Introduction
Parathyroidectomy is a highly effective therapy for primary hyperparathyroidism. The time-honoured bilateral neck exploration will guarantee cure in more than 95 per cent of patients.Reference Reeve, Babidge, Parkyn, Edis, Delbridge and Devitt1 In the era of minimally invasive surgery, emphases on less post-operative pain, shorter operation time, fewer procedure-related complications and faster recovery from surgery have also pervaded parathyroidectomy. To date, minimally invasive parathyroidectomy has already evolved as the preferred operation for sporadic primary hyperparathyroidism.Reference Duh2–Reference Stalberg, Sidhu, Sywak, Robinson, Wilkinson and Delbridge4
Different modalities of minimally invasive parathyroidectomy have been reported: radio-guided parathyroidectomy,Reference Denham and Norman5, Reference Goldstein, Blevins, Delbeke and Martin6 video-assisted parathyroidectomyReference Miccoli, Bendinelli, Berti, Vignali, Pinchera and Marcocci7, Reference Barczynski, Cichon, Konturek and Cichon8 and open mini-incision parathyroidectomy.Reference Brunaud, Zarnegar, Wada, Ituarte, Clark and Quh9, Reference Shindo, Rosenthal and Lee10 Open mini-incision parathyroidectomy remains the most popular option because of: its short learning curve, the advantage of being able to use conventional surgical instruments, the avoidance of radiation exposure (unlike radio-guided parathyroidectomy) and the feasibility of ambulatory surgery performed under local anaesthesia.Reference Udelsman11–Reference Stalberg, Delbridge, van Heerden and Barraclough13
However, double adenomas or multi-glandular disease can exist in primary hyperparathyroidism.Reference Harness, Ramsburg, Nishiyama and Thompson14, Reference Haciyanli, Lai, Morita, Duh, Kebebew and Clark15 Therefore, the success of minimally invasive parathyroidectomy is critically governed by the accuracy of pre-operative imaging to correctly predict cases of solitary adenoma. Ultrasonography and technetium-99m sestamibi scanning are the two most important pre-operative investigations to direct a focused parathyroidectomy approach. The positive predictive value of each modality is over 90 per cent.Reference Mazzeo, Caramella, Lencioni, Molea, De Liperia and Marcocci16–Reference Lo, Lang, Chan, Kung and Lam18
To further improve the outcome of parathyroidectomy, an intra-operative parathyroid hormone assay is believed by many endocrine surgeons to be essential in order to ascertain the completeness of removal of all hyperactive parathyroid glands.Reference Udelsman11, Reference Nussbaum, Thompson, Hutcheson, Gaz and Wang19–Reference Kandil, Alabbas, Bansal, Islam, Tufaro and Tufano24 Intra-operative parathyroid hormone monitoring might detect double adenomas and reduce treatment failure rate. Conversely, the usefulness of intra-operative parathyroid hormone monitoring has been questioned in some studies, as high cure rate after focused parathyroidectomy can be similarly achieved when routine intra-operative parathyroid hormone monitoring is not exercised.Reference Stalberg, Sidhu, Sywak, Robinson, Wilkinson and Delbridge4, Reference Agarwal, Barakate, Robinson, Wilkinson, Barraclough and Reeve25–Reference Mozzon, Mortier, Jacob, Soudan, Boersma and Proye27 Of note, all of those investigators were working in tertiary referral centres that are highly specialised in endocrine surgery. Such centres are extremely proficient in managing patients suffering from primary hyperparathyroidism. However, many patients with primary hyperparathyroidism undergo surgical treatment in regional hospitals where there is less experience.
It is interesting to investigate whether the satisfactory results of focused parathyroidectomy without intra-operative parathyroid hormone monitoring can be extrapolated to low-volume hospitals. To our knowledge, this issue has not been adequately investigated.
Our institution is a regional hospital, with 184 adult surgical beds, serving a population of 600 000 from the East Kowloon region in Hong Kong. Focused parathyroidectomy is contemplated when pre-operative imaging (ultrasonography and/or sestamibi scanning) clearly demonstrates solitary parathyroid adenomas in cases of clinically sporadic primary hyperparathyroidism. Intra-operative parathyroid hormone monitoring is usually not employed for these cases. We undertook a survey of the results of focused parathyroidectomy performed for primary hyperparathyroidism in a low-volume hospital.
