Risk factors for inadvertent parathyroidectomy

This report suggests that factors relating to inadvertent parathyroidectomy on univariable analyses include: a pre-operative indication of suspected or confirmed cancer, the extent of surgery, central neck dissection and re-operative thyroid surgery. In a recent systematic review^{Reference Bai, Chen and Chen7} of 2033 inadvertent parathyroidectomy events in 16 423 patients, risk factors for inadvertent parathyroidectomy included: malignancy (relative risk = 1.60), central neck dissection (relative risk = 2.35), total thyroidectomy (relative risk = 1.42) and re-operative surgery (relative risk = 1.81). More recent studies have also identified a pre-operative indication of malignancy as a risk factor for inadvertent parathyroidectomy on univariable^{Reference Chew, Li, Ng, Chan and Fleming6,Reference McGoldrick, Majeed, Achakzai and Redmond11,Reference Ataş, Akkurt, Saylam and Tez13,Reference Asya, Yumuşakhuylu, Gündoğdu, İncaz and Oysu25} or multivariable analysis.^{Reference Vasileiadis, Charitoudis, Vasileiadis, Kykalos and Karatzas9,Reference Zheng, Song, Cai, Wang, Han and Wu17} This study also demonstrated a pathological diagnosis of malignancy to be associated with a higher rate of inadvertent parathyroidectomy, like other studies.^{Reference Chew, Li, Ng, Chan and Fleming6,Reference Vasileiadis, Charitoudis, Vasileiadis, Kykalos and Karatzas9,Reference McGoldrick, Majeed, Achakzai and Redmond11,Reference Ataş, Akkurt, Saylam and Tez13,Reference Hone, Tikka, Kaleva, Hoey, Alexander and Balfour14,Reference Lin, Hsueh, Wu, Yu and Chao16,Reference Applewhite, White, Xiong, Pasternak, Abdulrasool and Ogawa19,Reference Karadeniz and Akcay21,Reference Barrios, Shafqat, Alam, Ali, Patio and Filarski23} Potential explanations for this include extrathyroidal extent of cancer into adjacent tissue, and the concomitant performance of central neck dissection, which is an independent risk factor for inadvertent parathyroidectomy, in this study as in others.^{Reference Chew, Li, Ng, Chan and Fleming6,Reference Vasileiadis, Charitoudis, Vasileiadis, Kykalos and Karatzas9,Reference Mencio, Calcatera, Ogola, Mahady, Shiller and Roe10,Reference Ataş, Akkurt, Saylam and Tez13,Reference Hone, Tikka, Kaleva, Hoey, Alexander and Balfour14,Reference Lin, Hsueh, Wu, Yu and Chao16,Reference Zheng, Song, Cai, Wang, Han and Wu17,Reference Applewhite, White, Xiong, Pasternak, Abdulrasool and Ogawa19,Reference Barrios, Shafqat, Alam, Ali, Patio and Filarski23} Parathyroid glands lying outside the thyroid capsule may be embedded within fibro-adipose tissue and/or mistaken for lymph nodes, and are therefore at risk of inadvertent removal during central neck dissection.^{Reference Zheng, Song, Cai, Wang, Han and Wu17}

This report found no association between gender and inadvertent parathyroidectomy, which is compatible with most other recent studies.^{Reference Chew, Li, Ng, Chan and Fleming6,Reference Alraddadi, Aldhahri, Almayouf, Alharbi, Malas and Nasrullah8–Reference McGoldrick, Majeed, Achakzai and Redmond11,Reference Hone, Tikka, Kaleva, Hoey, Alexander and Balfour14,Reference Lin, Hsueh, Wu, Yu and Chao16,Reference Zheng, Song, Cai, Wang, Han and Wu17,Reference Applewhite, White, Xiong, Pasternak, Abdulrasool and Ogawa19–Reference Du, Fang, Zhang, Cui, Zhao and Lou22,Reference Alanzi, Ghafouri, Khalifa, Hawsawi and Alzaidi24,Reference Asya, Yumuşakhuylu, Gündoğdu, İncaz and Oysu25} This study also found no association between age at surgery and inadvertent parathyroidectomy, in keeping with recent literature.^{Reference Chew, Li, Ng, Chan and Fleming6,Reference Vasileiadis, Charitoudis, Vasileiadis, Kykalos and Karatzas9–Reference Hone, Tikka, Kaleva, Hoey, Alexander and Balfour14,Reference Zheng, Song, Cai, Wang, Han and Wu17,Reference Applewhite, White, Xiong, Pasternak, Abdulrasool and Ogawa19,Reference Karadeniz and Akcay21–Reference Barrios, Shafqat, Alam, Ali, Patio and Filarski23}

