Near-infrared autofluorescence for parathyroidectomy in mild primary hyperparathyroidism: interpreting evidence from a randomized clinical study

Parathyroidectomy remains the only curative treatment for primary hyperparathyroidism (PHP), and with the development of rapid intraoperative parathyroid hormone (PTH) measurements and refinements in preoperative parathyroid imaging, focused or limited parathyroidectomy has increasingly replaced systematic 4-gland exploratory surgery (1-3). Focused parathyroidectomy reduces operative time, limits potential surgical complications compared with bilateral parathyroidectomy, and offers long-term cure (4,5). This more limited approach is ideal for single gland disease, which comprises 80–85% of PHP, and in cases where the adenoma can be localized with preoperative imaging (1,6). Roughly 15–20% of cases, however, involve more than one parathyroid gland (PTG), and in such cases, preoperative imaging may be unrevealing (7,8). In addition, multigland disease has been reported to be more common in cases of mild PHP, including cases where serum calcium levels may be normal (8,9). Such cases can present surgical challenges even for experienced surgeons.

In the recent article that was published in Surgery “Parathyroid near-infrared autofluorescence use for parathyroidectomy in mild PHP: Results from a randomized monocentric trial” by Frey et al., the authors set out to evaluate the application of near-infrared autofluorescence (NIRAF) technology in parathyroidectomy for mild PHP (10). In this single-institution trial, 132 patients were randomized (non-blinded) to classic parathyroidectomy (without the use of NIRAF, n=66) or parathyroidectomy with the use of camera-based NIRAF (n=66) (specifically the Fluobeam 800 device by Fluoptics, now part of Getinge). Patients were eligible for inclusion if diagnosed with sporadic mild PHP, defined by either a moderate hypercalcemia (<2.60 albumin-corrected serum calcium or serum calcium <2.85 mmol/L) plus normal or elevated serum PTH level (>15 pg/mL) or normocalcemia (albumin-corrected serum calcium ≤2.60 mmol/L) with elevated serum PTH level (>65 pg/mL). Exclusion criteria included age <18 years or >80 years of age, adults under guardianship, pregnancy/breastfeeding, hypocalciuiric hypercalcemia, and/or multiple endocrine neoplasia. The authors followed the French guidelines for surgical indications and all surgery was performed by one of two experienced surgeons, who have performed >40 parathyroidectomies a year for over 15 years (11). All procedures involved a planned bilateral neck exploration.

The authors hypothesized that the application of NIRAF technology would reduce surgical time, and the primary outcome was mean operating time, defined as from the start of the skin incision to the end of the skin closure. Secondary outcomes included the number of visualized PTGs during surgery, number of excised PTGs, number of resected pathologic PTGs (defined as parathyroid adenoma or hyperplasia at histopathologic examination), complication rates [hypocalcemia defined by an albumin-corrected serum calcium <2.00 mmol/L on post-operative day 1, recurrent laryngeal nerve (RLN) palsy and cervical hematoma requiring reintervention] and cure rates at a minimum of 6 months (either serum calcium <2.6 mmol/L in patients with preoperative hypercalcemia or serum PTH <65 pg/mL in patients with preoperative normocalcemia).

The authors found that mean operative time did not differ significantly between the two study groups (46.9±15.3 minutes for the classic parathyroidectomy and 51.2±22.9 minutes for the NIRAF group, P=0.21). The use of NIRAF did not significantly impact the number of identified or resected PTGs nor the rate of complications, and cure rates were found to be similar between groups (92.2% and 94.8%; P=0.72) at 6 months. The authors thus concluded that the application of NIRAF in the hands of experienced surgeons did not reduce operative time for parathyroidectomy during bilateral neck exploration in cases of mild PHP, but that further study may refine its use in surgical education and training.

The application of NIRAF for the identification of parathyroid tissue was first described in 2011, when it was demonstrated that PTGs exhibit autofluorescence when exposed to near infra-red light (12). Still relatively nascent in its application, NIRAF in thyroidectomy has been shown to reduce rates of temporary hypoparathyroidism following total thyroidectomy (13-17), improve rates of PTG identification during thyroid surgery (15,18) and reduce rates of inadvertent parathyroidectomy during thyroidectomy (14,15,17-19). Its role in surgical training remains an area of active investigation, but appears beneficial (20,21).

