The changing face of reoperative parathyroidectomy: a single-centre comparison of 147 parathyroid reoperations

Abstract

Introduction

Reoperative parathyroidectomy for persistent and recurrent primary hyperparathyroidism is dependent on radiology. This study aimed to compare outcomes in reoperative parathyroidectomy at a single centre using a combination of traditional and newer imaging studies.

Materials and methods

Retrospective case note review of all reoperative parathyroidectomies for persistent and recurrent primary hyperparathyroidism over five years (June 2014 to June 2019; group A). Imaging modalities used and their positive predictive value, complications and cure rates were compared with a published dataset spanning the preceding nine years (group B).

Results

From over 2000 parathyroidectomies, 147 were reoperations (101 in group A and 46 in group B). Age and sex ratios were similar (56 vs 62 years; 77% vs 72% female). Ultrasound use remains high and shows better positive predictive value (76% vs 57 %). 99mTc-sestamibi use has declined (79% vs 91%) but the positive predictive value has improved (74% vs 53%). 4DCT use has almost doubled (61% vs 37%) with better positive predictive value (88% vs 75%). 18F-fluorocholine positron emission tomography-computed tomography and ultrasound-guided fine-needle aspiration for parathyroid hormone are novel modalities only available for group A. Both carried a positive predictive value of 100%. Venous sampling with or without angiography use has decreased (35% vs 39%) but maintains a high positive predictive value (86% vs 91%). Cure rates were similar (96% vs 100%). Group A had 5% permanent hypoparathyroidism, 1% permanent vocal cord palsy and 1% haematoma requiring reoperation. No complications for group B.

Conclusion

Optimal imaging is key to good cure rates in reoperative parathyroidectomy. High-quality, non-interventional imaging techniques have produced a shift in the preoperative algorithm without compromising outcomes.

Introduction

Primary hyperparathyroidism (pHPT) is the third most common endocrine pathology. It is caused by the inappropriate over-secretion of parathyroid hormone (PTH).¹ It has a prevalence of approximately one in 1,000 patients but increases with age so that up to 2% of postmenopausal women have the disease.² Surgery represents the only definitive treatment for pHPT and most patients that undergo parathyroid surgery are cured. The best outcomes are achieved when the surgery is performed by high volume surgeons.³ Indeed, data from the UK Registry of Endocrine and Thyroid Surgery suggests that, at least for surgeons who submit to this national registry, a cure rate of 95.6% at the first operation is achievable.⁴

An ever-increasing number of patients are being referred for surgery due to the combination of an ageing population and a greater awareness of the disease and its adverse effects. This has resulted in an increase in the number of patients with biochemically mild pHPT in whom there is a greater risk of failure to cure at first-time surgery.⁵ In addition, localising imaging investigations in this group of patients are more likely to be negative. It is inevitable, therefore, that there will be an increase in the absolute number of patients requiring reoperative surgery.

Persistent primary hyperparathyroidism is pHPT that has not been cured at surgery and is defined by its presence at less than six months from the original parathyroidectomy; recurrent primary hyperparathyroidism is defined as pHPT that is initially cured but presents more than six months after the original surgery. Cure of this continuing disease in either form can only be achieved with reintervention. While persistent pHPT is usually related to the failure to identify the pathological parathyroid gland/s during the first operation, recurrent pHPT is less common and is usually a reflection of an underlying undetected multiple-gland disease process.⁶

Reoperative parathyroid surgery is associated with a lower rate of cure and a greater risk of surgical complications.^7,8 Distorted neck anatomy due to scarring and fibrosis from the original surgery, together with the fact that imaging investigations to localise disease before the original surgery are more likely to have been negative in this group of patients,⁹ results in an increased risk of bleeding, damage to the recurrent laryngeal nerve and failure to identify diseased parathyroid tissue.

