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Research Letters |

Retinoma Underlying Retinoblastoma Revealed After Tumor Response to 1 Cycle of Chemotherapy FREE

Helen Dimaras, PhD; Vikas Khetan, MD; William Halliday, MD; Elise Héon, MD, FRCSC; Helen S. L. Chan, MBBS; Brenda L. Gallie, MD
Arch Ophthalmol. 2009;127(8):1066-1068. doi:10.1001/archophthalmol.2009.178.
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Published online

Retinoma is a benign, elevated, gray, translucent retinal mass with cottage cheese–like calcification and hyperpigmented retinal pigment epithelium.1 Histopathological features include abundant fleurettes and nonproliferative cells. We report a case in which an underlying retinoma was revealed by collapse and massive vitreous dispersion of the overlying unilateral retinoblastoma after 1 cycle of chemotherapy. Pathological analysis of the enucleated eye confirmed retinoma.

A 2-year-old boy had leukokoria in the left eye. The left eye contained group D retinoblastoma,2 an endophytic posterior pole tumor with inferior vitreous seeding (Figure 1A). The right eye appeared unaffected.

Place holder to copy figure label and caption
Figure 1.

Retinoma discovered in a retinoblastoma eye removed after the main active tumor dispersed throughout the vitreous following 1 cycle of chemotherapy. A, The child had unilateral macular retinoblastoma (International Intraocular Retinoblastoma Classification group D) and was treated with chemotherapy (Toronto Protocol), with the possibility of saving the eye. B, A strong response to 1 cycle of chemotherapy resulted in “melting” of the original tumor but massive vitreous seeding. Collapse of the active retinoblastoma revealed a mass with features of retinoma (chorioretinal scarring, translucent mass, and calcification). Because the other eye was healthy, the affected eye was removed 3 weeks after the chemotherapy.

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Because there was potential for useful vision, treatment with chemotherapy followed by laser therapy was initiated. Three weeks after 1 cycle of systemic carboplatin-etoposide–vincristine sulfate treatment with high-dose cyclosporine (Toronto Protocol3,4), the main tumor showed marked reduction in size, revealing a translucent mass with moderate calcification overlying chorioretinal scarring (Figure 1B). However, the main active retinoblastoma had dispersed widely into the vitreous including anterior to the ora serrata inferiorly, so the eye was enucleated.

Pathological examination showed a solid posterior tumor tapering into the inner nuclear layer of the retina (Figure 2A). The residual retinal lesion had numerous fleurettes, consistent with retinoma5,6 (Figure 2B). Fleurette-rich regions were not reactive to Ki-67 and p53 antibodies, and mitotic figures were rare. At the edge of the gap in the tumor from which the necrotic vitreous seeds had emerged, small, round retinoblastoma cells with little cytoplasm and no fleurettes stained positive for Ki-67, indicating proliferation and p53. The vitreous contained necrotic cellular debris. The optic nerve, optic nerve head, subarachnoid space, and choroid were free of tumor.

Place holder to copy figure label and caption
Figure 2.

Pathological features of retinoma in the solid posterior pole tumor (central) in the eye removed 3 weeks after chemotherapy. A, From the temporal edge, the retina (RET), retinoma (R), and retinoblastoma (RB) were adjacent; at the nasal edge, the retinoma was contiguous with the inner nuclear layer of the retina (hematoxylin-eosin). B, Retinoblastoma and retinoma (hematoxylin-eosin, Ki-67, and p53 immunostain).

Graphic Jump Location

We previously reported that molecular analysis of this retinoblastoma showed a homozygous splice mutation (IVS12 + 1G>A)7; blood DNA had 2 normal RB1 alleles. Staining for pRb was negative, while the p75NTR tumor suppressor8 and senescence marker p16INK4a were highly expressed (case 5 in supplementary Table 2 from our previous article7).

