An atypical clinical/radiological presentation of Retinoblastoma in a 4-year-old child: A case report & educational lessons from Syria

Abstract

Introduction: 

Retinoblastoma (Rb), the most common intraocular malignancy of children, typically presents with leukocoria or strabismus, and in later stages, the most common sign may be proptosis. Radiological techniques show calcification as an important finding for the diagnoses. This neoplasm can mimic any orbital or ocular disease in its atypical clinical/radiological presentations, which delay the diagnosis leading to high mortality rates.

Case presentation: 

Here we report a case of a 4-year-old male child who presented to our hospital with ocular pain, edema, and inflammatory signs in the right eye, with no calcification. Clinical examination and radiological techniques suggested a broad spectrum of differential diagnoses, including orbital Inflammatory pseudotumor. The patient received intravenous fluids and antibiotic therapy, while awaiting further investigations. He was kept under observation status for days and discharged home with a stable condition. After 6 months, He developed severe painful proptosis with a large extraocular mass. Orbital magnetic resonance imaging showed an orbital mass extending outside the orbit in a non-functional eye. Therefore, right eye exenteration was performed, and pathologic examination revealed the diagnosis of Rb. Adjuvant chemotherapy was applied postoperatively. After 3 months of progressive decline because of distant multiple metastases, the patient died.

Clinical discussion & conclusion: 

Rb must be considered in the differential diagnosis for any intraocular disease, due to the importance of early diagnosis and management. In this manuscript, we aimed to present a case of Rb with atypical symptoms including ocular pain, edema, inflammatory signs, then proptosis, with no finding of calcification in a Syrian child, highlighting a bunch of educational lessons for healthcare workers in developing countries.

HIGHLIGHTS 

• At early stages of Retinoblastoma (Rb), most patients present with leukocoria and strabismus. At later stages, patients may exhibit proptosis, buphthalmos, or hypopyon.
• Patients also might be asymptomatic, or rarely with atypical presentations in advanced cases, including any orbital or ocular disease.
• Retinoblastoma (Rb) must be considered in the differential diagnosis for any intraocular disease, due to the importance of early diagnosis and management.
• Retinoblastoma (Rb) may lead to a diagnostic dilemma ends with death especially in developing countries.
• The management should be a team approach by the parents, pediatric oncologists, ophthalmologists, and radiologists.

1. Introduction

Retinoblastoma (Rb), the most common intraocular malignancy of children, occurs due to mutation of the Rb1 gene on chromosome 13q14 [¹]. Rb is often a highly calcified tumor, typically presents with leukocoria or strabismus, and in later stages, the most common sign may be proptosis [²]. Rb can mimic any orbital or ocular disease in its atypical clinical/radiological presentations, which delay the diagnosis and worsen the prognosis [³]. Delayed diagnosis of more than 6 months from the first clinical sign leads to spreading of Rb from the eye, and a 70% mortality rate in developing countries [⁴]. Herein, we present a case of a Syrian child with atypical clinical/radiological features, which led to lethal extensive complications.

2. Case presentation

A 4-year-old male child presented with ocular pain and edema in the right eye, within 3 days of evolution. Ophthalmological evaluation; bedside evaluation and slit-lamp examination included ocular annexes and anterior segments, revealed normal Intraocular pressure (IOP), eyelids edema, and conjunctival hyperemia. Direct and indirect pupillary reflexes were present, other anterior parts were within normal, posterior segments were difficult to evaluate due to the patient noncooperation. The left eye was normal. Computed tomography (CT) of the head and orbit, showed no calcification, nonspecific thickening structures, sclera, and adjacent tissue, with enhanced inflammatory tissues surrounding the optic nerve. Based on the clinical features, and the anatomical patterns. There were many differential diagnoses including orbital Inflammatory pseudotumor (OIP), orbital trauma, optic neuritis, etc. Magnetic resonance imaging (MRI) wasn't performed due to financial constraints. The patient received IV fluids and IV antibiotic therapy, while awaiting further investigations. He was kept under observation status for days and discharged home due to the insistence of the parents. After 6 months, he came back because of a worsening condition, developing severe painful proptosis with a large extraocular mass in the right eye (Fig. 1). The direct and indirect pupillary reflexes were absent and very hard to evaluate. Orbital and brain MRI showed an orbital mass, with high signal intensity on T1-weighted images and low signal intensity on T2-weighted images compared to the vitreous. The mass was developing outside the orbit and growing to involve muscles, optic nerve, and bony socket, especially in the anterior parts, extending along the optic nerve sheath to the level of the optic foramen to the anterior part of the cavernous sinus, with sinus effusion, bony destruction, and luxation of the eyeball (Figs. 2 and 3). Based on the MRI findings which were suspicious of Rb, neoadjuvant chemotherapy was performed, but with no response. Lid sparing exenteration was discussed thoroughly with parents. They hardly consented to the surgery, and right eye exenteration was performed. In the pathology report, macroscopic examination revealed a mass with no obvious anatomical signs, covered by skin with central ulceration; its cut surface shows wide infiltration by soft white tissue with areas of hemorrhage and necrosis; all resection margins are involved. Eye & orbital mass; Infiltration by small round blue cell tumor with extensive necrosis. The tumor involves the skin with ulceration. Resection margins are involved by the tumor. Specimen from the posterior orbit; wide infiltration by the tumor involving soft tissues (muscular, adipose, and fibrous tissues) and a fragment of optic nerve tissue. Specimen from upper and lower eyelids; focal infiltration by the tumor in both specimens. Microscopic examination demonstrated Flexner-Wintersteiner rosettes, with poorly differentiated tumor cells, large hyperchromatic nuclei, and numerous mitotic figures (Fig. 4). Tumoral cells were positive for NSE, focal and mild positive for Melanoma Cocktail (Fig. 5). According to these findings, the lesion was diagnosed as Rb. Six cycles of adjuvant chemotherapy (vincristine, carboplatin, and etoposide) were applied postoperatively. After 3 months of progressive decline because of distant multiple metastases to the brain and the right side of the mandible, the patient died.

