced retinoblastoma. Clin Ophthalmol 2011; 5:171-6.
13. Shields CL, Bianciotto CG, Ramasubramanian A, Lally SE, Jabbour P, Griffin GC, et al. Intra-arterial chemotherapy for retinoblastoma. Report #1: control of tumor, subretinal seeds, and vitreous seeds. Arch Ophthalmol 2011; 129:1399-1406.
14. Munier F, Gaillard MC, Balmer A, Soliman S, Podlisky G, Moulin AP, et al. Intravitreal chemotherapy for vitreous disease in retinoblastoma revisited: From prohibition to conditional indications. Br J Ophthalmol 2012; 96:1078-83.
15. Ghassemi F, Shields CL. Intravitreal melphalan for refractory or recurrent vitreous seeding from retinoblastoma. Arch Ophthalmol 2012; 130:1268-71.
16. Kivela T. The epidemiological challenge of the most frequent eye cancer: Retinoblastoma, an issue of birth and death. Br J Ophthalmol 2009; 93:1129-31.
17. Palamar M, Thangappan A, Shields CL. Evolution in regression patterns following chemoreduction for retino-blastoma. Arch Ophthalmol 2011; 129:727-30.
18. Xue K, Qian J, Yue H, Yuan YF, Zhang R. Retinoblastoma regression patterns and results following chemoreduction and adjuvant therapy. Zhonghua Yan Ke Za Zhi 2012; 48:625-30.
INTRODUCTION The priorities in managing a child with retinoblastoma are saving the patient’s life, globe salvation and preservation of vision.1,2 Tumor regression patterns in retinoblastoma seen after conservative management include type 0 (no remnant), type l (calcified remnant), type ll (non-calcified remnant), type lll (partially calcified remnant), and type lV (flat scar). These regression patterns following external beam radiotherapy were initially described by Dunphy.3
A better prediction of treatment success is seen in International Classification of Retinoblastoma (ICRB) staging system which is applicable to current therapies.4 According to ICRB group A, tumors include small intra- retinal tumors away from foveola and disc, all tumors 3 mm or smaller in greatest dimension, confined to the retina and all tumors that are located farther than 3 mm from the foveola and 1.5 mm from the optic disc. Included in group B, are all remaining discrete tumors confined to the retina, all other tumors confined to the
retina not in group A, and tumor-associated sub-retinal fluid less than 3 mm from the tumor with no sub-retinal seedings. Group C tumors include discrete local disease with minimal sub-retinal or vitreous seeding, tumor(s) that are discrete, sub-retinal fluid, present or past, without seeding involving up to one-fourth of the retina, local fine vitreous seeding may be present close to discrete tumor and local sub-retinal seeding less than 3 mm (2 DD) from the tumor. Group D tumors are diffuse disease with significant vitreous or sub-retinal seeding, tumor(s) may be massive or diffuse, sub-retinal fluid present or past without seeding, involving up to total retinal detachment. Diffuse or massive vitreous disease may include “greasy” seeds or avascular tumor masses, diffuse sub-retinal seeding may include sub-retinal plaques or tumor nodules. Group E tumors involve presence of any one or more of the following poor prognosis features: Tumor touching the lens, tumor anterior to anterior vitreous face involving ciliary body or anterior segment, diffuse infiltrating retinoblastoma, neovascular glaucoma, opaque media from hemorrhage, tumor necrosis with aseptic orbital cellulitis and phthisis bulbi.4,5
The rationale of the present study was to observe the different types of tumor regression patterns in different ICRB groups of retinoblastoma after completion of laser treatment and systemic chemotherapy.
The aim of the study was to document the most common pattern of tumor regression in pediatric eyes with retinoblastoma after completion of treatment.
ORIGINAL ARTICLE
Tumor Regression Patterns in Retinoblastoma Saemah Nuzhat Zafar, Sorath Noorani Siddiqui and Naima Zaheer
ABSTRACT Objective: To observe the types of tumor regression after treatment, and identify the common pattern of regression in our patients. Study Design: Descriptive study. Place and Duration of Study: Department of Pediatric Ophthalmology and Strabismus, Al-Shifa Trust Eye Hospital, Rawalpindi, Pakistan, from October 2011 to October 2014. Methodology: Children with unilateral and bilateral retinoblastoma were included in the study. Patients were referred to Pakistan Institute of Medical Sciences, Islamabad, for chemotherapy. After every cycle of chemotherapy, dilated fundus examination under anesthesia was performed to record response of the treatment. Regression patterns were recorded on RetCam II. Results: Seventy-four tumors were included in the study. Out of 74 tumors, 3 were ICRB group A tumors, 43 were ICRB group B tumors, 14 tumors belonged to ICRB group C, and remaining 14 were ICRB group D tumors. Type IV regression was seen in 39.1% (n=29) tumors, type II in 29.7% (n=22), type III in 25.6% (n=19), and type I in 5.4% (n=4). All group A tumors (100%) showed type IV regression. Seventeen (39.5%) group B tumors showed type IV regression. In group C, 5 tumors (35.7%) showed type II regression and 5 tumors (35.7%) showed type IV regression. In group D, 6 tumors (42.9%) regressed to type II non-calcified remnants. Conclusion: The response and success of the focal and systemic treatment, as judged by the appearance of different patterns of tumor regression, varies with the ICRB grouping of the tumor.
