From the Department of Ophthalmology, Faculty of Medicine, Semmelweis University, Budapest, Hungary.
The authors have no financial or proprietary interest in the materials presented herein.
Address correspondence to Erika Maka, Semmelweis University, Department of Ophthalmology, Tömou. 25–29, 1083 Budapest, Hungary.
Retinoblastoma is the most common primary intraocular malignant tumor of infancy and childhood. Classically, it manifests clinically as leukocoria with or without strabismus.1 Phthisis of the eye is an uncommon presenting sign of retinoblastoma that often occurs following a severe ocular inflammatory episode, possibly related to massive intraocular tumor infarction.2 We report a case of bilateral retinoblastoma in a patient presenting with phthisis of the left eye.
A 14-month-old girl was referred to our department for an intraocular tumor in her right eye and signs of inflammation of the smaller left eye. She had been born at 36 gestational weeks, the fourth child of a socially disadvantaged family. Her birth weight was 2,670 g. No perinatal abnormalities were noted. Abdominal and cranial ultrasonographic examination did not disclose any pathological alteration. Clinical history included a subconjunctival hemorrhage of 1-week duration in the left eye when she was 4 months old and strabismus developed 3 months later. However, the parents did not request an ophthalmologic examination. The left cornea became opaque 6 months later and at this time the parents did consult an ophthalmologist. There was no family history of retinoblastoma or other eye disease.
On the first ophthalmologic examination, the anterior segment of the right eye was normal. The corneal diameter was 10 mm. However, ophthalmoscopy revealed a 4-disc diameter, well-delineated, grayish-white mass lesion of 21 diopters prominence rising from the retina in the inferotemporal quadrant. Dilated, tortuous blood vessels fed the tumor and fine newly formed vessels running over the surface of the lesion were detected. The clinical diagnosis was retinoblastoma.
Enophthalmos was observed in the left side, with exotropia and perilimbal hyperemia. The corneal diameter was 9.5 mm and the stroma was opaque. The ocular fundus could not be visualized (Fig. 1).
Figure 1. The Left Eye of a 14-Month-Old Girl Is Smaller than the Right Eye and Has Opacification of the Cornea.
B-scan ultrasonography of the right eye (axial length: 19.5 mm) revealed a solid, dome-shaped lesion measuring 8 × 10 × 5.4 mm located temporally, below the level of the optic nerve head. The tumor exhibited high internal and low cortical reflectivity. A lesion with high surface reflectivity, very low internal reflectivity, and marked shadowing was also observed in the smaller left eye (axial length: 18 mm) (Fig. 2).
Figure 2. (A) A Lesion Below the Papilla Level with Medium Surface and High Internal Reflectivity in the Right Eye. (B) A Lesion with High Surface and Low Internal Reflectivity and Marked Shadowing in the Smaller Left Eye.
Orbital computed tomography revealed a 20 × 18 mm, partially calcified tumor in the right eye and an 8 × 11 mm, calcified mass lesion in the left eye. There was no bone destruction or intracranial lesion. Abdominal ultrasonography, chest radiography, and pediatric oncology evaluation did not disclose any abnormality. Bilateral retinoblastoma with gradually developed left-sided phthisis was diagnosed.
Enucleation of the painful left eye, which had no light perception, was performed. Subsequent histopathologic examination found a partially calcified mass (9 × 5 mm) related to the retina behind the lens. There was extensive tumor necrosis and only a small viable tumor nodule measuring 2 × 1 mm was recognized. The tumor contained undifferentiated neuroblastic cells without rosette formation. There was no sign of extraocular extension. Spontaneously regressed, mostly calcified retinoblastoma was diagnosed. Immunohistochemical examination (synaptophysin positivity) confirmed the neural origin of the tumor cells (Fig. 3).
Figure 3. (A) Overview of Enucleation Specimen Showing Extensive Tumor Necrosis with only a Small Tumor Nodule (arrow). (B) Small Tumor Nodule with Calcification (hematoxylin–Eosin, Original Magnification ×2.5). (C) Synaptophysin Positive Tumor Cells (immunohistochemical Reaction, Original Magnification ×40).
After enucleation of the left eye, the patient underwent six cycles of chemoreduction with vincristine, cisplatin/carboplatin, etoposide, and cyclophosphamide. The original lesion in the right eye regressed, but a new, smaller tumor developed. Plaque radiotherapy followed by transpupillary thermotherapy was applied. The patient is currently 6 years old and best-corrected visual acuity in her right eye is 0.5 (10/20). Ophthalmoscopic examination now reveals lesions showing “cottage-cheese” regression without evidence of recurrence, metastasis, or pinealoblastoma.