Fig. 1.: Severe proptosis with a large extraocular mass (associated with advanced Rb).

Fig. 2.: Axial, coronal, and sagittal post-gadolinium T1-weighted images, respectively. Showing massive enlargement of the intraocular heterogeneous enhancing mass with interruption of the sclera, extrascleral extension, and invasion of the optic nerve. Bony destruction is also noticed.

Fig. 3.: Axial, coronal, and sagittal T2-weighted images, respectively. showing luxation of the globe and retro ocular extension with sinus effusion. No invasion of the brain tissue is noticed.

Fig. 4.: a Poorly differentiated tumor cells, large hyperchromatic nuclei, and numerous mitotic figures with Flexner-Wintersteiner rosettes (H&E stain × 200), b Poorly differentiated tumor cells, large hyperchromatic nuclei, and numerous mitotic figures with Flexner-Wintersteiner rosettes (H&E stain × 400), c massive necrosis (H&E stain × 400).

Fig. 5.: a Immunohistochemistry of the neoplasm: positivity for NSE, b focal and mild positivity for Melanoma Cocktail.

3. Discussion

Rb is the most common eye childhood malignancy [⁴], typically before the age of 5 in 95% of patients [¹]. At early stages, most patients present with leukocoria and strabismus. At later stages, patients may exhibit proptosis, buphthalmos, or hypopyon [¹]. Leukocoria is presented in 60–80% of cases, and identified by lay people because of an inadvertent finding on flash photography [^1,2]. Patients also might be asymptomatic, or rarely with atypical presentations in advanced cases, including any orbital or ocular disease. Differential diagnosis DD of Rb includes simulating lesions (pseudoretinoblastomas) like Coats’ disease, persistent fetal vasculature (PFV), vitreous hemorrhage, ocular toxocariasis, familial exudative vitreoretinopathy (FEVR), rhabdomyosarcoma, etc [⁵]. Also, metastatic Rb can be a DD of OIP in children [⁶]. In our case, the patient's complaints were ocular pain, edema and inflammatory signs which are atypical presentations that led to misdiagnosis of OIP, delaying the correct diagnosis of Rb. The diagnosis of Rb is made early in developed countries while the tumor remains intraocular. However, in developing countries, most cases are diagnosed after a local invasion or distant metastases [^2,7]. If intraocular tumors are left untreated, extraocular spreading occurs within 6 months, by an invasion of either the optic nerve or the choroid into the cerebrospinal fluid (CSF), brain, spine, blood, lymph nodes, the soft tissues, or bones [⁸]. Metastatic Rb is considered to have a poor prognosis and only a few patients survive even after intensive chemotherapy [^2,7]. Rb is often a highly calcified tumor. Calcification is more often presented in older children and advanced disease, as a response to necrosis or tissue damage [²]. Using USG, Rb is typically an echogenic irregular retinal mass with focal acoustic shadows, ocular calcifications, and retinal detachment. However, it is not the imaging modality of choice in advanced Rb [^8,9]. CT has an 81–96% sensitivity of detection of calcifications in Rb and high specificity. Rb is discernible on CT as a mass of high density compared with the vitreous body, usually calcified and moderately enhanced after iodinated contrast medium administration. However, the sensitivity of CT in the evaluation of optic nerve invasion is very low, and in imaging intraocular soft tissue details are limited [⁹]. MRI is preferred in Rb because of the risk of radiation exposure (ionizing radiation) with CT imaging [^8,10]. The gold standard of Rb evaluation is the MRI of the orbits and brain [⁸]. It is the technique of choice to evaluate the intraocular tumors, determine disease extent, and its infiltration outside the eye [⁹]. MRI is the most superior non-invasive method in the detection of Rb optic nerve invasion, as it has an 80% specificity and a 74% sensitivity. Therefore, The European Retinoblastoma Imaging Collaboration (ERIC) released a guideline protocol for using MRI in Rb [¹⁰]. In the beginning, CT in our case suggested a broad spectrum of differential diagnoses; there was no finding of calcification, and that made us not think of Rb, especially since the symptoms were atypical, but when the disease progressed, MRI findings and clinical features were consistent with Rb. Rb is one of a few tumors which can be diagnosed and treated without histological confirmation via biopsy [^2,8]. Biopsy of Rb is rarely required, as it can induce extraocular spreading and seeding [²]. The gross appearance of Rb at the cut section of the eye depends on the stage of the tumor. It is presented with a white, encephaloid, or brain-like appearance, yellow necrotic areas, and chalky areas of calcification [^11,12]. Under the microscope, Rb may demonstrate large areas of necrosis and multifocal calcification. The viable tumor cells are small, hyperchromatic, and active cleavage with a high nuclear to cytoplasmic ratio [¹²]. These cells surround blood vessels and form a characteristic pseudorosette. We also find Flexner-Wintersteiner rosettes, which contain cells with projecting photoreceptors [¹¹]. In our case, the pathological study was made after lid sparing exenteration, and it was the way of a definitive diagnosis of Rb. Treatment decision depends on many factors including the prognosis of vision, age of the patient, location and size of the mass, and the presence or absence of seeding. Rb often needs a combination of therapies to optimize patient care [¹¹]. The treatment goals are first, saving the patient's life, and second, saving the vision. There are many treatment options like enucleation, laser photocoagulation, cryotherapy, thermotherapy, chemothermotherapy [⁷]. Enucleation is the definitive treatment of Rb. The frequency of enucleation gradually decreased due to improvement in other treatment methods [¹]. Currently, alternative approaches are being tested to avoid the toxicity of radiotherapy and chemotherapy and the risk of secondary tumors [⁷]. Our patient was treated with exenteration, and chemotherapy, as he had a very high-risk metastatic Rb due to the delay in diagnosis and treatment. These treatment methods did not stop the progression of the disease and the patient died. Finally, we have to mention that this work has been reported in line with the SCARE 2020 criteria [¹³].