Anglo-American guidelines for reoperative parathyroid surgery have emphasised the need for a stepwise approach to localisation prior to contemplating reintervention.¹⁰ Once the diagnosis and the need for surgery have been confirmed, all previous surgical and pathological reports (if available) must be reviewed to limit, wherever possible, the possible location/s of the missing parathyroid gland/s. Reintervention without reliable localisation or, at least, regionalisation of the abnormal parathyroid gland/s is ill-advised. The choice of which imaging modalities to use should be guided by a detailed review of the previous imaging by the surgeon and radiologist, the anatomical sites of interest and available radiological expertise. Non-invasive modalities should be requested initially and invasive investigations only used when the former fail to accurately localise disease. In recent years there have been important additions to the radiological armamentarium which offer additional localisation options. These have pushed the investigative algorithm towards less invasive radiological modalities.

This study aims to compare outcomes in reoperative parathyroidectomy at a single centre using a combination of traditional and newer imaging studies namely four-dimensional computed tomography (4-D CT) and 18F-fluorocholine positron emission tomography-computed tomography (FCH PET-CT) introduced in 2011 and June 2018, respectively.

Materials and methods

All patients undergoing reoperative parathyroid surgery for persistent or recurrent pHPT in the five years from June 2014 to June 2019 (group A) were identified from the prospectively maintained departmental database of the Department of Thyroid and Endocrine Surgery at Hammersmith Hospital, London. This cohort was compared with a previously published cohort of patients from the same institution, who underwent reoperative parathyroidectomy between October 2006 and May 2014 (group B).¹¹ Data collected included demographics, preoperative biochemistry, the presence of end organ damage, imaging results and the intraoperative and histopathological records from all previous interventions. Comparisons were made using a chi-square test (SPSS Statistics version 26). Successful reoperative parathyroidectomy was defined as postoperative normocalcaemia for six months and a histopathological specimen confirming abnormal parathyroid tissue. The results of imaging performed prior to reintervention were reviewed and compared with the operative and histopathological record from the reintervention to calculate the positive predictive value (PPV) for each investigative modality.

Results

It has been standard practice in our unit to perform dual modality localisation – ultrasound and technetium-99m radiolabelled methoxyisobutylisonitrile (99mTc-sestamibi) scans – on all patients before first-time parathyroidectomy. In more than 2,000 first-time parathyroidectomies performed in the department between 2006 and 2019, these investigations failed to localise disease in 34% of patients. During this same time period, 147 reoperative parathyroidectomies were performed. Of these, 101 patients had reoperative parathyroidectomy between June 2014 to June 2019 (group A) and 46 had their surgery between October 2006 and May 2014 (group B). The number of patients undergoing reoperative parathyroid surgery had increased but the demographics between the two groups were similar (Table 1).

Table 1.

Patient demographics

	Group A	Group B	p-value
Patients (n)	101	46
Female, n (%)	78 (77)	72 (n = 33)	NS
Median age (years)	56	62
Age range (years)	18–88	20–80	NS
Prior procedures, n (%):			NS
1	88 (87)	89 (n = 41)
2	11 (11)	11 (n = 5)
3	1 (1)	–
4	1 (1)	–
Indication for procedures, n (%):			NS
Persistence	81 (80)	76 (n = 35)
Recurrence	20 (20)	13 (n = 6)
Renal	1 (1)	10 (n = 5)
Presence of genetic disease, n (%):	5 (5)	6 (n = 3)
Multiple endocrine neoplasia type 1	3 (3)	6 (n = 3)
Tumour jaw syndrome	2 (2)	–
Concurrent thyroid disease	14 (14)	13 (28)

The median age of patients was marginally lower in the more recent group: 56 years in group A and 62 years in group B, although this was not statistically significant. The expected female predominance was present in both age groups: 77% (n = 78) patients in group A were female compared with 72% (n = 33) patients in group B (p = 0.66). The majority of patients in both group A and B were referred following previous parathyroid surgery performed elsewhere. However, the proportion was greater in group B: 78% (n = 36) of patients in group B compared with 60% (n = 61) in group A (p = 0.006). In group A, 87% (n = 88) of patients had undergone one previous operation, 11% (n = 11) of patients had two, 1% (n = 1) patient had three and 1% (n = 1) patient, four. Comparably in group B, 89% (n = 41) patients had undergone one previous operation and 11%(n = 5) patients, two operations (p = 0.97). Indications for surgery were similar between the two groups (Table 1).