Retinoblastoma is the most common primary intraocular malignant tumor of childhood. The most frequent presenting signs of retinoblastoma are leukocoria and strabismus, whereas pseudohypopyon, glaucoma, orbital inflammation, and proptosis occur much less frequently.1 Bilateral retinoblastoma with one phthisical eye related to spontaneous regression is a rare occurrence. The incidence of phthisis bulbi as a presenting sign of retinoblastoma is reported to be only 0.1% to 2.7%.3–5
Gallie et al. called attention to the high rate (1% to 2%) of spontaneous regression of retinoblastoma.6 However, in a series of 504 spontaneously regressed malignant tumors, retinoblastoma represented 6% of the cases and neuroblastoma represented 8% of the cases.7 The spontaneous regression of retinoblastoma can be identified in two distinct situations: with phthisis and with retinoblastoma-like lesions (called retinocytoma) in the eye(s) of the parent(s) of a child with retinoblastoma.8
The first case of spontaneous regression of retinoblastoma with one phthisical eye was reported by Knieper in 1911. Similar cases were reported by De Kleijn (1911), O’Connor (1917), Stallard (1936), Sovik (1952), Steward et al. (1956), Mehra and Banerji (1965), Khodadoust et al. (1977), Gangwar et al. (1982), and Ungaro et al. (2002).9–13 In most cases of spontaneously regressed retinoblastoma there is history of a red, painful eye.4,9–11,13
The largest series was reported in 1962 by Khodadoust et al., who found 13 cases of spontaneously regressed tumor in phthisical eyes.10 Verhoeff suggested that treatment with vitamin D could promote the calcification.14 Gallie et al. described five patients with phthisis bulbi.15
Between 1975 and 1991, Balmer et al.16 discovered 17 eyes with spontaneous regression: 16 presenting as retinoma and only 1 as phthisis bulbi. Among the offspring of these patients, 2 children with retinoblastoma also had phthisis bulbi. In the series reported by Mullaney et al. consisting of 272 patients, 9 eyes underwent enucleation for phthisis and all demonstrated histologic evidence of viable tumor cells.5 In our case, although the necrosis of the tumor was extensive, a small focus of viable cells was also noted.
In a retrospective study, Abramson et al.3 identified 32 presenting signs of retinoblastoma. Microphthalmos (4 cases, 0.3%) and phthisis of the eye (1 case, 0.1%) were extremely rare findings. In another retrospective study in the Congo, Kaimbo et al. found only 1 or 29 patients with retinoblastoma who had phthisis bulbi as the presenting sign.17 Harrison et al. reported a case of bilateral retinoblastoma presenting with simultaneous phthisis and buphthalmos.4 Histology confirmed viable retinoblastoma with poorly differentiated cells and areas of necrosis. In our case, the small viable tumor nodule contained undifferentiated neuroblastic cells without rosette formation.
The pathogenesis of spontaneous regression of retinoblastoma is unclear, but various hypotheses have been advanced. Verhoeff believed that calcification caused necrosis.14 Others have suggested an immunological mechanism, but pathologic analysis did not demonstrate a cellular immune reaction. The most widely accepted is an ischemic theory, namely that the tumor outgrows its blood supply and becomes necrotic. Occlusion of the central retinal artery has been observed occasionally, but whether this occurred prior to or after the necrosis could not be determined.2
Retinoma, retinocytoma, and spontaneously regressed retinoblastoma are currently considered similar entities. Several studies disclosed that although the loss or inactivation of both alleles of the RB1 tumor suppressor gene is necessary for initiation, it is not the only genomic change in retinoblastoma and additional genomic events are necessary for malignant transformation.18,19 Dimaras et al. demonstrated that although retinomas are benign they also display inactivation of both RB1 alleles, with a low level of genomic instability.20 Conversely, RB1 inactivation in the developing retina induces genomic instability. Epigenetic events also have an increasingly recognized role in oncogenesis. Changes in DNA methylation alter gene expression. Hypermethylation may affect the development of retinoblastoma through inactivation of the RB1 gene, whereas loss of hypermethylation may lead to spontaneous regression of the tumor.21
Many other conditions, such as trauma, infection, or endophthalmitis, can also lead to phthisis of the eye. We agree with the authors who postulated that retinoblastoma should be suspected in any child presenting with phthisis of unknown origin and a detailed examination of the other eye should be performed.4,5,10,11
Bilateral retinoblastoma with one phthisical eye is a rare condition. During the past 10 years (21 cases), this was the only case in our experience where the presenting sign was phthisis of the eye.