4. Conclusions

No child with Rb should lose his chance of a cure, or die from metastases, because of delayed diagnosis and treatment. The management of Rb should be a team approach by the parents, pediatric oncologists, ophthalmologists, and radiologists. They should retain a high index of suspicion for Rb in all children with intraocular disease. The picture described in this case report could be a resource for teaching and learning, since it represents a healthcare encounter involving a real patient with a real clinical problem in a developing country, that offers a lens in which to view single episodes of care to facilitate the understanding of a larger body of evidence in developing countries, which may be reflected in our guidelines in third world (Table 1).

Table 1: A summary of the educational lessons from this case.

Author agreement statement

We the undersigned declare that this manuscript is original, has not been published before, and is not currently being considered for publication elsewhere. We confirm that the manuscript has been read and approved by all named authors and that there are no other persons who satisfied the criteria for authorship but are not listed. We further confirm that the order of authors listed in the manuscript has been approved by all of us. We understand that the Corresponding Author is the sole contact for the Editorial process. She is responsible for communicating with the other authors about progress, submissions of revisions, and final approval of proofs.

Authorship

All authors attest that they meet the current ICMJE criteria for Authorship.

Provenance and peer review

Not commissioned, externally peer reviewed.

Sources of funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Ethical approval

Not applicable, because this article does not contain any studies with human or animal subjects.

Consent

Written informed consent was obtained from the patient family for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.

Author contribution

MH: Drafted the article, collected the patient's data, and managed the team. AM: Participated in collecting the data and drafting the article. BB: Performed the ophthalmologic examination, patient care, and participated in revising and the article. AG: Performed the chemotherapy, patient care, and participated in revising the article. ZA: The guarantor and supervisor, performed and confirmed the pathological diagnosis including immunohistochemistry, and critically revised the article. All authors have read and approved the manuscript.

Registration of research studies

It's a case report; not a clinical trial.

Guarantor

Prof. Dr. Zuheir Alshehabi.

Declaration of competing interest

The Authors declare that there is no conflict of interest.

Acknowledgements

The authors would like to thank Kinda Khalil for performing the immunohistochemistry staining of the tumor.

Abbreviations

Rb Retinoblastoma

IOP Intraocular pressure

OIP Orbital Inflammatory pseudotumor

USG Ultrasonography

CT Computed tomography

MRI Magnetic resonance imaging

CD Cluster of differentiation

IV Intravenous

NSE Neuron-specific enolase

PFV Persistent fetal vasculature

FEVR Familial exudative vitreoretinopathy

IRSS International Retinoblastoma Staging System

IIRC International Intraocular Retinoblastoma Classification

ICRB Intraocular Classification of Retinoblastoma

TNM tumor nodes metastasis

CNS The central nervous system

CSF Cerebrospinal fluid

ERIC The European Retinoblastoma Imaging Collaboration

H&E Hematoxylin and eosin