We carefully read the recent paper by Ramasubramanian and associates on the incidence of pineal gland cyst and pineoblastoma in retinoblastoma patients. Over a 12-year period this busy center saw only 4 pineoblastomas in 408 patients. Despite the small numbers of pineoblastomas and admitted absence of statistical significance, the authors concluded that “systemic chemotherapy…(may) possibly indicate a systemic protective effect.”

As pointed out by the authors (and all prior publications on the subject), only the children with the genetic form of retinoblastoma are at risk for the development of pineoblastomas, and all 4 of the patients in this series who developed pineoblastomas had the genetic form. Yet when the authors calculated the incidence in the chemotherapy and no chemotherapy group they included unilateral patients (most) who are not at risk. They found 3 pineoblastomas in 156 bilateral cases (only a few who may not have received systemic chemotherapy) and 1 pineoblastoma in 252 patients who did not receive chemotherapy. However, the authors state that 215 patients in the series had germline disease and since 193 were bilateral that means that only 22 of the unilateral patients (most who probably did not receive chemotherapy) were at risk for second cancers (not the 215 listed in the manuscript). One patient in that group (1/22; 4.5%) developed a pineoblastoma. Three of 198 bilateral patients (1.6%) developed a pineoblastoma. (Our calculations indicate this difference is not significant.)

The appropriate way to do the comparison would be to delete the unilaterals without germinal disease and compare those remaining patients who received chemotherapy to those who did not (those data are not presented in the manuscript, but with small numbers and selection bias we suspect that there will be no significant difference).

As pointed out by others, radiation does indeed contribute to the development of pineal malignancies in these children. When we abandoned radiation and began using systemic chemotherapy our incidence of pineoblastoma in bilateral patients dropped from 6% to under 2%, but a third of those developed before the patient was even diagnosed or treated for retinoblastoma (surely chemoreduction will have no influence on the incidence in these one third of patients). Since we abandoned systemic chemotherapy in New York (7 years ago) in favor of intraarterial chemotherapy (in all children older than 3 months of age) our incidence remains the same (under 2%). There is good established evidence that avoiding external beam irradiation (especially in the first year of life ) does decrease the incidence of these malignancies. In addition, 5 patients in this Philadelphia series received radiation; we are not told if any of them developed a pineoblastoma, but such information is important (and may distort the comparison of those who received chemotherapy and those who did not because it may attribute a pineoblastoma to one group when the cause may be radiation and unrelated to whether chemotherapy was or was not given).

The authors concluded that chemotherapy “possibly” decreases the incidence of pineal malignancies, but because of the small number of pineoblastomas (4 events in 12 years), absence of statistical significance, and inclusion of patients not at risk for pineoblastoma (and possibly those who received radiation), we believe that this paper does not provide evidence that systemic chemotherapy prevents trilateral disease.