Materials and methods
Patients
Focused parathyroidectomy has been conducted in our institution since November 2002. The data for patients diagnosed with primary hyperparathyroidism who underwent primary parathyroidectomy from November 2002 to October 2012 were retrieved from our hospital database. Those patients with a history of familial hyperparathyroidism, renal failure, or negative pre-operative localisation findings and concomitant total thyroidectomy were not selected to undergo focused parathyroidectomy. Likewise, focused parathyroidectomy was contraindicated if the pre-operative localisation findings were ambiguous, with more than one suspicious focus or discordant results as depicted by ultrasonography and sestamibi scanning. However, simultaneous ipsilateral hemithyroidectomy was not a contraindication for mini-incision parathyroidectomy.
Pre-operative localisation
Sestamibi scanning involved dual-phase, single-isotope imaging using technetium-99m sestamibi. The result was regarded as positive if persistent focal radioactivity was detected on the 2-hour delayed image. If transient uptake was shown on the early 15-minute image alone, it was not considered as positive for parathyroid adenoma.Reference Arici, Cheah, Ituarte, Mortia, Lynch and Siperstein17, Reference Boudreaux, Magnuson, Asher, Desmond and Peters28 Single photon emission computed tomography was not routinely performed. High-resolution ultrasonography was performed with a 8–12 MHz transducer equipped with colour duplex Doppler function. The diagnostic criterion of parathyroid adenoma was a well-defined hypoechoic or heterogeneous ovoid nodule that was hypervascular on Doppler imaging and was identified adjacent to the thyroid gland.Reference Arici, Cheah, Ituarte, Mortia, Lynch and Siperstein17, Reference Boudreaux, Magnuson, Asher, Desmond and Peters28
Surgical technique
The operation was performed under either general or local anaesthesia; this was determined according to the anaesthetic risk for individual patients, and the personal preference of surgeons and patients.Reference Carling, Donovan, Rinder and Udelsman29 Similarly, the surgical procedure could be implemented in either day-case surgery or in-patient settings.Reference Shindo, Rosenthal and Lee10, Reference Cohen, Finkelstein, Brunt, Haberfeld, Kangrga and Moley12
A transverse cervical skin incision measuring about 2.5 cm was made. The exact position of the incision was guided by the pre-operative imaging findings. The incision could be enlarged if better exposure was required or simultaneous hemithyroidectomy was planned. A lateral approach as described by Shindo and RosenthalReference Shindo and Rosenthal30 was adopted as the most frequent means of access to the parathyroid adenoma. The thyroid lobe was identified after dissection between the sternomastoid and strap muscles. The middle thyroid vein was controlled and divided. The thyroid lobe was then retracted: the parathyroid adenoma could often be identified and dissected without difficulty. The superior thyroid pedicle needed to be divided for some superior parathyroid adenomas. After frozen section examination confirmed the diagnosis of abnormal parathyroid gland, the operation was concluded and the wound was sutured in layers, without drainage.
Post-operative management
Post-operatively, parathyroid hormone was checked on day 1, while calcium was monitored for at least 2 consecutive days for all patients, including the day-case surgery patients. When patients developed symptomatic hypocalcaemia, calcium supplement with or without vitamin D was administered. Fibre-optic laryngoscopy was conducted whenever patients suffered from any voice change after surgery. Persistent hyperparathyroidism was defined as hypercalcaemia associated with elevated parathyroid hormone levels within six months post-operatively. If this happened beyond six months after parathyroidectomy, recurrent hyperparathyroidism was diagnosed.
Ethics
Informed consent was obtained from all patients prior to parathyroidectomy. The patients were treated in accordance with the ethical standards of the Helsinki Declaration of 1975. They were well informed about the possibility of bilateral neck exploration and the risk of therapy failure.
Statistical analysis
Continuous variables were expressed as means ± standard deviations (SDs) and analysed using paired t-tests. Categorical variables were analysed using the chi-square test or Fisher's exact test, as appropriate. The results were considered statistically significant if the p-value was less than 0.05. All significant tests were two-sided. SPSS® version 13 software was used for data computation.
