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Year : 2022  |  Volume : 2  |  Issue : 1  |  Page : 170-174

A rare case of bilateral retinoblastoma metastasizing into the forearm

1 Vitreoretinal Services, Chaithanya Eye Hospital and Research Institute; Department of Research, Chaithanya Innovation in Technology and Eyecare (Research), Trivandrum, Kerala, India
2 Vitreoretinal Services, Chaithanya Eye Hospital and Research Institute, Trivandrum, Kerala, w, Trivandrum
3 Department of Imageology, Regional Cancer Center, Trivandrum, Kerala, India
4 Department of Pathology, Regional Cancer Center, Trivandrum, Kerala, India

Date of Submission22-Mar-2021
Date of Acceptance28-Aug-2021
Date of Web Publication07-Jan-2022

Correspondence Address:
Dr. Jay U Sheth
Surya Eye Institute and Research Center, Mumbai - 400 080, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijo.IJO_658_21

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We present a case of an 8-year-old boy who had undergone chemotherapy with transpupillary thermotherapy for bilateral retinoblastoma (RB) at the age of 6 months. The patient had left forearm pain at the present visit. Bilateral ocular examination did not reveal any signs of RB reactivation. However, bone scan with technetium 99m-methyl diphosphonate (99mTc–MDP) and magnetic resonance imaging (MRI) showed the presence of metastasis in the proximal end of the ulnar bone, which was confirmed on bone marrow biopsy. Based on PCR study and molecular analysis, Ewing's sarcoma was ruled out and the patient was confirmed to have metastatic RB. Subsequently, he underwent chemotherapy along with wide excision of left proximal ulna + extracorporeal radiation therapy (ECRT) + plate reconstruction. At 15-month follow-up, the patient was stable with absence of recurrence of RB. This case highlights the need for long-term follow-up of patients with RB and the need for timely detection and management of metastasis.

Keywords: Leukocoria, metastasis, retinoblastoma, ulnar bone

How to cite this article:
Soman M, Iqbal S, Katoor J, Puthiyedath N, Sheth JU, Nair U. A rare case of bilateral retinoblastoma metastasizing into the forearm. Indian J Ophthalmol Case Rep 2022;2:170-4

How to cite this URL:
Soman M, Iqbal S, Katoor J, Puthiyedath N, Sheth JU, Nair U. A rare case of bilateral retinoblastoma metastasizing into the forearm. Indian J Ophthalmol Case Rep [serial online] 2022 [cited 2022 Aug 14];2:170-4. Available from: https://www.ijoreports.in/text.asp?2022/2/1/170/334969

Retinoblastoma (RB) is one of the most common intraocular childhood malignancies characterized by biallelic inactivation of the tumor suppressor gene RB1.[1] With early diagnosis and adequate treatment, more than 95% of patients are long-term survivors. Extraocular metastatic spread of retinoblastoma is a rare event that mostly happens within the first three years of initial diagnosis and usually mostly involves the central nervous system. Cases of distant metastasis from RB usually carry a poor prognosis.[1]

We report a case of treated bilateral retinoblastoma metastasizing to the left forearm. The patient subsequently underwent multidisciplinary therapy including surgical excision of mass from left forearm, and no recurrence was noted at 15-month follow-up. Written informed consent was obtained from the patient for publication of this case report and the accompanying images.

  Case Report Top

An 8-year-old boy, a diagnosed case of bilateral retinoblastoma, came to us for regular ocular follow-up. The patient is the first child of a nonconsanguineous marriage with no significant family history. He was diagnosed to have bilateral retinoblastoma elsewhere after being presented with leukocoria in the left eye (OS) at the age of 6 months. Based on the International Classification of Retinoblastoma (ICRB), he had Group-C and Group-D intraocular RB in the right eye (OD) and OS, respectively. No cerebrospinal fluid (CSF) or bone marrow (BM) analysis was performed at baseline. Initially, he underwent six cycles of chemotherapy, Vincristine, Etoposide, Carboplatin (VEC), in 2011. As the residual disease was present after chemotherapy, he also received subsequently focal transpupillary thermotherapy (TTT) and periocular carboplatin treatment in April 2012, following which the tumor regressed well. He was under periodic follow-up, and regular clinical and ophthalmological follow-up examinations were unremarkable for the next 6 years.