- Shields CL, Shields JA. Intraocular Tumors: An Atlas and Textbook. Philadelphia: Lippincott, Williams & Wilkins; 2008.
- Zimmerman LE. Retinoblastoma and retinocytoma. In: Spencer WH, ed. Ophthalmic Pathology. San Francisco: American Academy of Ophthalmology; 1985:1326–1328.
- Abramson DH, Frank CM, Susman M, Whalen MP, Dunkel IJ, Boyd NW 3rd, . Presenting signs of retinoblastoma. J Pediatr. 1998;132:505–508. doi:10.1016/S0022-3476(98)70028-9 [CrossRef]
- Harrison D, Richards J, Andronikou S, Welman C. Bilateral retinoblastoma presenting with simultaneous phthisis bulbi and buphthalmos. J Pediatr Ophthalmol Strabismus. 2003;40:161–163.
- Mullaney PB, Karcioglu ZA, al-Mesfer S, Abboud EB. Presentation of retinoblastoma as phthisis bulbi. Eye. 1997;11:403–408.
- Gallie BL, Ellsworth RM, Abramson DH, Phillips RA. Retinoma: spontaneous regression of retinoblastoma or benign manifestation of the mutation?Br J Cancer. 1982;45:513–521.
- Challis GB, Stam HJ. The spontaneous regression of cancer: a review of cases from 1900 to 1987. Acta Oncol. 1990;29:545–550. doi:10.3109/02841869009090048 [CrossRef]
- Abramson DH. Retinoma, retinocytoma, and the retinoblastoma gene. Arch Ophthalmol. 1983;101:1517–1518.
- Gangwar DN, Jain IS, Gupta A, Sharma PC. Bilateral spontaneous regression of retinoblastoma with dominant transmission. Ann Ophthalmol. 1982;14:479–480.
- Khodadoust AA, Roozitalab HM, Smith RE, Green WR. Spontaneous regression of retinoblastoma. Surv Ophthalmol. 1977;21:467–47810. doi:10.1016/S0039-6257(77)80003-9 [CrossRef]
- Mehra KS, Banerji C. Spontaneous regression of retinoblastoma. Br J Ophthalmol. 1965;49:381–382. doi:10.1136/bjo.49.7.381 [CrossRef]
- Arnold EL, Smith JLS, Steward JK. Spontaneous regression of retinoblastoma. Br J Ophthalmol. 1956;40:449–461. doi:10.1136/bjo.40.8.449 [CrossRef]
- Ungaro ABS, da Cunha SL, Santo RM. Congenital retinoblastoma: report of a case. Arq Bras Oftalmol. 2002;65:571–573. doi:10.1590/S0004-27492002000500014 [CrossRef]
- Verhoeff FH. Retinoblastoma undergoing spontaneous regression: calcifying agent suggested in treatment of retinoblastoma. Am J Ophthalmol. 1966;62:573–574.
- Gallie BL, Phillips RA, Ellsworth RM, Abramson DH. Significance of retinoma and phthisis bulbi for retinoblastoma. Ophthalmology. 1982;89:1393–1399.
- Balmer A, Munier F, Gailloud C. Retinoma and phthisis bulbi: benign expression of retinoblastoma [article in French]. Klin Monatsbl Augenheilkd. 1992;200:436–439. doi:10.1055/s-2008-1045786 [CrossRef]
- Kaimbo WK, Mvitu MM, Missotten L. Presenting signs of retinoblastoma in Congolese patients. Bull Soc Belge Ophtalmol. 2002;283:37–41.
- Singh AD, Santos CM, Shields CL, Shields JA, Eagle RC Jr, . Observations on 17 patients with retinocytoma. Arch Ophthalmol. 2000;118:199–205.
- Sampieri K, Mencarelli MA, Epistolato MC, et al. Genomic differences between retinoma and retinoblastoma. Acta Oncologica. 2008;47:1483–1492. doi:10.1080/02841860802342382 [CrossRef]
- Dimaras H, Khetan V, Halliday W, et al. Loss of RB1 induces non-proliferative retinoma: increasing genomic instability correlates with progression to retinoblastoma. Hum Mol Genet. 2008;17:1363–1372. doi:10.1093/hmg/ddn024 [CrossRef]
- Greger V, Passarge E, Höpping W, Messmer E, Horsthemke B. Epigenetic changes may contribute to the formation and spontaneous regression of retinoblastoma. Hum Genet. 1989;83:155–158. doi:10.1007/BF00286709 [CrossRef]