Predictors of Multigland Disease in Primary Hyperparathyroidism: A Scoring System with 4D-CT Imaging and Biochemical Markers

Discussion

Identifying cases of MGD preoperatively is an important role of parathyroid imaging when considering whether to offer minimally invasive parathyroidectomy rather than traditional bilateral neck exploration as an initial operation. In potential reoperation cases, MGD poses particular challenges due to distorted anatomy and scar tissue, and appropriate preoperative suspicion is essential in guiding surgical decision-making and preoperative counseling. Although prior studies using 4D-CT have described a range of sensitivities and specificities for MGD, typically superior to scintigraphy and sonography, no existing studies compare the imaging characteristics of MGD and SGD on 4D-CT.^{4⇓⇓⇓–8,13} In this study, we found that a size threshold of <7 mm on 4D-CT favors MGD over SGD, but additional imaging and biochemical data can be used to calculate MGD scores and identify a subset of patients with a high likelihood of MGD.

In clinical practice, radiologists will first suspect MGD on the basis of detection of >1 candidate lesion for hyperplastic glands or adenoma. Our study found that identifying multiple lesions on 4D-CT is neither sensitive nor specific for MGD. Almost one-quarter of patients with MGD only had 1 gland seen prospectively (false-negative), while more than one-quarter of patients with SGD had additional less suspicious candidate lesions (false-positive). Thus, the sign of multiple lesions is not sufficient to guide clinical decision-making, and additional criteria are needed for the radiologist to call MGD with confidence.

Another imaging sign of MGD on 4D-CT is smaller lesion size than that in SGD, which corroborates previous reports based on pathology findings.¹⁰ A single cutoff value based on the mean or median lesion size was not helpful, but categorization of lesions by <7 and >13 mm had higher specificity (85%) for predicting and excluding MGD, respectively. Using size alone is limited for predicting MGD in most patients, however, who have lesions between 7 and 13 mm. Our MGD prediction model improves the ability to predict MGD in more patients by using size in combination with other variables. Our study found that composite MGD scores of ≥4, ≥5, and 6 had specificities of 81%, 93%, and 98%, respectively, and could be applied to more patients than a size cutoff of <7 mm. The composite MGD score was also an improvement over biochemical data alone. The cutoff values for WIN that were required to achieve high specificity for either MGD or SGD resulted in very low sensitivities.

The sensitivities for predicting MGD were low for composite MGD scores ≥4, but the scoring system does not aim to detect all patients with MGD. The primary aim is to identify a subset of patients in whom MGD should be suspected. One clinical implication to the radiologist is that a higher composite MGD score may prompt the radiologist to search for additional lesions after the first lesion is found, thereby avoiding “satisfaction of search” errors. However, the radiologist should be aware that even on detailed review, it may not be possible to see the additional lesions; a third of MGD lesions in our study could not be seen on 4D-CT, even with knowledge of the surgical findings. In the setting in which there is a single lesion but a high composite MGD score (ie, small lesion and relatively low serum PTH and calcium levels), the radiologist should still communicate the increased probability of MGD. The surgeon can use this information to counsel the patient about parathyroidectomy. Conversely, when >1 lesion is seen in a patient with a low composite MGD score (ie, a large lesion and high serum PTH and calcium levels), additional smaller lesions can be reported as much less suspicious if they are not clearly abnormal.

Previous clinical models for MGD have also emphasized the value of high specificity rather than high sensitivity.^10,14 Kebebew et al¹⁴ proposed a multifactorial model based on serum calcium levels, serum PTH levels, and concordant-versus-discordant results of sonography and scintigraphy. Mazeh et al¹⁰ proposed a multifactorial model for predicting MGD with high specificity, by using a combination of WIN and the weight of the resected parathyroid lesion. Our scoring system offers advantages over these models, which did not include imaging signs and were only helpful to the surgeon for decision-making after imaging was complete, or intraoperatively.

We proposed 2 scoring systems to predict MGD and found both to have similar results in predicting it. For the radiologist, the 4D-CT MGD score has the advantage of using only imaging findings, but the composite MGD score may be more reproducible and reliable. This possibility is because the 4D-CT MGD score is based on only 2 sets of data, lesion size and the ability to visualize additional lesions. The latter characteristic may be interpreted with high interobserver variability because the second lesion may be overlooked if not suspected. In contrast, lesion size and biochemical markers are objective criteria.

There were several limitations to this study. First, this was a retrospective study from 2 academic institutions with 2 different neuroradiologists interpreting the original 4D-CT examinations. There were minor technical differences between the acquisition and reconstruction parameters from the 2 institutions, but imaging protocols were alike with regard to the number of phases acquired and timing of the arterial phase, which we believe are the most important controllable factors. Both institutions achieved similar interpretation accuracy for both SGD and MGD, which is reassuring for confirming the external validity of the data. Second, the characteristics of the lesions were based on the original radiology reports. We did not re-interpret the imaging because we thought there would be recall bias. The fact that we did not re-interpret the imaging studies under blinded conditions is potentially a confounding factor because the original radiology reports were often influenced by clinical information such as surgical history and data from previous sonography and scintigraphy results. However, the use of the original reports is, to some extent, a strength of this study because it reflects the performance of 4D-CT under true clinical conditions. A third potential limitation is the heterogeneity of the study group with respect to whether prior surgery was performed. In theory, there may be differences between patients undergoing initial surgery and those undergoing a reoperation with respect to the presence of MGD, particularly because undertreated MGD is a cause of failed parathyroidectomy. However, these differences did not appear to be a confounding factor in our study. Patients undergoing reoperation were distributed between SGD and MGD in a proportion similar to that of patients undergoing initial exploration, and a missed single adenoma was the leading cause of recurrent/persistent hyperparathyroidism in our group, which was in keeping with findings in the existing literature.^15,16 Given the importance of determining the probability of MGD in the setting of a potential reoperation, it is essential to include these patients in the analysis.