Two types of NIRAF technology have been developed for use during thyroid/parathyroid surgery. Camera-based technology, such as the one used in this study, and probe-based technology, both of which involve a learning curve to utilize optimally. The camera-based technology involves holding a camera placed in a sterile sheath above the operative field to apply near-infrared light to the exposed surgical anatomy. This offers a broad field of view, and the surgeon must then use a gray-scale monitor to subjectively assess areas of NIRAF activity in the surgical field. Probe-based technology is more akin to the use of RLN monitoring in that a sterile, disposable hand-held probe is placed in direct contact with the tissue of interest. After calibration, when the probe is in contact with tissue, an auditory signal is generated, and a quantitative assessment of NIRAF activity (known as a detection ratio) is displayed on a monitor. False positives (such as brown fat, colloid nodules, metastatic lymph nodes) and false negatives (such as incorrect calibration of the probe, distance from the surgical field, depth of tissue being interrogated) should be kept in mind (21,22).

Frey et al.’s study (10) adds to the growing body of literature on the application of NIRAF during parathyroid surgery, offering a real-world practical experience of the use of camera-based NIRAF technology during parathyroid surgery in a prospective randomized study design. A power calculation was performed based on an unpublished pilot study by the two main investigators (Eric Mirallie and Cecile Caillard), where the mean operating time for 60 patients with PHP undergoing bilateral parathyroidectomy was 50 minutes, standard deviation of 25 minutes. The authors then hypothesized a 25% reduction in operating time with the use of NIRAF technology. In the NIRAF group, the camera was utilized to identify all four PTGs after dissection of the thyroid and either before dissection of the fibrofatty tissues or after dissection of this tissue if no signal had been visualized. However, the assumptions underlying the sample size calculation may have been overly optimistic, with a hypothesized 25% reduction in operative time using NIRAF camera, but such a large effect size may not be realistic in the context of experienced surgeons. This assumption could have resulted in the study being underpowered to detect smaller, but potentially clinically meaningful, differences in operative time or secondary outcomes, contributing to the study results.

The application of NIRAF during parathyroidectomy, however, has been less well studied than its application in thyroidectomy, and a few key concepts should be kept in mind when considering the conclusions of Frey et al.’s study (10).

Importantly, both the camera and probe-based devices have a limit to the depth of penetration (generally 3 mm) of the NIRAF signal (23,24). And thus, while both forms of NIRAF technology can be applied to “map” PTG tissue, the technology does not replace knowledge of surgical anatomy, surgical judgment, or experience in locating and identifying PTGs. Surgical experience, therefore, remains one of, if not the, key drivers of operative time. In Frey et al.’s study (10), although all patients in both study arms were intended to have bilateral exploration, 125 of 132 patients (94.7%) had abnormal PTGs localized on imaging before surgery. Three patients (4.6%) in the non-NIRAF study group and 2 patients (3.4%) in the NIRAF group ultimately underwent unilateral neck exploration at the surgeon’s choice.

In addition, the NIRAF signal of normal PTGs differs from that of abnormal PTGs. The normal parathyroid tissue from which the adenoma evolves remains as a bright cap exhibiting the classic strong NIRAF signal, while the adenomatous portions of the abnormal gland are more heterogeneous and may be less bright (25-28). NIRAF signal intensity also appears to vary between single and multigland disease although other authors have reported similar median parathyroid to thyroid NIRAF ratios between single vs multigland disease (27,29). Such variation in NIRAF signal intensity may lead to false positive or false negative interpretation of abnormal PTGs, which could increase surgical time. Surgeon practice surrounding the use of frozen section confirmation and intraoperative PTH sampling may also significantly vary operative time in the setting of NIRAF. While NIRAF signal has been shown to correlate with parathyroid tissue—potentially obviating the need for frozen section—and the use of NIRAF may replace intraoperative PTH evaluation in select cases, to date, there is no consensus on the degree of signal intensity that indicates normal vs. abnormal parathyroid tissue (30,31). Visual deep learning models hold promise to establish these norms (28).

Operative time—the primary outcome of Frey et al.’s study (10)—during any parathyroidectomy is heavily influenced by surgical experience and results of preoperative imaging. At the surgeon’s judgment, surgery was concluded when all 4 PTGs were identified with at least one judged to be macroscopically pathologic. In cases of missing PTGs despite dissection in the typical anatomic locations, surgery was concluded when at least one macroscopically normal and one macroscopically abnormal gland were identified (corresponding to preoperative imaging when positive). The extent of surgical experience of the two surgeons in this study limits the application of the study results to a general population.

RLN palsy was one of the secondary outcomes of this study. However, RLN neuromonitoring was utilized at the surgeon’s judgment and for only 20 (30.8%) and 18 (30.5%) of the classic parathyroidectomy and NIRAF parathyroidectomy patients, respectively. The authors also did not report on the use of pre- or postoperative laryngoscopy for assessment of RLN injury. An estimated 30–50% of patients with RLN paralysis may have normal voice function (32). This limits the authors’ ability to comment on this potential complication as a secondary outcome.