All patients had pre- and postoperative flexible nasoendoscopy. Intraoperative PTH monitoring (‘stat IOPTH’, Future Diagnostics, Wijchen, Netherlands) was used as an adjunct to surgery in all cases except those where a unilateral exploration of the previously unexplored side of the neck was planned.

Analysis of the imaging modalities used showed that ultrasound and 99mTc-sestamibi were used in the majority of patients, although there was a significant decrease in the use of sestamibi imaging from 91% in group B to 78% in group A (p = 0.01). In both cases the positive predictive value significantly improved from 57% to 76% for ultrasound (p < 0.01) and from 53% to 74% for sestamibi (p < 0.01). The use of 4-D protocol CT almost doubled from 37% in group B to 61% in group A (p < 0.01) and this was accompanied by an improvement in the PPV from 75% to 88% (p = 0.02). FCH PET-CT and ultrasound-guided fine-needle aspiration for parathyroid hormone levels were new investigations exclusively available for group A thus far showing a PPV of 100%. The increased use of noninvasive imagining modalities has led to a decrease in the use of selective venous sampling with or without angiography from 39% to 25% (p = 0.03; Fig 1). Notwithstanding, the latter modality maintains a high PPV of 88% (Table 2).

Figure 1.

The imaging modalities used in the two groups

Table 2.

Summary of the positive predictive values of imaging studies performed

Modality	Positive predictive value (%)		p-value
	Group A	Group B
Noninvasive:
Ultrasonography	76	57	< 0.01
99mTc-sestamibi	74	53	< 0.01
4-D CT	88	75	0.02
FCH PET-CT	100	–	–
Invasive:
Ultrasound-guided FNA for PTH	100	–	–
Venous sampling ± angiography	86	91	NS

4-D, four-dimensional; CT, computed tomography; FCH, 18F-fluorocholine; FNA, fine-needle aspiration; PET, positron emission tomography

In group A, most of the pathological glands found at reoperation were in eutopic positions 67% (n = 68) while 32% (n = 33) glands were deemed ectopic. Eight per cent of patients (n = 8) had supernumerary glands. This shows an identical distribution to that previously reported in group B (Table 3).

Table 3.

Position of excised parathyroid glands

Position	Group A		Group B
	(n)	(%)	(n)	(%)
Eutopic	68	67	31	67
Ectopic:	33	32	15	32
Intrathyroidal	3	3	4	9
Mediastinal	5	5	4	9
Intrathymic	15	15	3	7
Adjacent to submandibular gland	0	0	2	4
In the carotid sheath	4	4	1	2
Parathyromatosis	0	0	1	2
Retro-oesophageal	2	2	0	0
Superior descended	2	2	0	0
Unidentified	2	2	0	0
Supernumerary	8	8	4	9

Ninety-six percent of patients (n = 97) who underwent reoperative parathyroidectomy in group A were biochemically cured as opposed to 100% (n = 46) of patients in group B. (p = 0.17). The complications encountered in group A were of one (1%) permanent vocal cord palsy, five (5%) of permanent hypoparathyroidism and one (1%) haematoma requiring reoperation. No complications were reported in group B.

Discussion

This comparison of the recent practice of reoperative parathyroid surgery in our department with our previously published series underlines the increasing frequency of reoperative parathyroid surgery and reflects the developments in preoperative localisation strategies. The imaging armamentarium for reoperative cases has become more extensive with the most recent addition being the availability of FCH PET-CT.