Results
Clinicopathological characteristics
A total of 126 patients diagnosed with sporadic primary hyperparathyroidism underwent surgical treatment between November 2002 and October 2012. Twenty-one patients were contraindicated for focused parathyroidectomy because of: negative localisation (n = 11), a multifocal parathyroid lesion on localisation investigation (n = 3), a discordant localisation result (n = 1) or planned simultaneous bilateral thyroid resection (n = 4). An intra-operative parathyroid hormone assay was employed in three other patients. Focused parathyroidectomy was offered to the remaining 105 patients, who were evaluated in this study. The clinicopathological data are summarised in Table I.
Table I Clinicopathological data summary
Data represent numbers (and percentages) of patients unless indicated otherwise. SD = standard deviation
Concerning the final pathological diagnoses, 101 patients (97.1 per cent) had a single adenoma. Double adenomas (ipsilateral side) were encountered in only one patient (1.0 per cent). Parathyroid carcinoma was diagnosed in two patients (1.9 per cent). The pathological diagnosis in the remaining case was dubious, as no abnormal parathyroid gland was found during surgery and the patient refused reoperation. The mean follow-up period was 56.9 ± 35.3 months, with a minimal follow-up time of 3 months.
Operative data
A total of two patients (1.9 per cent) required a conversion to bilateral exploration. In both cases, only solitary parathyroid adenomas were found, which corresponded to the localisation investigation results; these patients were cured following surgery. The reason for conversion in one case was initial failure of adenoma identification intra-operatively. The adenoma was eventually found after a futile contralateral neck exploration. In the remaining case, bilateral exploration was (incorrectly) requested, despite one adenoma having already been found.
Focused parathyroidectomy was performed under general anaesthesia in 38 patients (36.2 per cent) and under local anaesthesia in 67 patients (63.8 per cent). Ambulatory surgery was implemented in 25 patients (23.8 per cent), while the remaining patients underwent in-patient procedures (Table I).
Biochemical results
Post-operative serum calcium, alkaline phosphatase and parathyroid hormone levels were significantly lower than the pre-operative values on paired t-test (Table II). The mean (±SD) pre- and post-operative serum calcium, alkaline phosphatase and parathyroid hormone levels were 2.86 ± 0.2 mmol/l versus 2.27 ± 0.11 mmol/l, 189.03 ± 32.79 IU/l versus 80.86 ± 32.41 IU/l, and 33.1 ± 50.1 pmol/l versus 5.07 ± 3.61 pmol/l, respectively.
Table II Biochemical parameters
Data represent mean ± standard deviation values. *Paired t-test. †Serum reference range = 2.15–2.55 mmol/l; ‡serum reference range = 1.6–6.9 pmol/l; **serum reference range = 35–104 IU/l
Pre-operative localisation tests
Ultrasonography was performed on 102 patients and parathyroid adenomas could be localised in 86 patients (84.3 per cent). Sestamibi scanning was performed on 101 patients and adenomas were identified in 86 patients (85.1 per cent). There was no difference in the ability to detect parathyroid adenoma between ultrasonography and sestamibi scanning (Fisher's exact test, p = 0.45).
Treatment outcome
Two patients had persistent hypercalcaemia following parathyroidectomy. In both cases, the adenoma could not be recognised intra-operatively. One patient was later cured by re-exploration after repeat sestamibi scanning revealed a right inferior parathyroid adenoma at the same site as depicted on the first imaging scan. The adenoma was located just behind the right brachiocephalic artery. The other patient refused further intervention and continued to have mild hypercalcaemia. Recurrent hyperparathyroidism was not encountered in this series.
Operative complications
Surgical complications were uncommon. These consisted of: transient vocal fold palsy in two patients (1.9 per cent), permanent vocal fold palsy in one patient (1.0 per cent) and transient hypocalcaemia in seven patients (6.7 per cent). No patient had permanent hypocalcaemia. ‘Hungry bone syndrome’ was responsible for three of the seven patients suffering from transient hypocalcaemia, which resulted in prolonged hospitalisation.
