Incidence of Pineal Gland Cyst and Pineoblastoma in Children With Retinoblastoma During the Chemoreduction Era

insertion techniques have embraced the NCI, and it has allowed them to do safe Descemet stripping automated endothelial keratoplasty (DSAEK) surgery. It is a welcome contribution to this field. Drs. Belin and Hannush have highlighted page 6 of our publication,1 where we discuss the reasoning behind our decision not to use viscoelastic for the NCI-placed tissue, and they state that not using viscoelastic is atypical and not ‘‘standard practice.’’ The implication is that if we had used viscoelastic for the NCI tissue in this study, we would have had less cell loss for this randomized arm of the study. Standard practice with the NCI: The company that manufactures the NCI, Fischer Surgical (St. Louis, Missouri, USA) sponsored a breakfast meeting to talk about the product on October 20, 2010, during the meeting of the American Academy of Ophthalmology. At that meeting, which was moderated by Dr. Belin, a speaker, Dr. Anthony Lubniewski of Washington University (St. Louis, Missouri, USA), emphasized that one of the benefits of the NCI was that viscoelastic did not need to be used at all, so the cost savings resulting from omitting viscoelastic would offset the added expense of the device (confirmed by personal communication, August 26, 2013). In addition, the majority of surgeons using the NCI here on the West Coast also did not use viscoelastic at the time of our study. Therefore, not using viscoelastic would appear to be the preferred practice. However, just like Drs. Belin and Hannush, I do not have a scientific, broad-based survey of surgeons to produce the data that would demonstrate what is the ‘‘standard practice.’’ Endothelial protection with viscoelastic: Would a viscoelastic coating have improved our endothelial cell loss with the NCI? Not necessarily. The platform Endoserter device is very similar to the NCI and although Endoserter investigators2 used viscoelastic, their endothelial cell loss was 28%. Similarly, the Endoglide insertion device uses viscoelastic, and the cell loss has been reported at 26%.3 With the NCI’s internal fluid flow directly under the donor endothelium, any cohesive viscoelastic placed would likely be washed off during the extension of the platform for delivery of the tissue, eliminating any protective effect of the viscoelastic. Nonetheless, whether or not there is improved endothelial survival if viscoelastic is used to coat the donor tissue when using the NCI remains an unanswered question that calls for hard data. Until investigators perform a prospective, randomized, masked study of this question, the data from our highly controlled study stands. The NCI device and other insertion devices, for that matter, despite all of their other user benefits, have not been proven with prospective data to provide better endothelial cell survival than a well-established forceps insertion technique. Marketing the devices to the contrary contradicts the best available data. MARK A. TERRY

Portland, Oregon VOL. 156, NO. 6

REFERENCES

1. Terry MA, Straiko MD, Goshe J, Shamie N, Shah A, Alqudah AA, Davis-Boozer D. Endothelial keratoplasty: a prospective, randomized, masked clinical trial comparing an injector to forceps for tissue insertion. Am J Ophthalmol 2013;156(1):61–68. 2. Foster JB, Swan KR, Vasan RA, Greven MA, Walter KA. Small incision DSAEK: a comparison of a small incision tissue injector and forceps techniques. Cornea 2012;31(1): 42–47. 3. Gangwani V, Obi A, Hollick EJ. A prospective study comparing EndoGlide and Busin glide insertion techniques in Descemet stripping endothelial keratoplasty. Am J Ophthalmol 2012;153(1):38–43.

Incidence of Pineal Gland Cyst and Pineoblastoma in Children With Retinoblastoma During the Chemoreduction Era EDITOR: WE CAREFULLY READ THE RECENT PAPER BY RAMASUBRA-

manian and associates on the incidence of pineal gland cyst and pineoblastoma in retinoblastoma patients.1 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

CORRESPONDENCE

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in the manuscript, but with small numbers and selection bias we suspect that there will be no significant difference). As pointed out by others,2 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 life3) 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. DAVID H. ABRAMSON IRA J. DUNKEL BRIAN P. MARR JASMINE FRANCIS Y. PIERRE GOBIN

New York, New York CONFLICT OF INTEREST DISCLOSURES: THE AUTHORS have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

REFERENCES

1. Ramasubramanian A, Kytasty C, Meadows AT, Shields JA, Leahey A, Shields CL. Incidence of pineal gland cyst and pineoblastoma in children with retinoblastoma during the chemoreduction era. Am J Ophthalmol 2013;156(4): 825–829.e2. 2. Marees T, Moll AC, Imhof SM, de Boer MR, Ringens PJ, Leeuwen FE. Re: more about second cancers after retinoblastoma. J Natl Cancer Inst 2010;102(11):831–832.

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3. Abramson DH, Frank CM. Second nonocular tumors in survivors of bilateral retinoblastoma: a possible age effect on radiation-related risk. Ophthalmology 1998;105(4):573–579 [discussion 579–580].

REPLY WE THANK ABRAMSON AND ASSOCIATES FOR THEIR COM-

ments regarding our report and welcome the opportunity to clarify our conclusions. In our study, only 1 of 252 patients that had received systemic chemotherapy developed pineoblastoma, while 3 of 156 patients, who did not receive chemotherapy, developed pineoblastoma.1 Abramson and associates correctly point out that only patients with the genetic form of retinoblastoma are at risk for pineoblastoma and hence only they should be included in the analysis, a fact that we well recognize. However, we wish to point out that their interpretation of our study data is not accurate. In our study, there were 193 bilateral retinoblastoma patients and among the 215 unilateral retinoblastoma patients, 22 were confirmed as having a germline mutation. Therefore, there were 215 patients with the genetic form of retinoblastoma, placing them at risk for the development of pineoblastoma. In this group, 1 of 180 patients that received chemotherapy developed pineoblastoma and 3 of 35 patients that did not receive chemotherapy developed pineoblastoma, and this difference is statistically significant (P ¼ .014). In our study, there were total 408 patients and 5 patients were treated primarily with external beam radiation, and none of them developed pineoblastoma. In addition, 35 patients were treated with external beam radiation secondarily, for recurrence following chemoreduction. Among the 215 patients with germline mutation, there were 36 patients that required external beam radiation and 1 developed pineoblastoma. We found that external beam radiation did not correlate with pineoblastoma (P ¼ .5). Abramson and associates suggested that with the elimination of external beam radiation therapy, the incidence of pineoblastoma decreased to 2% in their center and one third of those developed pineoblastoma prior to the diagnosis of retinoblastoma. However, it is possible that the majority, or two thirds, could have been prevented from the development of pineal tumor if they had received systemic chemotherapy. There has been a decline in the incidence of pineoblastoma2,3 worldwide, and this could be attributed to multiple factors including the increased use of systemic chemotherapy, especially in children with bilateral disease, or the decreasing use of external beam radiation. Though the numbers are small and it is difficult to obtain good statistical tests, our study demonstrates a lower incidence of pineoblastoma in patients with the genetic form of retinoblastoma who have received systemic

AMERICAN JOURNAL OF OPHTHALMOLOGY

DECEMBER 2013