A retrospective review of 1114 thyroidectomies by Barrios et al.^{Reference Barrios, Shafqat, Alam, Ali, Patio and Filarski23} found that, on multivariable analysis, low-volume surgeons had a significantly higher incidence of inadvertent parathyroidectomy. In contrast, a study by Lin et al.^{Reference Lin, Hsueh, Wu, Yu and Chao16} reported that surgeon volume has no influence on inadvertent parathyroidectomy. Similarly, this study found that the seniority of the first surgeon had no association with the occurrence of inadvertent parathyroidectomy, in concordance with other recent studies.^{Reference Chew, Li, Ng, Chan and Fleming6,Reference Asya, Yumuşakhuylu, Gündoğdu, İncaz and Oysu25} Junior surgeons in this series were always supervised, and it is possible that ‘high-risk’ patients were more likely to have a senior surgeon as the first operator.

No association was found between the number of parathyroid glands seen per lobe resected and inadvertent parathyroidectomy. On the contrary, a retrospective review of 1767 total thyroidectomies by Applewhite et al.^{Reference Applewhite, White, Xiong, Pasternak, Abdulrasool and Ogawa19} reported that the number of glands identified intra-operatively was inversely correlated with the number of glands seen on histological review. While this supports the approach of ‘routine’ parathyroid gland identification, dissection in search of all four parathyroid glands poses the risk of inadvertent damage to parathyroid blood supply,^{Reference Chang and Lang26} and, given the possibility of ectopic glands,^{Reference Wang27,Reference Phitayakorn and McHenry28} the identification of all parathyroid glands may not always be possible.

Some studies have reported that a larger weight of thyroid tissue was associated with an increased incidence of inadvertent parathyroidectomy.^{Reference Vasileiadis, Charitoudis, Vasileiadis, Kykalos and Karatzas9,Reference Zheng, Song, Cai, Wang, Han and Wu17} Conversely, other studies, like this one, report that a smaller weight of thyroid gland was predictive of a higher rate of inadvertent parathyroidectomy,^{Reference Christakis, Zacharopoulou, Galanopoulos, Kafetzis, Dimas and Roukounakis12} or found no relationship at all.^{Reference Chew, Li, Ng, Chan and Fleming6,Reference Hone, Tikka, Kaleva, Hoey, Alexander and Balfour14,Reference Barrios, Shafqat, Alam, Ali, Patio and Filarski23} Similarly, this report found a lower thyroid volume to be associated with a higher risk of inadvertent parathyroidectomy, whereas other studies reported that a greater volume increased the risk of inadvertent parathyroidectomy,^{Reference Vasileiadis, Charitoudis, Vasileiadis, Kykalos and Karatzas9} or found no association.^{Reference Christakis, Zacharopoulou, Galanopoulos, Kafetzis, Dimas and Roukounakis12}