Taking into consideration the learning curve for adopting new technology as well as cost considerations, refinements in the application of NIRAF technology in parathyroidectomy are expected as its use broadens. Additional study is needed to identify where NIRAF technology may be most useful in parathyroid surgery. Multicenter studies evaluating camera- and probe-based technology for single and multigland disease, localizing versus non-localizing disease on imaging, and primary and secondary or tertiary hyperparathyroidism are needed. Nevertheless, NIRAF technology holds promise to improve surgical technique as well as surgical training.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Annals of Thyroid. The article has undergone external peer review.

Peer Review File: Available at https://aot.amegroups.com/article/view/10.21037/aot-2025-1-18/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://aot.amegroups.com/article/view/10.21037/aot-2025-1-18/coif). G.W.R. serves as an unpaid editorial board member of Annals of Thyroid from July 2023 to December 2027. G.W.R. has received research grants (no personal fees) from Eisai, Medtronic and Getinge. He is the program director of the Mass. Eye & Ear Endocrine Surgery Clinical Fellowship, which receives partial funding from Medtronic, and is the President of the International Thyroid Oncology Group (ITOG) and the World Congress on Thyroid Cancer (WCTC), and is the American College of Surgeons (ACS) Otolaryngology Governor. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Kurtom S, Carty SE. Primary Hyperparathyroidism: Part Two: Surgical Management. Surg Clin North Am 2024;104:799-809. [Crossref] [PubMed]
2. Di Marco A, Mechera R, Glover A, et al. Focused parathyroidectomy without intraoperative parathyroid hormone measurement in primary hyperparathyroidism: Still a valid approach? Surgery 2021;170:1383-8. [Crossref] [PubMed]
3. Mazeh H, Chen H, Leverson G, et al. Creation of a "Wisconsin index" nomogram to predict the likelihood of additional hyperfunctioning parathyroid glands during parathyroidectomy. Ann Surg 2013;257:138-41. [Crossref] [PubMed]
4. Bergenfelz A, Lindblom P, Tibblin S, et al. Unilateral versus bilateral neck exploration for primary hyperparathyroidism: a prospective randomized controlled trial. Ann Surg 2002;236:543-51. [Crossref] [PubMed]
5. Westerdahl J, Bergenfelz A. Unilateral versus bilateral neck exploration for primary hyperparathyroidism: five-year follow-up of a randomized controlled trial. Ann Surg 2007;246:976-80; discussion 980-1. [Crossref] [PubMed]
6. Eligal S, Mekel M, Weinberger JM, et al. Minimally Invasive Parathyroidectomy: Can Intraoperative Parathyroid Hormone Monitoring be Omitted?. World J Surg 2022;46:1908-14. [Crossref] [PubMed]
7. Hellums RN, Pichardo PFA, Lesh RW, et al. Biochemical Profile of and Factors Associated With Recurrence in Primary Hyperparathyroidism. JAMA Otolaryngol Head Neck Surg 2025;151:888-95. [Crossref] [PubMed]
8. Trébouet E, Bannani S, Wargny M, et al. Mild sporadic primary hyperparathyroidism: high rate of multiglandular disease is associated with lower surgical cure rate. Langenbeck's Archives of Surgery 2019;404:431-8.
9. Balachandra S, Wang R, Akhund R, et al. Patients with normocalcemic versus hypercalcemic hyperparathyroidism: What's really the difference? Am J Surg 2025;244:116272. [Crossref] [PubMed]
10. Frey S, Bannani S, Caillard C, et al. Parathyroid near-infrared autofluorescence use for parathyroidectomy in mild primary hyperparathyroidism: Results from a randomized monocentric trial. Surgery 2025;177:108878. [Crossref] [PubMed]
11. Calzada-Nocaudie M, Chanson P, Conte-Devolx B, et al. Management of asymptomatic primary hyperparathyroidism: French Society of Endocrinology expert consensus. Ann Endocrinol (Paris) 2006;67:7-12. [Crossref] [PubMed]
12. Paras C, Keller M, White L, et al. Near-infrared autofluorescence for the detection of parathyroid glands. J Biomed Opt 2011;16:067012. [Crossref] [PubMed]
13. Weng Y, Jiang J, Min L, et al. Intraoperative near-infrared autofluorescence imaging for hypocalcemia risk reduction after total thyroidectomy: Evidence from a meta-analysis. Head & Neck 2021;43:2523-33.
