Patients with a history of heritable retinoblastoma are at increased risk for non-retinoblastoma second primary tumours (SPT), most commonly bone sarcoma, leiomyosarcoma, other soft tissue sarcoma, malignant melanoma, lung cancer and midline brain tumours.rrrr There is emerging data that there may also be an increased risk of other common solid cancers, including bladder and breast cancer.
Reduced penetrance RB1 pathogenic variants are associated with an increased risk of SPT, including an increased risk for carriers who have not had retinoblastoma, although there is insufficient data to accurately quantify the risk for this subgroup.r
The SPT risk for patients who are somatic mosaics is unknown and screening for SPT in these individuals should be individualised.
The overall risk of developing a SPT is approximately 36% by 40 years after diagnosis of retinoblastoma. The magnitude of the SPT risk is influenced by the retinoblastoma treatment protocol. Changing treatment regimens over time mean it is difficult to give accurate specific risks for newly diagnosed children; however, the following general observations can be made:
- Radiotherapy is becoming less common in the treatment of retinoblastoma;
- The risk of a SPT is lowest in the group treated with enucleation or focal treatment only, higher for the group treated with radiotherapy, and highest for the group treated with radiotherapy plus chemotherapy;
- Radiotherapy is the strongest risk factor for sarcoma in the periorbital region;
- Radiotherapy plus systemic chemotherapy are the strongest risk factors for a second malignancy outside the radiation field; and
- Certain systemic chemotherapy agents are associated with an increased risk of haematological malignancy (mainly leukaemia), and this risk is predominantly (but not exclusively) in the first three years after treatment and related to cumulative exposure.
The risk of sarcoma is influenced by the retinoblastoma treatment received and is higher in those who received systemic chemotherapy along with radiotherapy.rrr External beam radiotherapy has the strongest effect in the field exposed and there is a radiation dose–response relationship for all sarcoma types. Chemotherapy is a stronger risk factor for tumours outside the radiotherapy field. The risks of sarcoma vary by tumour location as well as patient age and sex.r (see figure 3 in article)
More than 50% of bone and soft tissue sarcomas occur in the head and neck, most often the periorbital region (e.g. orbit, nasal cavity, paranasal sinus), and risk is strongly linked to the use radiotherapy;rrr however, surveillance MRI of the periorbital region has not been systematically studied.
A study of annual whole-body MRI (WBMRI) in a small cohort of retinoblastoma survivors demonstrated WBMRI can detect sarcoma, but with only modest specificity (92.1%) and poor sensitivity (66.7%).r The positive predictive value of WBMRI was low (0.4).
Published papers often do not give detail about the lower limits of the age range at diagnosis and where WBMRI is used there is no consensus about the age to start.r When recommended, some experts suggest starting at age 8 years, and others recommend starting at either age 8 years or when the child is able to tolerate WBMRI without anaesthesia, whichever comes later. In non-irradiated patients, sarcomas typically present after a minimum of a 10-year latent period from the diagnosis of retinoblastoma. The latent period is shorter in patients who received radiotherapy, mainly for head and neck sarcoma.r (see figure 3 in article)
Midline brain tumour
Trilateral retinoblastoma refers to the co-occurrence of unilateral or bilateral retinoblastoma and a midline brain tumour. Midline brain tumours are uncommon, with a risk of less than 2-5% for germline RB1 pathogenic variant carriers.rrMost (approximately 75%) involve the pineal gland. Roughly one-third of midline brain tumours are diagnosed at the time of retinoblastoma diagnosis, providing support for baseline screening.r More than 80% of midline brain tumours are diagnosed within three years of retinoblastoma diagnosis, and over 90% within five years.r
There has been no systematic study of CNS surveillance for midline brain tumours. A recent meta-analysis of 211 published RB1-associated midline brain tumours reported a median survival of 9.4 months (95% CI, 8–13), with a 5-year survival rate of 15.5%.r The survival was lower for children who had central nervous system (CNS) symptoms (median 7 months; 5-year 0%) compared to children without CNS symptoms (median 32 months; 5-year 48.7%). Smaller tumours were also associated with better prognosis than larger tumours (tumour diameter 20 mm 5-year survival 60.5% versus tumour diameter ≥20 mm 5-year survival 13.5%). However, these data are subject to publication bias.
Although evidence for a benefit of ongoing surveillance for midline brain tumours is limited, many retinoblastoma treatment centres in the USA recommend brain MRI (including pineal images) every six months until age five years. This is not common practice in Europe where it is felt the burden of screening is too high given the small absolute risk of midline brain tumours.r