Location of excised glands

Intrathyroidal parathyroid glands were previously believed to be a rare occurrence,^{Reference Wang27} but recent studies suggest that the incidence of intrathyroidal glands ranges from 2.2 to 50 per cent.^{Reference Bai, Chen and Chen7,Reference Vasileiadis, Charitoudis, Vasileiadis, Kykalos and Karatzas9,Reference Christakis, Zacharopoulou, Galanopoulos, Kafetzis, Dimas and Roukounakis12,Reference Ataş, Akkurt, Saylam and Tez13,Reference Özden, Erdoğan, Simsek, Saylam, Yıldız and Tez15–Reference Yazici, Bozkurt, Citgez, Kaya, Mihmanli and Uludag18,Reference Karadeniz and Akcay21,Reference Phitayakorn and McHenry28} In this study, intrathyroidal parathyroid glands were found in 10.9 per cent of specimens with reported inadvertent parathyroidectomy. In this series, extracapsular parathyroid glands were found in 53.3 per cent of inadvertent parathyroidectomy specimens. Similarly, other recent studies report that 37–86 per cent of inadvertently excised parathyroid glands are extracapsular.^{Reference Vasileiadis, Charitoudis, Vasileiadis, Kykalos and Karatzas9,Reference Christakis, Zacharopoulou, Galanopoulos, Kafetzis, Dimas and Roukounakis12,Reference Ataş, Akkurt, Saylam and Tez13,Reference Özden, Erdoğan, Simsek, Saylam, Yıldız and Tez15–Reference Yazici, Bozkurt, Citgez, Kaya, Mihmanli and Uludag18,Reference Abboud, Sleilaty, Braidy, Zeineddine, Ghorra and Abadjian20} Meticulous intra-operative identification of parathyroid glands may contribute to a reduction in the incidence of inadvertent parathyroidectomy.^{Reference Applewhite, White, Xiong, Pasternak, Abdulrasool and Ogawa19,Reference Abboud, Sleilaty, Braidy, Zeineddine, Ghorra and Abadjian20} Recognition of inadvertent parathyroidectomy during surgery allows auto-transplantation of the inadvertently resected parathyroid gland,^{Reference Abboud, Sleilaty, Braidy, Zeineddine, Ghorra and Abadjian20} a practice that may reduce the risk of long-term hypoparathyroidism.^{Reference Edafe, Antakia, Laskar, Uttley and Balasubramanian3}

Pathology reporting in inadvertent parathyroidectomy

A high proportion of histopathology reports did not mention the presence or absence of parathyroid tissue. Like other retrospective studies examining factors relating to inadvertent parathyroidectomy, our no inadvertent parathyroidectomy group included patients in whom there was no mention of the parathyroid tissue in the formal histopathology report, assuming that no mention of parathyroid equates to true absence of parathyroid in the specimen.

Of the reports with no mention of parathyroid tissue, a review of a sample of slides found that 10.2 per cent contained parathyroid tissue. Conversely, in 3.0 per cent of specimens where parathyroid tissue was described in the histopathology report, a review could not confirm this finding. These findings are suggestive of under-reporting of inadvertent parathyroidectomy. The inconsistency in reporting of inadvertent parathyroidectomy may in part be explained by the Royal College of Pathologists’ standards and datasets for reporting cancers. For thyroid cancer histopathology reports, it is recommended that the presence of any parathyroid tissue or glands should be stated, but reporting of inadvertent parathyroidectomy is not considered to be a core data item.^{Reference Stephenson, Sarah and Johnson29} Highlighting the importance of inadvertent parathyroidectomy amongst pathologists and emphasising its role as a marker of quality – for both the operation and histology reporting – may help address the problem.

Inadvertent parathyroidectomy and post-surgical hypoparathyroidism or hypocalcaemia

This study identified a six-month post-surgical hypoparathyroidism or hypocalcaemia rate of 10.4 per cent, with the incidence rising to 19.8 per cent in those who had an inadvertent parathyroidectomy. The high incidence of six-month post-surgical hypoparathyroidism or hypocalcaemia in this cohort may be explained by the relatively high rate of central neck dissection (an independent risk factor for permanent hypoparathyroidism),^{Reference Salem, Bergenfelz, Nordenström and Almquist30} and the criteria used to define six-month post-surgical hypoparathyroidism or hypocalcaemia (patients requiring calcium or vitamin D supplements at six months).

