Clinical Impact of Rare Subtypes of Parathyroid Adenoma: A Systematic Review

: Background: Parathyroid lipoadenoma, oncocytic parathyroid adenoma, and water-clear cell parathyroid adenoma (WCCA) are exceptionally rare subtypes of parathyroid adenoma, whose real clinical impact remains unclear. Methods: We performed a literature review and comparison of these uncommon subtypes of parathyroid adenoma, as these lesions may be associated with distinct clinical, pathological and radiological phenotypes. Results: The three groups were comparable in terms of age and gender, mainly affecting middle-aged women. As for the biochemical findings, although PTH level did not show statistically significant differences among the three adenomas, in the two-tail comparison between WCCAs and lipoadenomas, there was a trend towards higher PTH values (p = 0.058). However, serum calcium levels differed significantly, with higher levels in WCCAs than in lipoadenomas (12.1 vs. 11.3 mg/dL; p = 0.002). From a preoperative point of view, ultrasound positivity was significantly higher in WCCAs than in lipoadenomas and oncocytic adenomas (97% vs. 50% vs. 55.3%, p < 0.001), compared to scintigraphy positivity, which was comparable between subtypes and relatively suboptimal (66.7% vs. 64.3% vs. 61.3%; p = 0.825); WCCAs also had an overall more voluminous morphological phenotype. Conclusions: This review, although limited by its reliance primarily on case reports and small case series, confirms that lipoadenoma, oxyphilic adenoma, and WCCAs are rare but clinically relevant subtypes of parathyroid adenoma. These entities may be associated with atypical presentations of primary hyperparathyroidism (including difficult preoperative localization and clinicopathological features raising suspicion of malignancy) and should be recognized as a potential source of diagnostic difficulty. A better understanding of these rare subtypes may improve clinicopathological interpretation, increase awareness of potential diagnostic pitfalls and support a more personalized diagnostic and surgical approach in the future.