RE: Reply in response to “Regarding “The ‘Outline Sign’: Thin Hyperenhancing Perimeter as an MR Imaging Feature of Meningioma. A Useful Tool in the Temporal Bone Region for Differentiating Meningiomas from Schwannomas and Paragangliomas””

We would like to thank the letter authors for their interest in our article and the opportunity to clarify methodologic aspects that were raised as concerns.

First, we agree that timing of contrast administration is important to consider in all imaging studies. With this in mind, all MRI studies in our cohort were performed where acquisition of post-contrast images occurred within the immediate time period following injection of IV contrast, and the first sequence obtained following contrast injection was the axial spin echo T1-weighted sequence. The imaging protocol has remained consistently the same during the time period in which the MRI examinations in our cohort were performed. As such, any heterogeneity would presumably be random (in addition to being agnostic to tumor type), and any bias arising from heterogeneity of contrast timing would therefore bias the results toward the null. In other words, it would underestimate the effect observed. We are confident that the Outline Sign we observed and compared with various tumor types are not a result of contrast timing differences, rather they are a result of the tumor type.

Second, the letter authors raise concern about the use of meningiomas elsewhere. This study is about observation of the Outline Sign in meningiomas. We have observed this sign in meningiomas in locations supratentorially and in the posterior fossa. As can be seen with our data, it was indeed not the case that unless the Outline Sign was present, it was not a meningioma (the sign is not sensitive). Instead our results supported that if the sign was present, there was a high likelihood that it was a meningioma. In practice, we have encountered diagnostic conundrums where this sign has been useful to help weigh our differential considerations. Indeed, when we now employ the Outline Sign retrospectively to cases with known surgical pathology correlation, it has proven useful in cases where we were prospectively incorrect. For this study, however, we chose to concentrate our attention on a location where this sign would make the most impact and the most difference in radiological interpretation, diagnostic confidence, and resultant clinical decision-making. Indeed, the posterior fossa is a challenging location in that there are other tumor types, namely schwannomas and paragangliomas, that can be considered, but the treatment of these lesions is widely variable based on considerable risk due to the proximity of multiple cranial nerves. 1 This trio of tumors (1) can all exist in this location and can all extend inferiorly out the skull base, (2) often have similar imaging appearances, (3) are histologically benign entities (overwhelmingly) that may not justify or absolutely require biopsy or surgery when watchful surveillance or radiation are viable options, 2 and (4) create a diagnostic dilemma that is much less prevalent for a meningioma candidate in a parafalcine location or another supratentorial dural location, for example. When these 3 tumor types were examined for the Outline Sign by blinded Head and Neck subspecialty readers, statistically significant differences were obtained, with a high specificity of the Outline Sign for meningiomas. Certainly, it would be interesting to apply this sign for a future study of histopathologically proven meningiomas in many locations, in larger cohorts, and with other histologic tumor types as confounders.

Finally, the letter authors mention the small sample size, which we also mentioned in our limitations. When we first designed our study approach, we were committed to adhering to the stringent criterion of having a histopathologic diagnostic gold standard in order to produce a high-quality study. For benign tumors in the skull base/posterior fossa regions, surgical resection is often not performed due to high morbidity in these locations relative to clinical benefit. 1-6 As such, there were a limited number of histopathologically-proven cases among our vast hospital database. In fact, however, this speaks to the importance of this sign. It can be very helpful for characterizing lesions in an anatomical location where biopsy or surgery is often challenging or ill-advised. The fact that we were able to examine as many skull base/posterior fossa tumors as we did with resultant statistical significance demonstrates the utility of this sign. That said, we would like to point out that from a strictly statistical perspective, power is a measure of how likely a study would detect an effect if the effect were truly present. A low power would reduce one’s chances of seeing a statistically significant result and increase the chance of a false negative outcome. In our study, however, we did in fact have positive results, and they were statistically significant results, which leads now to whether they are true positive or false positive, and this is described by the p-value. Our results and their p-values were duly noted in our article. Regardless, we welcome the authors and other readers to provide their own cases to replicate and verify our findings in larger cohorts.

Thank you for your comments and your readership.

Anil K. Vasireddi. MD
Katherine L. Reinshagen. MD
Donghoon Shin. MD
Laura V. Romo, MD
Amy F. Juliano, MD

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