Discussion
The overall cure rate after focused parathyroidectomy performed (for primary hyperparathyroidism) without intra-operative parathyroid hormone monitoring in this series was 98 per cent, which is equivalent to the results reported from high-volume centres.Reference Agarwal, Barakate, Robinson, Wilkinson, Barraclough and Reeve25–Reference Mozzon, Mortier, Jacob, Soudan, Boersma and Proye27 Suliburk et al.Reference Suliburk, Sywak, Sidhu and Delbridge31 described their experience of minimally invasive parathyroidectomy conducted without intra-operative parathyroid hormone measurement in 1020 patients. The cure rate in that large-scale study approached 98 per cent. In our hospital, approximately 100 cases of focused parathyroidectomy were accumulated over a 10-year period. This indicates that respectable parathyroidectomy outcomes can also be replicated in relatively low-volume hospitals if appropriate patients are selected. Similarly, a study from another low-volume hospital in Turkey demonstrated efficacious findings for focused parathyroidectomy performed without routine intra-operative parathyroid hormone monitoring in selected patients with sporadic primary hyperparathyroidism.Reference Haciyanli, Genc, Damburaci, Oruk, Tutuncuoglu and Erdogan32 The surgeons involved in our series are well trained in head and neck surgery; surgeons performing occasional neck surgery might not be able to reproduce the same results. The long duration of follow up (mean of 56.9 months) proves that disease control after focused parathyroidectomy was durable.
The use of intra-operative parathyroid hormone monitoring during focused parathyroidectomy is contentious. We have reviewed the papers published over the past six years that report outcomes of focused parathyroidectomy performed for primary hyperparathyroidism at various institutions; the findings are summarised in Table III.Reference Shindo, Rosenthal and Lee10, Reference Suliburk, Sywak, Sidhu and Delbridge31, Reference Lombardi, Raffaelli, Traini, Di Stasio, Carrozza and De Crea33–Reference Wong, Foo, Lau, Sarin and Kiruparan42 As the failure rate is generally less than 5 per cent, only those studies with over 100 patients were included for meaningful comparison. If more than one article was published by the same institution, only the most representative study was included.
Table III Literature review findings*
* For studies on routine intra-operative parathyroid hormone monitoring versus no intra-operative parathyroid hormone monitoring for focused parathyroidectomy. FU = follow-up; IOPTH = intra-operative parathyroid hormone monitoring; USG = ultrasonography; MIBI = sestamibi scanning; n/a = not available
The treatment success rate among the different institutions is comparable, ranging from 96 to 100 per cent, regardless of whether or not intra-operative parathyroid hormone monitoring was used. We should interpret some study findings with caution though as only the rate of persistent hyperparathyroidism was reported if the follow-up duration was less than six months. The overall failure rate is expected to be higher after prolonged follow up when recurrent hyperparathyroidism figures are included.