Key Words: Retinoblastoma. Chemotherapy. Sporadic retinoblastoma. Hereditary retinoblastoma.
Department of Pediatric Ophthalmology, Al-Shifa Trust Eye Hospital, Rawalpindi.
Correspondence: Dr. Sorath Noorani Siddiqui, Associate Professor and Consultant Pediatric Ophthalmologist, Pakistan Institute of Ophthalmology, Head, Department of Pediatric Ophthalmology and Strabismus, Al-Shifa Trust Eye Hospital, Rawalpindi, Pakistan. E-mail: [email protected]
Received: November 18, 2015; Accepted: November 09, 2016.
METHODOLOGY This study was conducted in the Department of Pediatric Ophthalmology and Strabismus, Al-Shifa Trust Eye Hospital, Rawalpindi, from October 2011 to October 2014. Approval for the study was obtained from Institutional Review Board. Informed consent was obtained from the parents of the patients. The participants did not receive a stipend. Authors did not have financial or proprietary interest in any material or method mentioned. Children with sporadic or hereditary retinoblastoma, unilateral or bilateral retinoblastoma were included to observe the regression of retinoblastoma after focal consolidating measures and systemic intravenous chemotherapy. Children with group E ICRB retinoblastoma and with intracranial spread were excluded. The tumors which did not show regression after treatment were also excluded from the study.
Diode laser was applied using Iridis Machine (Quantel medical). For intravenous chemotherapy, patients were referred to oncologist. Standard protocol using Carboplatin, Etoposide and Vincristine was followed. After every cycle of chemotherapy, examination under anesthesia was scheduled to record the response of the treatment. After dilation of pupils, indirect ophthalmoscopy was performed in each patient to monitor changes in the appearance of tumor. At the end of chemotherapy cycles and adjuvant focal treatment, final pattern of tumor regression was recorded. Regression patterns type 0 (no remnant), type I (calcified remnant), type II (non- calcified remnant), type III (partially calcified remnant), and type IV (flat scar) were recorded on RetCam II.
The variables of the current study were groups A, B, C, D of international classification of retinoblastoma (ICRB) and type I - IV regression patterns of tumors. Descriptive statistics using SPSS (IBM, USA) version 17 were applied to calculate frequencies and percentages of ICRB tumor groups and type I - IV regression patterns of tumors.
RESULTS Seventy-four tumors in 30 eyes of 28 patients were included in the study. Mean age of these children was 1.66 ±1.65 years. Girls and boys were 39.3% (11) and 60.7% (17), respectively. Twenty-six children (92.9%) had bilateral and 2 (7.1%) had unilateral retinoblastoma.
Overall, 74 tumors were included in the study. ICRB was used to classify these tumors. ICRB group B was observed as the most common tumor type. Out of 74 tumors, 3 (4.05%) were ICRB group A tumors and 43 (58.10%) were ICRB group B tumors. Fourteen (18.81%) tumors belonged to ICRB group C and remaining 14 (18.81%) were ICRB group D tumors.
Type IV regression appeared as most common pattern of retinoblastoma regression after completion of focal treatment and systemic chemotherapy. Overall, 39.1% (n=29) tumors showed type IV regression (Figure 1), followed by type II regression pattern seen in 29.7% (n=22, Figure 2), type III regression in 25.6% (n=19, Figure 3), and type I regression pattern was observed in 5.4% (n=4, Figure 4). All group A tumors (100%) showed type IV regression. Most group B tumors (n=17, 39.5%) showed type IV regression. Out of 14 ICRB group C tumors, 5 tumors (35.7%) showed type II regression and 5 tumors (35.7%) showed type IV regression. In cases of group D, 6 tumors (42.9%) regressed to type II non- calcified remnants. Table I shows ICRB groups of retinoblastoma and different patterns of tumor regression in all 74 tumors.
Tumor regression patterns in retinoblastoma
Table I: Tumor regression patterns in different ICRB groups. ICRB groups and patterns of regression in retinoblastoma tumours (n=74 tumours).
