With approximately one case per 15,000 to 20,000 live births, retinoblastoma is one of the rare cancers [1]. For those affected – mostly children under the age of three – and their families, the diagnosis of retinal tumor brings great challenges. On the one hand, the genetic component of the disease cannot be neglected, and on the other hand, therapy is not infrequently associated with long-term damage. Especially in hereditary retinoblastoma, lifelong tumor follow-up is essential.
Whether familial or not, the focus is on one gene: RB1. This is a tumor suppressor gene on chromosome 13q14, coding for the so-called “retinoblast protein” Rb. If this fails, retinoblasts degenerate, resulting in infantile retinal tumors: retinoblastomas. Here, the type of mutation – it can be deletions, insertions, translocations, or point mutations – is less significant than affecting both alleles of RB1. This was already described by the US geneticist and oncologist Alfred Knudson in his famous “two-hit hypothesis”. Two “hits” are needed to switch off the tumor suppressor gene; only when both alleles are mutated does a normal retinal cell turn into a cancer cell [1]. This process can be significantly shortened in the presence of a germline mutation. This is because if the function of an allele is already switched off, only one “hit” is needed to cause the degeneration of the cell. If, on the other hand, there is no germline mutation, this requires two random mutations. No wonder, then, that hereditary retinoblastoma accounts for about half of all cases and usually occurs earlier [2].
Hereditary retinoblastoma: consequences for the whole family
In contrast to sporadic retinoblastoma, the hereditary form usually occurs bilaterally and sometimes multifocally – a logical consequence of the germline mutation present, which affects all cells equally and thus also makes them equally susceptible to cancer development. The germline mutation can either be inherited or occur de novo, which is more common. Accordingly, only 10% of patients have a positive family history [1]. It is important not to miss family cases. This is because not only the risk for the development of retinoblastoma is significantly increased by RB1 germline mutations, but also that for the development of other cancers such as bone and soft tissue sarcomas [2]. Genetic testing with appropriate counseling should be performed in all patients to provide optimal care for the entire family. Ophthalmologic and genetic examinations of parents and siblings are also highly valued [2].
After surviving the disease, tumor follow-up in hereditary retinoblastoma plays a central role. On the one hand, the aim is to detect retinoblastoma recurrences early by regular ophthalmoscopy. On the other hand, second malignancies should be prevented. These occur within 40 years in approximately 32% of affected individuals [3]. They are particularly common after radiotherapy, with an increased incidence of malignancies of the periorbital region, and after chemotherapy.
The cat’s eye: symptoms, diagnosis, classification
In general, retinoblastomas often remain undetected for a long time. The classic first symptom is the lack of a red reflex, the so-called “leukocoria”, also known as “cat’s eye”. In this process, the tumor reflects incident light and makes the pupil appear white. Other possible symptoms – not always easy to recognize in young children – include strabismus, visual deterioration, glaucoma, eye pain, and exophthalmos. Sometimes cognitive or motor developmental disorders occur, which are caused by more extensive deletions on chromosome 13 [4].
If retinoblastoma is suspected, the workup essentially includes ophthalmoscopy, sonography, and MRI [2]. A metastasis search may be necessary, and in any case human genetic clarifications should be performed. Once the diagnosis is established, retinoblastoma can be classified using different systems. In principle, a distinction is made between intraocular tumors – i.e. tumors confined to the eye – and extraocular tumors. While the International Classification System for Intraocular Retinoblastoma (ICRB) (Table 1) is used for intraocular retinoblastomas, extraocular malignancies are classified using the International Retinoblastoma Staging System (IRSS) (Table 2). [5]. Furthermore, there is a TNM classification which can be applied to all retinoblastomas [5]. The more extensive the finding, the worse the prognosis. If the lethality is less than 5% with early diagnosis and therapy, almost all untreated patients die, mostly from the consequences of metastasis. ICRB classification provides an approximate prediction of the chances of therapeutic success. Thus, in risk groups A-C, the eye can be saved in more than 90% of cases, in group D only about half of the patients get away without enucleation, and in those affected in group E, enucleation is primarily performed [5].
Therapy: A tightrope walk
In the treatment of retinoblastoma, it is important to find an optimal balance between minimizing risk and preserving sight. Radiation has become less important due to the increased risk of second malignancies and eye-preserving therapy is increasingly used, even for large lesions. [1]. In general, due to the rarity of the disease, treatment should be performed at specialized centers. Factors influencing the choice of therapy are, in addition to the stage, the pattern of infestation and the age of the child. In principle, either the eye is removed (enucleation) or eye-preserving therapy is given, using radiation, laser, cryotherapy, and/or chemotherapy [2].
For the therapy of intraocular retinoblastoma without vitreous seeding different focal treatment methods are available, especially laser, cryo-, thermo-chemo- and brachytherapy. While laser therapy is mainly used for posterior findings, cryotherapy is mainly used for peripheral tumors. If these methods are insufficient to remove the lesion or if the thickness is greater than 2 but less than 4 mm, either local heating is performed after prior systemic carboplatin administration (thermochemotherapy) or brachytherapy is performed using episcleral seeds [1]. Other bulb-preserving options include superselective intra-arterial chemotherapy, which usually involves the delivery of melphalan directly into the ocular vasculature via catheter, and intravitreal chemotherapy. Melphalan is also usually used in the latter method, and it is applicable even in vitreous seeding [2].
In some cases, systemic chemotherapy is necessary to reduce tumor volume prior to the use of focal therapeutic procedures. Carboplatin, cyclophophamide, etoposide, and/or vincristine are used for this purpose [1]. Percutaneous irradiation is nowadays reserved for special circumstances due to the increased risk of second malignancies and is used especially for recurrences [1].
If it is an advanced retinoblastoma, enucleation – removal of the bulb and parts of the optic nerve – usually cannot be bypassed. This is particularly problematic in the case of bilateral infestation; attempts are always made to preserve at least the one-sided eyesight. By using a glass eye as soon as possible, the bony development of the facial skull can be supported and a good cosmetic result can be achieved [1]. In cases where R0 resection cannot be achieved, adjuvant chemotherapy or radiotherapy follows surgery.
Literature:
- AMBOSS Knowledge: Retinoblastoma. www.amboss.com/de/wissen/Retinoblastom (last accessed Jan 04, 2022).
- DKG: Retinoblastoma. www.krebsgesellschaft.de/onko-internetportal/basis-informationen-krebs/krebsarten/weitere-krebsarten/retinoblastom.html (last accessed on 04.01.2022)
- Speer, Gahr: Pediatrics. 4th ed. Springer 2013.
- Broaddus E, Topham A, Singh AD: Survival with retinoblastoma in the USA: 1975-2004. Br J Ophthalmol. 2009; 93(1): 24-27.
- Fabian ID, Reddy A, Sagoo MS: Classification and staging of retinoblastoma. Community eye health. 2018; 31(101): 11-13.
InFo ONCOLOGY & HEMATOLOGY 2022; 10(1): 44-45.
