Bilateral Extraocular Retinoblastoma Presenting With Buphthalmia and Phthisis Bulbi
Control at EMRO
Cairo, December, 2008

Figure 1. Clinical appearance at presentation. Massive right orbital mass and left eye phthisis bulbi.

A 2-year-old girl was referred to the JP. Hospital Garrahan from a distant province in Argentina with a diagnosis of suspected retinoblastoma. Her mother reported that she had been aware of leukocoria in the child's right eye since she was four months of age. The child lives in a rural area in a small house with her seven siblings. There is no family history of ocular malignancies. According to the mother's report, the girl was taken repeatedly to the primary care physicians, as well as ophthalmologists, none of whom recognized the potential serious implications of the finding. One month before being referred to the hospital, a rapidly growing, painful orbital mass developed and the child became blind. On physical examination, the child appeared to be in pain and severely malnourished, but neurological examination was normal. There were no enlarged lymph nodes (including the cervical and pre-auricular areas) or hepato-splenomegaly. A presumptive diagnosis of bilateral extraocular retinoblastoma was made. Investigations were performed to determine the extent of disease (i.e., disease stage). An ophthalmological examination revealed the presence of a right orbital mass and left phthisis bulbi (shrinkage of the eye) (Figure 1). Orbital and brain CT scan that showed an extensive orbital mass with calcifications in the right orbit and no evident CNS dissemination. Several skull periosteal lesions were evident on the CT scan examination. Abdominal ultrasound and bone scintigraphy were normal. A bone marrow examination, including bilateral aspirates and a biopsies, showed massive infiltration by non-hematopoietic cells that occasionally formed rosettes. These cells were positive for the ganglioside GD2 by immunocytology. Lumbar puncture and examination of the cytospin failed to show any malignant cell in the CSF. Other laboratory tests were normal, except for mild thrombocytopenia (110,000/mm³).

The child was categorized as Stage 4 (metastatic) retinoblastoma and treated initially with chemotherapy including cisplatin, cyclophosphamide, vincristine and etoposide as per the US Children's Oncology Group (COG) protocol.

Teaching points

1) Presentation with extraocular retinoblastoma

This patient presented with concomitant pthisis bulbi and an orbital mass, suggesting extraocular retinoblastoma. Extraocular retinoblastoma is distinctly uncommon in developed countries, but it is the most common presentation in low income countries¹. However, in middle income countries like Argentina, less than 5% of cases have retinoblastoma that has extended beyond the eye. Most patients with extraocular dissemination of retinoblastoma have unilateral retinoblastoma, bilateral retinoblastoma with extraocular dissemination being less common. Even more uncommon is the presentation with concomitant orbital mass and pthisis bulbi, as in the present case. This was reported in fewer than 1% of cases in a recent series². Phthisis bulbi occurs after an ocular inflammatory episode possibly related to intraocular tumor infarction. In most cases the tumor is not visible because of intraocular disruption. The majority of patients with extraocular disease, however, present with painful orbital masses. Pain, usually a consequence of long-standing glaucoma, leads to irritability and contributes to poor nutrition. Sometimes, irritability is a sign of increased intracranial pressure, such that a careful evaluation of the CNS is mandatory. Advanced extraocular disease is probably the consequence of delayed diagnosis of retinoblastoma, as is clearly the case in the present patient, who was seen by several physicians (including ophthalmologists) who failed to make an accurate diagnosis. In many countries, campaigns for increasing awareness of the presenting signs of retinoblastoma in order to promote earlier diagnosis have been were launched³.

2) Staging of retinoblastoma

The metastatic pattern of retinoblastoma includes involvement of the CNS, which the tumor may reach either through the optic nerve or through the systemic circulation. Systemic dissemination usually presents with metastases to the bone and the bone marrow. Other sites of dissemination include the liver. Therefore, staging of extraocular retinoblastoma should include CNS imaging. Magnetic resonance imaging (MRI) is preferred in order to avoid the radiation exposure associated with a CT scan, since patients with retinoblastoma are predisposed to the development of second malignancies, particularly within irradiated sites. In our case, the more rapid access to CT scanning was felt to outweigh the benefits of MRI, since it was important to initiate therapy immediately. Bone marrow examination is mandatory and should preferably include at least two biopsies from different sites since involvement may be patchy and tumor invasion may be missed with a single aspirate⁴. The use of immunocytology examination, e.g., using GD2 as in the present case, may increase the likelihood of finding retinoblastoma cells and confirming their identity⁴. Occasionally, circulating retinoblastoma cells may be detected in advanced cases⁵. Bone marrow involvement was suspected in this case because of thrombocytopenia, but there were no evident circulating cells.