ICRB Number of Pattern of regression
tumors Type I Type II Type III Type IV
Calcified tumor regression Non-calcified tumor regression Combination of type I and II Atrophic tumor regression
Cottage cheese appearance Fish flesh appearance Calcified and non-calcified Chorioretinal atrophic scar tumor regression
A 3 Frequency 3 (100%)
(Percent)
B 43 Frequency 1 (2.3%) 11 (25.6%) 14 (32.6%) 17 (39.5%)
(Percent)
C 14 Frequency 2 (14.3%) 5 (35.7%) 2 (14.3%) 5 (35.7%)
(Percent)
D 14 Frequency 1 (7.1%) 6 (42.9%) 3 (21.4%) 4 (28.6%)
(Percent)
Total 74 Frequency 4 (5.4%) 22 (29.7%) 19 (25.6%) 29 (39.1%)
(Percent)
Figure 1b: Regressed tumors with type IV pattern.
Journal of the College of Physicians and Surgeons Pakistan 2016, Vol. 26 (11): 896-899 897
DISCUSSION Retinoblastoma is a common intraocular malignancy in childhood which poses a major threat to patients' survival.6,7 Clinically, leukocoria is considered to be the commonest presentation.8,9 Intravenous chemotherapy is used worldwide and remains the most common treatment modality for retinoblastoma and prevention of systemic metastasis.10 Chemotherapy is usually combined with focal treatment for treating retino- blastoma. Commonly used focal treatment options include laser photocoagulation, trans-pupillary thermotherapy and cryotherapy.1 Visual prognosis after treatment with primary chemotherapy along with local treatment has been reported in a study.11 Shield recognized the effectiveness of intravenous chemo- therapy in the management of retinoblastoma.10 Shields reported increased tumor control with globe salvage from 30% to 70% after intravenous chemotherapy.1 In the last decade, the modality of intra-arterial chemotherapy has been investigated.12,13 Recently, intra-vitreal chemotherapy used for recurrent vitreous seeds has shown good results.14,15
Survival of retinoblastoma patients varies in different parts of the world. Literature shows that survival of
retinoblastoma patients is 30% in Africa, 60% in Asia, and 97% in North America.16 Treatment of retino- blastoma requires specialised skills. Treating physician needs to be familiar with diagnostic workup, staging of malignancy to provide appropriate treatment. Another clinical skill which plays a significant role in treating retinoblastoma is to clinically appreciate the response of tumor to systemic chemotherapy and focal treatment; which in turn, results into regression of tumor. The five regression patterns of retinoblastoma are based on clinical features observed on indirect ophthalmoscopy, including the presence and absence of calcium in the tumors.3
In this study, type IV was the most common regression pattern. This is similar to a larger study at Wills Eye Institute where type IV regression was the most frequently observed pattern in 57% of tumors.17 Type 0 regression was identified in 2%, type I in 13%, type II in 5%, and type III in 23% in their study. Immediately following 6 cycles of chemoreduction, types III (33%) and IV (32%) regression patterns were the most frequently observed by Palamer et al.17 Similar results were seen in a study where type III (n = 25), and type IV (n = 71) regressions were the most common patterns reported after chemoreduction.18 Ghassemi et al. reported type IV regression as the most common type seen 6 - 8 months following systemic chemoreduction and tumor consolidation (trans-pupillary thermotherapy [TTT] or cryotherapy.15 This observation is comparable to the present findings.
Type lll and type lV regressions may show tumor recurrence.18 Such correlation between regression patterns and their significance needs longer-term follow- up. The presented patients are being monitored for any recurrence of the tumors or new tumors by regular examination under anesthesia (EUA). It is important to note any tumor recurrence in cases of type lll and type lV regressions, during ongoing chemotherapy and after completion of all cycles of chemotherapy. EUA was carried out at the study centre after every chemotherapy cycle and focal laser treatment as required. Stable regression patterns in a study were observed to be types 0, l and lV.17 The same study also reported that most of the evolution in regression pattern occurred in the first 6 months after termination of chemoreduction (CRD).17
The 'retinocytoma', like non-calcified regression seen histopathlogically after CRD, were most likely type II and type III.19 These benign cellular elements seen in type II and III may cause a gradual change in the appearance of the scar, which however, is not found in regression type 0, l and IV.17 It is essential for the treating physician to be familiar with the various regression patterns of the tumor during and after the completion of chemotherapy.
Saemah Nuzhat Zafar, Sorath Noorani Siddiqui and Naima Zaheer
898 Journal of the College of Physicians and Surgeons Pakistan 2016, Vol. 26 (11): 896-899
Figure 2a: Fundus photograph showing a macular tumor at presentation.
Figure 2b: Regressed tumor with type II pattern.
Figure 3a: Fundus photograph showing 3 large tumors.
Figure 3b: Regressed tumors with type III pattern.
Figure 4a: Fundus photograph showing a large tumor at presentation.
Figure 4b: Regressed tumor with type I pattern.
Tumor regression patterns in retinoblastoma
Journal of the College of Physicians and Surgeons Pakistan 2016, Vol. 26 (11): 896-899 899
CONCLUSION The response and success of the focal and systemic treatment is judged by the patterns of tumor regression on clinical examination, which vary in different groups. Some patterns may require regular surveillance.
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