In October 2018 when the child was 8 years old, he presented with pain in the left upper forearm. Systemic examination was within normal limits. No visible mass lesion was seen in the left forearm region. Ophthalmic examination revealed best-corrected Snellen visual acuity of 6/6, N6 in OD and CF 1 m, <N36 in OS. The left eye showed a round, mid-dilated, sluggish reacting pupil with Grade 3 Relative Afferent Pupillary Defect (RAPD). The rest of the anterior segment was within the normal limit. Dilated fundus examination showed attached retina in both eyes with regressed calcified tumor mass in inferonasal quadrant of right eye and areas of chorioretinal scarring in the periphery [Figure 1]a. The left eye showed regressed calcified mass involving temporal disc margin and macula with peripheral pigmentary changes [Figure 1]b. No vitreous seeding or subretinal fluid was noted in either of the eyes. Routine blood evaluation and Chest X-ray were normal. No cells were present on CSF examination. Computerized tomography (CT) scan of thorax was normal and there was no evidence of pulmonary metastasis. Magnetic resonance imaging (MRI) brain did not reveal any central nervous system (CNS) metastasis or pineoblastoma. Whole-body scan was done with 15mCi of 99mTc-MDP (Technetium 99m-methyl diphosphonate), showing abnormally increased localization of radiopharmaceutical seen only at the proximal end of radius/ulna, suggestive of possible metastasis. MRI bone showed abnormal hyperintensity in metaphysis and diaphysis of left ulnar bone, with cortical erosion and erosion on the radial side [Figure 2]a, [Figure 2]b, [Figure 2]c. Bone marrow biopsy from the iliac crest region showed moderate cellular marrow with erythroid, myeloid series with eosinophilia, and megakaryocytes. Trucut biopsy of the left ulna was done, which showed malignant round cell neoplasm infiltrating the bone indicative of micrometastasis [Figure 3]a. Tumor cells were synaptophysin diffuse moderate positive, chromogranin focal granular positive, CD-56 (the neural cell adhesion molecule [NCAM]) diffuse strong positive, leukocyte common antigen (LCA) negative, myogenin negative, and desmin negative [Figure 3]b. MIC-2, a specific marker for Ewing's sarcoma, showed diffuse granular membrane staining. Possibilities of metastatic retinoblastoma and localized Ewing's sarcoma/primitive neuroectodermal tumor (PNET) were considered.
Figure 1: (a) Wide-field fundus photograph of the right eye showing the regressed multifocal Retinoblastoma with a calcific lesion at 4 o'clock and atrophic lesions at 8 and 1 o'clock locations. (b) Wide-field fundus photograph of the left eye illustrating the regressed calcific retinoblastoma involving the macula and overlying the temporal disc margin

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Figure 2: (a and b) Post-contrast coronal T1-weighted magnetic resonance imaging (MRI) images showing patchy heterogeneous enhancement of marrow involving the meta-diaphyseal region of the proximal ulna (red arrowheads)

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Figure 3: (a) Biopsy section from bone showing sheets of small round cells with scanty pale cytoplasm and hyperchromatic round nuclei. Immunohistochemistry revealed CD56 (b) and synaptophysin (c) diffusely positive, CD99 (d) granular cytoplasmic and membrane positive, and chromogranin (e) focal weak positivity

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Molecular studies were sought, and real-time polymerase chain reaction (PCR) studies for translocation with Ewing's sarcoma (EWS FLI1 types 1 and 2: EWS-ERG and EWS-FEV) were found to be negative. A diagnosis of metastatic retinoblastoma was made. He underwent wide excision of left proximal ulna + extracorporeal radiation therapy (ECRT) + plate reconstruction [Figure 4]a and [Figure 4]b following which he completed chemotherapy (2 cycles of IV inj. vincristine 1.5 mg + inj. adreomycin 23 mg + inj. cyclophosphamide 470 mg × 2 days, followed by alternative cycles of inj. cisplatin 80 mg IV + inj. etoposide 80 mg + IV inj. vincristine 1.5 mg and inj. adreomycin 23 mg + inj. cyclophosphamide 470 mg × 2 days for 3 cycles each; a total of 8 cycles) between October 2018 and April 2019. Follow-up ocular examination showed no additional changes. He was advised regular ocular and systemic follow-up. The child has completed 15 months of follow-up, and a follow-up MRI was normal.
Figure 4: (a and b) Pre- and post-operative X-ray images of left forearm with post-operative images showing evidence of plate and screw fixation involving proximal shaft of the ulna