We concluded that the active retinoblastoma (Figure 1A) arose from retinoma (Figure 2B) originating in the inner nuclear layer of the retina (Figure 2A). Chemotherapy killed the dividing retinoblastoma cells, which collapsed into the vitreous. The nondividing translucent retinoma was unaffected by chemotherapy but became evident only after chemotherapy (Figure 1B). This retinoma shows all of the described features: clinical,1 histopathological,6 and molecular.7

Clinically, retinoma is a translucent intraretinal mass with calcification and/or choroidal scarring that remains benign for the lifetime of the individual in 1.5%1 to 10%9 of predisposed persons. Several examples of clinically recognized retinoma that progressed to retinoblastoma have been documented.912 The transition from retinoma to retinoblastoma is usually so rapid that the benign lesions are rarely observed clinically, but we have previously shown that they are relatively common in eyes removed for retinoblastoma.7 Most eyes enucleated for retinoblastoma do not undergo therapy prior to removal, so the underlying retinoma is usually hidden by the proliferating tumor (Figure 1A).

Tso et al13 considered the fleurettes observed in pathological specimens with retinoblastoma to be radiation resistant rather than a sign of tumor regression. Later, Tso14 speculated that the proportions of fleurettes intermingled with Flexner-Wintersteiner and Homer Wright rosettes indicated to what degree the tumor was benign. We speculate that the intermingling of the fleurettes with rosettes results from retinoblastoma growing out of and invading the precursor retinoma. The idea that clinical retinomas represent spontaneous regression1517 of retinoblastoma is not supported by pathological analysis given that they show no scarring or necrosis, whether treated or not.7

Molecular analysis shows that retinomas and their adjacent retinoblastomas in enucleated eyes carry identical RB1 mutations, indicating a common origin followed by clonal progression from benign to malignant tumor.7 Genomic instability at low levels in retinoma may be the first consequence of loss of RB1, which becomes more advanced in the adjacent retinoblastoma.7

In our case, chemotherapy destroyed most of the malignant retinoblastoma, unveiling an underlying retinoma that was recognized clinically and confirmed by histopathological analysis and molecular studies. Although retinoma is frequently observed in eyes with retinoblastoma on pathological examination, it is rarely documented clinically because it is commonly overgrown by the malignant retinoblastoma, which obscures its detection.

Correspondence: Dr Helen Dimaras, The Division of Hematology/Oncology, The Hospital for Sick Children, 555 University Ave, Room 7260, Toronto, ON M5G 1X8, Canada (helen.dimaras@sickkids.ca).

Author Contributions: Drs Dimaras and Gallie had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Financial Disclosure: None reported.

Funding/Support: This study was supported in part by grants to Dr Gallie from the National Cancer Institute of Canada, the Canadian Retinoblastoma Society, and the Royal Arch Masons of Canada.