Until recently, there was no consensus staging system for retinoblastoma and many staging systems have been developed, such that comparison of results in published data can be difficult. However, a recent international group developed a new staging system and most cooperative groups involved in the treatment of retinoblastoma have agreed to adopt it⁶. This initiative also includes the procedure, arrived at by consensus, for the pathological examination of enucleated eyes in order to have common definitions for whether there is involvement of the various layers of the eye (choroid and sclera)⁷. Complete work-up for metastases must include bone scintigraphy in extraocular cases or where there is a clinical suspicion of bone meatastasis (e.g., persistent localized bone pain or swelling)⁸.

3) Treatment of Retinoblastoma

Patients with retinoblastoma should be evaluated by a multidisciplinary team and treated in tertiary care centers. Mutilating surgical procedures such as orbital excenteration, leading to facial disfigurement without therapeutic benefit, should be strongly discouraged⁹. Since retinoblastoma is a chemosensitive tumor, initial chemotherapy is the treatment of choice. Standard chemotherapy normally includes a platinum derivative such as carboplatin or cisplatin¹⁰, an alkylating agent such as cyclophosphamide or ifosfamide¹¹ and etoposide^{10, 11}. Other active drugs include anthracyclines¹² and topotecan¹³. Presurgical (neoadjuvant) chemotherapy will generally permit more limited surgery - usually after three or four cycles – to be performed, e.g., orbital excenteration can be avoided^{14, 15}.

Despite being a chemosensitive tumor, extraocular retinoblastoma usually relapses with conventional treatment¹⁶, so metastatic retinoblastoma was considered to be incurable until more intensive regimens, including high-dose chemotherapy and stem cell rescue^{17, 18} were explored. A current international initiative led by the COG involves the use of high-dose chemotherapy and stem cell rescue. Such treatment is expensive and requires appropriate facilities and knowledge, which is not widely available in the developing world (it is available at the Garrahan hospital and will be used in this child). The prognosis of children with CNS dissemination, however, remains dismal, even with high-dose chemotherapy, and most cases are treated palliatively in less developed countries.

4) Prevention of metastatic retinoblastoma

Metastatic retinoblastoma is more frequent in less developed countries, almost certainly as a consequence of delayed diagnosis¹⁹. This is a social problem with multiple causes. The INCTR retinoblastoma strategy group is conducting a survey of affected families to try to identify the factors that influenced delayed diagnosis. Many countries have launched campaigns directed towards raising public awareness that leukocoria may be an early sign of cancer3. However, it is difficult to estimate their impact, and such campaigns need to reach a high fraction of the population to be successful. In addition, awareness of the early signs of retinoblastoma among primary care physicians, pediatricians and ophthalmologists needs to be raised. Screening of retinoblastoma would imply ocular examinations under anesthesia, which is not generally feasible in less developed countries and since retinoblastoma occurs only in 1/17,000 cases, the cost-benefit ratio is unlikely to be favorable. Screening of children in families known to be predisposed genetically to retinoblastoma, however, should be done, but even in mid-income countries only some 45% of children in this situation are screened – a suboptimal situation²⁰. More emphasis should be given to the screening of children in afflicted families.

Delayed diagnosis is not the only factor predisposing to metastatic disease. Treatment refusal is another quite common phenomenon in less developed countries²¹. This problem requires a different solution, particularly education about the existence of prosthetic eyes (and making such prostheses available). Demonstrating their use in enucleated children could greatly allay fears of disfigurement, and sufficient time to adapt to the idea of enucleation (which is provided when neoadjuvant therapy is given first) could also be helpful. Above all, sensitivity and training of staff in discussing options and consequences with the parents is a vital component of ensuring that treatment is accepted promptly and metastasis and death, hopefully, avoided.

Claudia Sampor, Veronica Celis Passini and Guillermo Chantada
Hospital JP Garrahan,
Buenos Aires, Argentina

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