Pang et al.Reference Pang, Stalberg, Sidhu, Sywak, Wilkinson and Reeve43 alluded that the estimated improvement of cure of primary hyperparathyroidism with routine intra-operative parathyroid hormone monitoring is probably 1 per cent. Thereby, the number of patients needed to undergo treatment to gain a benefit of intra-operative parathyroid hormone monitoring is 100. In other words, parathyroid hormone monitoring is overused in 99 out of 100 occasions. The financial implication of this is considerable. In addition, unnecessary neck exploration performed in cases of false negative intra-operative parathyroid hormone monitoring findings should not be neglected.Reference Stalberg, Sidhu, Sywak, Robinson, Wilkinson and Delbridge4, Reference Tan, Wilkinson and Levenson44 In this series, the two futile operations were carried out because of failure to identify the parathyroid adenoma. Lew et al.Reference Lew, Rivera, Irvin and Solorzano35 likewise echoed that an inability to find the abnormal parathyroid glands is the main cause of treatment failure in focused parathyroidectomy. The outcome in such circumstances will not be rectified by an intra-operative parathyroid hormone assay. Thus, we favour to reserve intra-operative parathyroid hormone measurement for certain cases only; specifically, if repeat parathyroidectomy is required, if there is negative or multifocal uptake on pre-operative localisation investigations, if there are discordant localisation findings, or if there is familial hyperparathyroidism.Reference Hwang, Morris, Ro, Park, Ituarte and Hong36
There is no doubt that localisation imaging is essential to the success of focused parathyroidectomy. However, it is unclear whether ultrasonography or sestamibi scanning alone, or both, are needed prior to surgery. Ultrasonography has been found to have similar sensitivity to sestamibi scanning. Thus, Mazzeo et al.Reference Mazzeo, Caramella, Lencioni, Molea, De Liperia and Marcocci16 recommended the former technique as the first localisation test because it is devoid of any radiation, it is widely available and it is inexpensive. Another bonus of ultrasonography is its ability to identify significant thyroid lesions, which are commonly present in primary hyperparathyroidism.Reference Boudreaux, Magnuson, Asher, Desmond and Peters28 Furthermore, the anatomical relationship between the parathyroid adenoma and thyroid gland is more clearly shown on ultrasonography than sestamibi scanning. In contrast, sestamibi scanning has been recommended by other investigators as the primary localisation investigation because of its high sensitivity for solitary parathyroid adenoma.Reference Lo, Lang, Chan, Kung and Lam18, Reference Moure, Larranaga, Dominguez-Gadea, Luque-Ramirez, Nattero and Gomez-Pan40 We are in agreement with Kandil et al.,Reference Kandil, Malazai, Alrasheedi and Tufano45 who purport that ultrasonography and sestamibi scanning are complementary to each other. We recommend that both modalities are performed prior to focused parathyroidectomy.
Simultaneous hemithyroidectomy during focused parathyroidectomy is feasible, as illustrated in this series, because hemithyroidectomy can be duly accomplished under local anaesthesia.Reference Spanknebel, Chabot, DiGiorgi, Cheung, Lee and Allendorf46 Therefore, ipsilateral thyroid abnormality does not contravene the conduct of focused parathyroidectomy. Of course, the incision should be lengthened to about 4 cm in such circumstances.
One of the advantages of focused parathyroidectomy over conventional bilateral neck exploration is a lower incidence of post-operative hypocalcaemia.Reference Bergenfelz, Kanngiesser, Zielke, Nies and Rothmund3, Reference Tibblin, Bondeson and Ljungberg47, Reference Bergenfelz, Lindblom, Tibblin and Westerdah48 Severe post-parathyroidectomy hypocalcaemia is nowadays a rare complication because of the early detection of primary hyperparathyroidism and early intervention. Nevertheless, three cases of hungry bone syndrome were encountered in this series and resulted in prolonged hospital stay. The pre-operative calcium, parathyroid hormone and alkaline phosphatase levels in the affected patients were markedly elevated. The risk factors for developing hungry bone syndrome include: high pre-operative levels of calcium, parathyroid hormone and alkaline phosphatase; a large adenoma (more than 5 cm); osteitis fibrosa cystica; and patient age of more than 60 years.Reference Bhattacharyya, Buckler and New49 Preventive measures against hungry bone syndrome should be undertaken. Calcium and vitamin D supplements can be cautiously prescribed one week before surgery. However, the role of bisphosphonate in this aspect is yet to be elucidated.Reference Bhattacharyya, Buckler and New49, Reference Anzai, Yokoyama, Ohba, Ito, Fujimaki and Kojima50
• Focused parathyroidectomy for primary hyperparathyroidism is often performed with intra-operative parathyroid hormone monitoring
• Specialist institutions have shown that good surgical outcomes can be achieved without intra-operative parathyroid hormone monitoring in select patients
• This study investigated whether these findings could be extrapolated to a low-volume hospital
• A successful outcome was attained without intra-operative parathyroid hormone monitoring; pre-operative localisation findings should be unequivocal
To conclude, when pre-operative ultrasonography or sestamibi scanning identify unequivocal solitary parathyroid adenoma (without discordance) in patients with sporadic primary hyperparathyroidism, a satisfactory outcome after focused parathyroidectomy without routine intra-operative parathyroid hormone monitoring can be reproduced in low-volume hospitals.