Gallie  BLEllsworth  RMAbramson  DHPhillips  RA Retinoma: spontaneous regression of retinoblastoma or benign manifestation of the mutation? Br J Cancer 1982;45 (4) 513- 521
PubMed Link to Article
Linn Murphree  A Intraocular retinoblastoma: the case for a new group classification. Ophthalmol Clin North Am 2005;18 (1) 41- 53, viii
PubMed Link to Article
Chan  HSLGrogan  TMDeBoer  GHaddad  GGallie  BLLing  V Diagnosis and reversal of multidrug resistance in paediatric cancers. Eur J Cancer 1996;32A (6) 1051- 1061
PubMed Link to Article
Gallie  BLBudning  ADeBoer  G  et al.  Chemotherapy with focal therapy can cure intraocular retinoblastoma without radiotherapy. Arch Ophthalmol 1996;114 (11) 1321- 1328
PubMed Link to Article
Radnót  M Elements of photoreceptors in retinoblastomas (author's transl) [in German]. Albrecht Von Graefes Arch Klin Exp Ophthalmol 1977;202 (1) 63- 70
PubMed Link to Article
Margo  CHidayat  AKopelman  JZimmerman  LE Retinocytoma: a benign variant of retinoblastoma. Arch Ophthalmol 1983;101 (10) 1519- 1531
PubMed Link to Article
Dimaras  HKhetan  VHalliday  W  et al.  Loss of RB1 induces non-proliferative retinoma: increasing genomic instability correlates with progression to retinoblastoma. Hum Mol Genet 2008;17 (10) 1363- 1372
PubMed Link to Article
Dimaras  HGallie  BL The p75 NTR neurotrophin receptor is a tumor suppressor in human and murine retinoblastoma development. Int J Cancer 2008;122 (9) 2023- 2029
PubMed Link to Article
Balmer  AMunier  FGailloud  C Retinoma: case studies. Ophthalmic Paediatr Genet 1991;12 (3) 131- 137
PubMed Link to Article
Eagle  RC  JrShields  JADonoso  LMilner  RS Malignant transformation of spontaneously regressed retinoblastoma, retinoma/retinocytoma variant. Ophthalmology 1989;96 (9) 1389- 1395
PubMed Link to Article
Singh  ADSantos  CMShields  CLShields  JAEagle  RC  Jr Observations on 17 patients with retinocytoma. Arch Ophthalmol 2000;118 (2) 199- 205
PubMed Link to Article
Dimaras  HCoburn  BPajovic  SGallie  BL Loss of p75 neurotrophin receptor expression accompanies malignant progression to human and murine retinoblastoma. Mol Carcinog 2006;45 (5) 333- 343
PubMed Link to Article
Tso  MOZimmerman  LEFine  BSEllsworth  RM A cause of radioresistance in retinoblastoma: photoreceptor differentiation. Trans Am Acad Ophthalmol Otolaryngol 1970;74 (5) 959- 969
PubMed
Tso  MO Clues to the cells of origin in retinoblastoma. Int Ophthalmol Clin 1980;20 (2) 191- 210
PubMed
Demirci  HEagle  RC  JrShields  CLShields  JA Histopathologic findings in eyes with retinoblastoma treated only with chemoreduction. Arch Ophthalmol 2003;121 (8) 1125- 1131
PubMed Link to Article
Park  JJGole  GAFinnigan  SVandeleur  K Late presentation of a unilateral sporadic retinoblastoma in a 16-year-old girl. Aust N Z J Ophthalmol 1999;27 (5) 365- 368
PubMed Link to Article
Messmer  EPRichter  HJHöpping  WHavers  WAlberti  W Non-ocular, malignant secondary tumor following spontaneous healing of a retinoblastoma (“retinoma,” “retinocytoma”) [in German]. Klin Monatsbl Augenheilkd 1987;191 (4) 299- 303
PubMed Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.

Retinoma discovered in a retinoblastoma eye removed after the main active tumor dispersed throughout the vitreous following 1 cycle of chemotherapy. A, The child had unilateral macular retinoblastoma (International Intraocular Retinoblastoma Classification group D) and was treated with chemotherapy (Toronto Protocol), with the possibility of saving the eye. B, A strong response to 1 cycle of chemotherapy resulted in “melting” of the original tumor but massive vitreous seeding. Collapse of the active retinoblastoma revealed a mass with features of retinoma (chorioretinal scarring, translucent mass, and calcification). Because the other eye was healthy, the affected eye was removed 3 weeks after the chemotherapy.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Pathological features of retinoma in the solid posterior pole tumor (central) in the eye removed 3 weeks after chemotherapy. A, From the temporal edge, the retina (RET), retinoma (R), and retinoblastoma (RB) were adjacent; at the nasal edge, the retinoma was contiguous with the inner nuclear layer of the retina (hematoxylin-eosin). B, Retinoblastoma and retinoma (hematoxylin-eosin, Ki-67, and p53 immunostain).

