Purpose <p>Accurate preoperative localization of parathyroid adenomas is essential to enable targeted and minimally invasive surgery in patients with primary hyperparathyroidism (pHPT). A variety of imaging techniques are available for this purpose. In routine clinical practice, cervical ultrasound (US) combined with scintigraphy is most commonly used as the initial diagnostic approach. However, the optimal strategy or combination of imaging modalities for reliable localization prior to surgery and its relevance for postoperative outcomes remains a matter of ongoing discussion. The aim of this study was therefore to evaluate the diagnostic performance of different preoperative imaging modalities and their combinations for the detection and localization of parathyroid pathology in a large cohort of patients treated at a specialized thyroid center. This study investigated how well the values reported under controlled study conditions translate to clinical practice and real-world application.</p> Methods <p>This retrospective study included 325 patients who underwent minimally invasive parathyroidectomy for primary hyperparathyroidism between January 2015 and December 2023. All patients were evaluated with respect to the preoperative imaging modalities used for localization of the pathological parathyroid gland. In most cases, the standard diagnostic approach consisting of cervical US and scintigraphy was performed initially. When these examinations did not provide conclusive localization, additional imaging techniques were applied, including magnetic resonance imaging (MRI), computed tomography (CT), or 18-fluorocholine PET-CT (18-F PET-CT). In selected cases, invasive selective venous blood sampling (SVS) was also performed.</p> <p>The diagnostic performance of the different imaging modalities was assessed with regard to correct preoperative localization of the adenoma. Furthermore, the influence of factors such as concomitant thyroid disease, previous thyroid or parathyroid surgery, adenoma size and weight, as well as biochemical parameters including calcium and parathyroid hormone levels before, during, and after surgery was analyzed.</p> Results <p>The primary endpoint of postoperative normalization of parathyroid hormone levels after minimally invasive parathyroidectomy was achieved in 94.2% of patients undergoing surgery. The combination of US and scintigraphy as the primary examination procedures was able to provide clear information regarding the localization of the adenoma in 51% of cases, in all other cases one or more additional imaging procedure had to be performed. On average, three examination modalities (triple localization methods) had to be performed per patient (IQR 2.00 - 3.00), with MRI as the most common supplemented procedure, so that in the end a median of two examinations (IQR 1.00 - 3.00) consistently indicated the correct localization. Related to the individual method, US had the highest over-all sensitivity (69.4%) of the imaging procedures. Scintigraphy and SPECT-CT had a similarly high sensitivity of 58.0% for scintigraphy and 56.4% for SPECT-CT. MRI still achieved a sensitivity of 52.9%, CT 36.6%, 18-fluocholine PET-CT 100% and selective venous blood sampling only 60%. The values in clinical practice and broader real-world application with exception of 18-fluocholine PET-CT were below those reported under controlled study conditions. </p> <p>US, scintigraphy, SPECT-CT and MRI each showed a decrease in the sensitivity of correct preoperative localization in the presence of simultaneous thyroid disease. Selective venous blood sampling showed a drop in sensitivity from 80% without prior surgery to 28.6% with prior thyroid or parathyroid surgery. </p> <p>The mean values of correctly selected parathyroid adenomas suggested that larger and more heavy parathyroid adenomas were more likely to be recognized. It was shown that parathyroid adenomas examined by US, scintigraphy, SPECT-CT and additional MRI had a significantly lower volume (<i>p</i> = 0.004) and weight (<i>p</i> = 0.045) than those examined by US and scintigraphy alone. </p> <p>The possibility of successful preoperative localization did not depend on the specific parathyroid hormone level. In contrast, it was shown that higher preoperative calcium levels do not necessarily correlate with easier imaging detection, but lower calcium levels are more often associated with greater diagnostic effort. In contrast, preoperatively determined parathyroid hormone correlated moderately with adenoma weight (<i>r</i> = 0.44; <i>p</i> &lt; 0.001) and adenoma volume (<i>r</i> = 0.17, <i>p</i> = 0.024), whereas calcium showed only weak, albeit significant, correlations with adenoma weight (<i>r</i> = 0.20; <i>p</i> = 0.005) and volume (<i>r</i> = 0.17; <i>p</i> = 0.024).</p> <p>Without concomitant thyroid disease, the US determined volume correlated very strongly with the histopathologically determined volume with a Spearman correlation coefficient of 0.702 (<i>p</i> &lt;.001). With concomitant thyroid disease, the Spearman correlation coefficient decreased to 0.60 (<i>p</i> &lt;.001), although there was still a strong correlation.</p> Conclusion <p>The findings of this study indicate that the combination of cervical ultrasound and scintigraphy remains an effective first-line imaging strategy for the localization of parathyroid adenomas in the majority of patients undergoing surgery for primary hyperparathyroidism in routine clinical practice. This approach was associated with a high success rate of minimally invasive parathyroidectomy in a specialized thyroid center. Nevertheless, a considerable proportion of patients required additional imaging modalities to achieve reliable preoperative localization, with MRI representing the most frequently used supplementary technique.</p>