This report found significant relationships between inadvertent parathyroidectomy and both transient and permanent post-surgical hypoparathyroidism or hypocalcaemia, consistent with other reports.^{Reference Bai, Chen and Chen7,Reference Vasileiadis, Charitoudis, Vasileiadis, Kykalos and Karatzas9,Reference Ataş, Akkurt, Saylam and Tez13,Reference Lin, Hsueh, Wu, Yu and Chao16,Reference Zheng, Song, Cai, Wang, Han and Wu17,Reference Barrios, Shafqat, Alam, Ali, Patio and Filarski23} However, other studies report no association between inadvertent parathyroidectomy and hypocalcaemia.^{Reference Chew, Li, Ng, Chan and Fleming6,Reference Özden, Erdoğan, Simsek, Saylam, Yıldız and Tez15,Reference Yazici, Bozkurt, Citgez, Kaya, Mihmanli and Uludag18,Reference Abboud, Sleilaty, Braidy, Zeineddine, Ghorra and Abadjian20–Reference Du, Fang, Zhang, Cui, Zhao and Lou22} Most published studies on the relationship do not evaluate the viability and vascularisation of preserved parathyroid glands, or parathyroid gland auto-transplantation – factors that may influence the development of post-surgical hypoparathyroidism or hypocalcaemia. We found no significant relationship between the number of excised glands and post-surgical hypoparathyroidism or hypocalcaemia; however, the number of patients who had two or more inadvertently excised glands was low, thereby limiting the power of statistical analysis.

Preventative methods

Surgical loupes have been shown to improve identification of anatomy intra-operatively, and may reduce post-operative complications following thyroid surgery.^{Reference D'Orazi, Panunzi, di Lorenzo, Ortensi, Cialini and Anichini31} Alraddadi et al.^{Reference Alraddadi, Aldhahri, Almayouf, Alharbi, Malas and Nasrullah8} found that, in a series of 270 thyroidectomies (where 65.4 per cent of patients were operated on with loupes), loupes had no significant influence on the inadvertent parathyroidectomy rate. In contrast, Pata et al.^{Reference Pata, Casella, Mittempergher, Cirillo and Salerni32} compared 126 patients undergoing total thyroidectomy with the routine use of 2.5× loupe magnification with a control group of 118 patients operated on without the use of loupes; these authors found that the inadvertent parathyroidectomy rate was significantly lower with loupes than without loupes (12.7 per cent vs 25.4 per cent respectively, p = 0.01).

Near-infrared autofluorescence has been shown to be a valuable aid in the identification of parathyroid glands intra-operatively because of their autofluorescent properties,^{Reference Kim, Lee, Jung, Kim, Kim and Hwang33} but its role in preventing inadvertent parathyroidectomy is unclear.^{Reference DiMarco, Chotalia, Bloxham, McIntyre, Tolley and Palazzo34,Reference Benmiloud, Godiris-Petit, Gras, Gillot, Turrin and Penaranda35} A recent systematic review and meta-analysis by Wang et al.,^{Reference Wang, Zhu, Liu, Yao and Wu36} which included 7 studies involving 1480 patients, assessed the ability of near-infrared autofluorescence to protect parathyroid gland function during thyroid surgery. The results suggest that near-infrared autofluorescence significantly reduces the risk of inadvertent parathyroidectomy and hypocalcaemia on the day after surgery

Extracapsular inadvertent parathyroidectomy could be used as a surrogate marker for the quality of surgery. With a better understanding of the risk factors for inadvertent parathyroidectomy, confounding variables could be adjusted for, allowing surgeons to benchmark their performance. An unusually high rate of extracapsular inadvertent parathyroidectomy cases could alert surgeons to review their practice and surgical approach. A prerequisite for this would be mandatory reporting of inadvertent parathyroidectomy, including the location of excised parathyroid glands, acknowledging that intrathyroidal parathyroid gland excision is unavoidable.

Limitations

The main limitation of our study is its retrospective nature. Inherent in this are the elements of missing data – most notably data on weight and volume, some histopathology slides, and data on long-term post-surgical hypoparathyroidism or hypocalcaemia. The no inadvertent parathyroidectomy group included all patients who had no mention of parathyroid tissue in the histopathology report; however, this had a 10 per cent false negative rate. Data on parathyroid auto-transplantation were not recorded, nor was the viability of preserved parathyroid glands, both of which may have influenced the rate of post-surgical hypoparathyroidism or hypocalcaemia. The number of patients who had two or more inadvertently excised parathyroid glands was low, limiting analysis of the relationships between the number of excised glands and outcomes related to post-surgical hypoparathyroidism or hypocalcaemia.