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  Discussion Top

Metastatic retinoblastoma, especially distant metastasis, represents a rare event in retinoblastoma but is reported in many developed countries.[2],[3] The frequency of metastatic retinoblastoma ranges from 4.8% to 11%.[3],[4] In patients with nonheritable retinoblastoma, subsequent malignancies are rare; however, primary sarcomas in the radiation field or elsewhere in the body can occur after previous external beam radiation therapy (EBRT).[5] Jubran et al.[6] suggested four patterns of metastatic retinoblastoma, each having different clinical features and outcomes: trilateral retinoblastoma, regional metastasis, extension into the (CNS), and distant metastasis. Leal et al.[7] reported that the most common site of metastasis was the central nervous system (83.9%) in a large series from the developing world. They reported that these children had high mortality and that the use of cisplatin as a primary chemotherapeutic agent was related to longer disease-free intervals. In another series, 20 out of 23 eyes of metastatic retinoblastoma had cranial involvement. One most commonly affected site of distant metastases is the bone marrow, infiltrated by tumor cells spread with the blood flow.[4],[6] These metastases may present as bone lesions and have to be carefully distinguished from other primary bone tumors.

Tumors with small blue round cell morphology include leukemias, lymphomas, Ewing's sarcoma, alveolar rhabdomyosarcoma, desmoplastic small round cell tumor (DSRCT), Ewing's sarcoma-like tumors, undifferentiated round cell sarcomas, osteosarcoma, or neuroblastoma with very different prognosis and varying treatments.[5] These tumors can be diagnosed and classified by immunohistochemistry and/or methods of molecular pathology.[8] Ting et al.[5] reported the usefulness of molecular pathology in ruling out Ewing's in a case of distant metastasis. The CD99, FLI1, and negative EWSR1- FISH assay is of particular relevance to exclude non-Ewing's sarcoma subtypes with small blue round cell morphology. Our case also points out that ancillary molecular testing, including immunohistochemistry, can further contribute to exclude rare differential diagnoses and discriminate metastatic retinoblastoma, especially in the setting of round cell tumors on histopathology. Though there are a handful of case reports of skeletal metastasis in bilateral RB, EBRT is often a common risk factor for such late-onset skeletal metastasis.[5],[9],[10],[11],[12],[13] However, our case represents a rare presentation of a long bone involvement without a prior history of EBRT. [Table 1] provides a literature review of RB patients with late-onset extraocular long bone metastasis without CNS involvement.
Table 1: Literature review of patients of retinoblastoma with late onset extraocular long bone metastasis without CNS involvement

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Retinoblastoma patients these days commonly receive globe-preserving therapy regimens and achieve survival rates of more than 95%. Therefore, an increase in primary subsequent malignancies or metastases may be expected, especially years after initial treatment. Hence, periodical evaluation of these patients is mandatory, although there are no guidelines regarding the follow-up protocol. However, the general consensus is that these patients need 6-monthly MRI, BM, and CSF analysis as is the protocol for extraocular retinoblastoma.[14] As whole-body MRI is not easily available, performing serial positron emission tomography (PET) scans would be ideal when such skeletal metastasis occurs. A regular follow-up of these cases and performing relevant investigations on the basis of symptoms and clinical presentations is the best approach. Even with regard to management, there is no standard of care; many cases in the literature managed successfully with wide excision and chemotherapy.[13] However, the contribution of external beam radiation therapy is still debatable. The Children's Oncology Group (COG) reported that intensive multimodality therapy including high-dose chemotherapy with autologous hematopoietic stem cell rescue was curative for the majority of patients with metastatic retinoblastoma without CNS metastasis.[15] However, this included nonskeletal metastasis as well.[15] The regimen includes induction chemotherapy usually consisting of vincristine, cyclophosphamide, cisplatin, and etoposide, followed by a high-dose chemotherapy regimen including carboplatin and thiotepa alone or with etoposide/topotecan.[15] Retinoblastoma-free and event-free survival at 5 years was 67% and 59%, respectively.[15]

  Conclusion Top

In conclusion, this case highlights the role of long-term periodic follow-up of RB patients and the occurrence of distant metastasis even in the absence of an EBRT treatment. Distant metastases of retinoblastomas including bone lesions should be included in the differential diagnosis of bone tumors in RB patients. Ancillary molecular testing including immunohistochemistry can aid in differentiating causes of bone metastasis and should be considered while devising strategies for surveillance in these patients.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.