Graphic Jump Location

Tables

References

Gallie  BLEllsworth  RMAbramson  DHPhillips  RA Retinoma: spontaneous regression of retinoblastoma or benign manifestation of the mutation? Br J Cancer 1982;45 (4) 513- 521
PubMed Link to Article
Linn Murphree  A Intraocular retinoblastoma: the case for a new group classification. Ophthalmol Clin North Am 2005;18 (1) 41- 53, viii
PubMed Link to Article
Chan  HSLGrogan  TMDeBoer  GHaddad  GGallie  BLLing  V Diagnosis and reversal of multidrug resistance in paediatric cancers. Eur J Cancer 1996;32A (6) 1051- 1061
PubMed Link to Article
Gallie  BLBudning  ADeBoer  G  et al.  Chemotherapy with focal therapy can cure intraocular retinoblastoma without radiotherapy. Arch Ophthalmol 1996;114 (11) 1321- 1328
PubMed Link to Article
Radnót  M Elements of photoreceptors in retinoblastomas (author's transl) [in German]. Albrecht Von Graefes Arch Klin Exp Ophthalmol 1977;202 (1) 63- 70
PubMed Link to Article
Margo  CHidayat  AKopelman  JZimmerman  LE Retinocytoma: a benign variant of retinoblastoma. Arch Ophthalmol 1983;101 (10) 1519- 1531
PubMed Link to Article
Dimaras  HKhetan  VHalliday  W  et al.  Loss of RB1 induces non-proliferative retinoma: increasing genomic instability correlates with progression to retinoblastoma. Hum Mol Genet 2008;17 (10) 1363- 1372
PubMed Link to Article
Dimaras  HGallie  BL The p75 NTR neurotrophin receptor is a tumor suppressor in human and murine retinoblastoma development. Int J Cancer 2008;122 (9) 2023- 2029
PubMed Link to Article
Balmer  AMunier  FGailloud  C Retinoma: case studies. Ophthalmic Paediatr Genet 1991;12 (3) 131- 137
PubMed Link to Article
Eagle  RC  JrShields  JADonoso  LMilner  RS Malignant transformation of spontaneously regressed retinoblastoma, retinoma/retinocytoma variant. Ophthalmology 1989;96 (9) 1389- 1395
PubMed Link to Article
Singh  ADSantos  CMShields  CLShields  JAEagle  RC  Jr Observations on 17 patients with retinocytoma. Arch Ophthalmol 2000;118 (2) 199- 205
PubMed Link to Article
Dimaras  HCoburn  BPajovic  SGallie  BL Loss of p75 neurotrophin receptor expression accompanies malignant progression to human and murine retinoblastoma. Mol Carcinog 2006;45 (5) 333- 343
PubMed Link to Article
Tso  MOZimmerman  LEFine  BSEllsworth  RM A cause of radioresistance in retinoblastoma: photoreceptor differentiation. Trans Am Acad Ophthalmol Otolaryngol 1970;74 (5) 959- 969
PubMed
Tso  MO Clues to the cells of origin in retinoblastoma. Int Ophthalmol Clin 1980;20 (2) 191- 210
PubMed
Demirci  HEagle  RC  JrShields  CLShields  JA Histopathologic findings in eyes with retinoblastoma treated only with chemoreduction. Arch Ophthalmol 2003;121 (8) 1125- 1131
PubMed Link to Article
Park  JJGole  GAFinnigan  SVandeleur  K Late presentation of a unilateral sporadic retinoblastoma in a 16-year-old girl. Aust N Z J Ophthalmol 1999;27 (5) 365- 368
PubMed Link to Article
Messmer  EPRichter  HJHöpping  WHavers  WAlberti  W Non-ocular, malignant secondary tumor following spontaneous healing of a retinoblastoma (“retinoma,” “retinocytoma”) [in German]. Klin Monatsbl Augenheilkd 1987;191 (4) 299- 303
PubMed Link to Article

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