14. Lu W, Chen Q, Zhang P, et al. Near-Infrared Autofluorescence Imaging in Thyroid Surgery: A Systematic Review and Meta-Analysis. J Invest Surg 2022;35:1723-32. [Crossref] [PubMed]
15. Lu D, Pan B, Tang E, et al. Intraoperative strategies in identification and functional protection of parathyroid glands for patients with thyroidectomy: a systematic review and network meta-analysis. Int J Surg 2024;110:1723-34. [Crossref] [PubMed]
16. Hsu HW, Huang SH, Lee SH, et al. Impact of Intraoperative Interventions on Hypocalcemia Post-Total Thyroidectomy: A Meta-Analysis. J Otolaryngol Head Neck Surg 2025;54:19160216251333355. [Crossref] [PubMed]
17. Canali L, Russell MD, Sistovaris A, et al. Camera-based near-infrared autofluorescence versus visual identification in total thyroidectomy for parathyroid function preservation: Systematic review and meta-analysis of randomized clinical trials. Head & Neck 2025;47:225-34.
18. Safia A, Abd Elhadi U, Massoud S, et al. The impact of using near-infrared autofluorescence on parathyroid gland parameters and clinical outcomes during total thyroidectomy: a meta-analytic study of randomized controlled trials. International Journal of Surgery 2024;110:3827-38.
19. Wang B, Zhu CR, Liu H, et al. The Ability of Near-Infrared Autofluorescence to Protect Parathyroid Gland Function During Thyroid Surgery: A Meta-Analysis. Front Endocrinol (Lausanne) 2021;12:714691. [Crossref] [PubMed]
20. Solórzano CC, Thomas G, Baregamian N, et al. Detecting the Near Infrared Autofluorescence of the Human Parathyroid: Hype or Opportunity? Ann Surg 2020;272:973-85. [Crossref] [PubMed]
21. Silver Karcioglu AL, Triponez F, Solórzano CC, et al. Emerging Imaging Technologies for Parathyroid Gland Identification and Vascular Assessment in Thyroid Surgery: A Review From the American Head and Neck Society Endocrine Surgery Section. JAMA Otolaryngol Head Neck Surg 2023;149:253-60. [Crossref] [PubMed]
22. Solórzano CC, Thomas G, Berber E, et al. Current state of intraoperative use of near infrared fluorescence for parathyroid identification and preservation. Surgery 2021;169:868-78. [Crossref] [PubMed]
23. Han YS, Kim Y, Lee HS, et al. Detectable depth of unexposed parathyroid glands using near-infrared autofluorescence imaging in thyroid surgery. Front Endocrinol (Lausanne) 2023;14:1170751. [Crossref] [PubMed]
24. Di Marco AN, Palazzo FF. Near-infrared autofluorescence in thyroid and parathyroid surgery. Gland Surg 2020;9:S136-46. [Crossref] [PubMed]
25. Demarchi MS, Karenovics W, Bédat B, et al. Autofluorescence pattern of parathyroid adenomas. BJS Open 2021;5:zraa047. [Crossref] [PubMed]
26. Kose E, Kahramangil B, Aydin H, et al. Heterogeneous and low-intensity parathyroid autofluorescence: Patterns suggesting hyperfunction at parathyroid exploration. Surgery 2019;165:431-7. [Crossref] [PubMed]
27. Akgun E, Berber E. Near-Infrared Autofluorescence Signatures of Single- vs Multigland Disease in Primary Hyperparathyroidism. JAMA Otolaryngol Head Neck Surg 2024;150:979-85. [Crossref] [PubMed]
28. Akgun E, Ibrahimli A, Berber E. Near-Infrared Autofluorescence Signature: A New Parameter for Intraoperative Assessment of Parathyroid Glands in Primary Hyperparathyroidism. Journal of the American College of Surgeons 2025;240:84-93.
29. Pannu AY, O'Connor-Manson MR, Wyld L, et al. Near-infrared fluorescent imaging for parathyroid identification and/or preservation in surgery for primary hyperparathyroidism. Front Endocrinol (Lausanne) 2023;14:1240024. [Crossref] [PubMed]
30. De Leeuw F, Breuskin I, Abbaci M, et al. Intraoperative Near-infrared Imaging for Parathyroid Gland Identification by Auto-fluorescence: A Feasibility Study. World J Surg 2016;40:2131-8. [Crossref] [PubMed]
31. Indelicato P, Barbieri D, Salerno E, et al. Near-Infrared Autofluorescence or Intraoperative Parathyroid Hormone Determination as a Surgical Support Tool in Primary Hyperparathyroidism: Too Close to Call?. Cancers (Basel) 2024;16:4018. [Crossref] [PubMed]
32. Randolph GW, Kamani D. The importance of preoperative laryngoscopy in patients undergoing thyroidectomy: voice, vocal cord function, and the preoperative detection of invasive thyroid malignancy. Surgery 2006;139:357-62. [Crossref] [PubMed]