  References Top

MacKay CJ, Abramson DH, Ellsworth RM. Metastatic patterns of retinoblastoma. Arch Ophthalmol 1984;102:391-6.  Back to cited text no. 1
Karcioglu ZA, al-Mesfer SA, Abboud E, Jabak MH, Mullaney PB. Workup for metastatic retinoblastoma. A review of 261 patients. Ophthalmology 1997;104:307-12.  Back to cited text no. 2
Cozza R, De Ioris MA, Ilari I, Devito R, Fidani P, De Sio L, et al. Metastatic retinoblastoma. Single institution experience over two decades. Br J Ophthalmol 2009;93:1163-6.  Back to cited text no. 3
Gunduz K, Muftouglu O, Gunalp I, Unal E, Tacyildiz N. Metastatic retinoblastoma: Clinical features, treatment and prognosis. Ophthalmology 2006;113:1556-8.  Back to cited text no. 4
Ting SC, Kiefer T, Ehlert K, Goericke SL, Hinze R, Ketteler P, et al. Bone metastasis of retinoblastoma five years after primary treatment. Am J Ophthalmol Case Rep 2020;17;19:100834.  Back to cited text no. 5
Jubran RF, Erdreich-Epstein A, Buturini A, Murphree AL, Villablanca JG. Approaches to treatment for extraocular retinoblastoma. Children's Hospital Los Angeles experience. J PediatrHematol Oncol 2004;26:31-4.  Back to cited text no. 6
Leal-Leal CA, Rivera-Luna R, Flores-Rojo M, Juárez-Echenique JC, Ordaz JC, Amador-Zarco J. Survival in extra-orbital metastatic retinoblastoma: Treatment results. Clin Transl Oncol 2006;8:39-44.  Back to cited text no. 7
Terry J, Calicchio ML, Rodriguez-Galindo C, Perez-Atayde AR. Immunohistochemical expression of CRX in extracranial malignant small round cell tumors. Am J Surg Pathol 2012;36:1165-9.  Back to cited text no. 8
Hadley NA, Kearns R, Kapp W. Bone metastasis from retinoblastoma. Iowa Orthop J 1993;13:214-7.  Back to cited text no. 9
Mulligan ME, Smith SE, McCarthy EF Jr. Isolated lower extremity metastases, 9 years after initial diagnosis of retinoblastoma. Skeletal Radiol 2006;35:774-7.  Back to cited text no. 10
Kuruva M, Mittal BR, Kashyap R, Bhattacharya A, Marwaha RK. Bilateral retinoblastoma presenting as metastases to forearm bones four years after the initial treatment. Indian J Nucl Med 2011;26:115-6.  Back to cited text no. 11
[PUBMED]  [Full text]  
Kelsey LGR, Vayego CF, Inafuku CY, Timóteo da Rocha E, dos Santos MJ, Alves WEFM, et al. Detection of extraocular lesions in a patient with bilateral retinoblastoma using 18F-FDG PET/CT. Biomed J Sci Tech Res 2019;17:12632-4.  Back to cited text no. 12
Vempuluru VS, Jakati S, Kaliki S. Delayed metastasis in patients with intraocular retinoblastoma: A review of three cases. Eur J Ophthalmol 2021;31:2042-7.  Back to cited text no. 13
Rao R, Honavar SG. Recent developments in retinoblastoma. DJO 2016;27:50-61.  Back to cited text no. 14
Dunkel IJ, Khakoo Y, Kernan NA, Gershon T, Gilheeney S, Lyden DC, et al. Intensive multimodality therapy for patients with stage 4a metastatic retinoblastoma. Pediatr Blood Cancer 2010;55:55-9.  Back to cited text no. 15


  [Figure 1], [Figure 2], [Figure 3], [Figure 4]

  [Table 1]


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