This study has confirmed the value of ultrasound and 99mTc-sestamibi/single-photon emission CT (SPECT) as baseline investigations but also the added value of using ultrasound-guided fine-needle aspiration for PTH and 4-D CT as worthwhile alternatives to selective venous sampling as second-line investigation modalities. The growing experience with FCH PET-CT appears to be relegating selective venous sampling and angiography to a position of last resort when all other modalities have been equivocal or negative (Fig 2).

Figure 2.

Fused coronal image from 18F-fluorocholine positron emission tomography computed tomography (FCH PET-CT) demonstrates focal localisation of the radiopharmaceutical in the left carotid sheath, confirmed as being an ectopic parathyroid gland at subsequent surgery

Ultrasound performed by an experienced operator should nearly always be the first-line investigation. Ultrasound is inexpensive and noninvasive and, while associated with a relatively low PPV, has been used in recent years in conjunction with a guided fine-needle aspiration for PTH in equivocal cases where distinction from a lymph node or thyroid nodule is required.^12–13 99mTc-sestamibi provides functional information and can be combined with single-photon emission CT and low-dose CT. Hybrid SPECT-CT combines functional and anatomical imaging of parathyroids and has typically been used in addition to ultrasound as a first-line investigation in reoperative surgery. However, there has been a decrease in the use of this modality when compared with previous years, mainly because of the introduction of 4-D CT.

4-D CT is derived from three-dimensional CT with an added dimension of contrast medium enhancement over time.¹⁴ This modality has been shown to be considerably better than both ultrasound and 99mTc-sestamibi/SPECT-CT in localising parathyroid disease in patients with recurrent or persistent pHPT after previous surgery but is reporter dependent.^15,16 Our study confirms this high PPV and, anecdotally, successful localisation is improving as experience with this modality increases. Similarly, the value of FCH PET-CT in identifying pathological parathyroid glands has recently become apparent.^17–20 Choline is a physiological component of the cell membrane, and its expression is increased in neoplasms with high membrane turnover such as parathyroid adenomas.²¹ The published results of the usefulness of this agent in localising parathyroid disease are currently limited to small heterogeneous case series, but are promising.^22,23 A 2019 small UK study in the reoperative setting of 12 cases with negative first-line scans reported successful localisation with FCH PET-CT and subsequent surgical cure in seven patients (58%).²⁰ In the group A cohort of patients in our own study (four patients), the PPV was 100%. The numbers in this study are limited, however, and larger cohorts are needed to clarify the role of this imaging modality taking cost and radiation exposure into consideration.

It is becoming clear that interventional radiological localisation techniques in the form of selective venous sampling and parathyroid arteriography are destined to be used less as a consequence of the developments in alternative localisation studies,^24,25 although they may still be required in some individuals (Fig 3).²⁶ They are, however, highly operator-dependent techniques and have a risk, albeit small, of complications including groin haematoma, contrast medium related anaphylaxis, acute renal failure and stroke.

Figure 3.

Image from right anterior oblique selective right internal mammary artery digital subtraction angiogram demonstrates a focal vascular blush (arrow) consistent with an ectopic anterior mediastinal parathyroid gland. Venous sampling performed at the same procedure confirmed this as being the source of parathyroid hormone. The patient subsequently underwent a curative parathyroidectomy performed via a mini-sternotomy.

This cohort reveals a surgical failure rate of 4%, which is comparable to published data.^27,28 Although statistically not significant, this is an increase when compared with the previously published cohort. Similarly, there has been an increase in the complication rate in group A. As the service in our unit develops, patients being managed have biochemically milder disease. In addition, the increased reliance on imaging modalities and, perhaps, greater ambition in patient selection criteria for reoperative parathyroid surgery may account for these changes.

Conclusion

Reoperative parathyroidectomy remains as challenging as ever, but the adaptation of old imaging techniques and the arrival of novel modalities, is changing the approach to preoperative work-up of these patients. The preoperative identification of an accurately localised target lesion is critical in maximising the chances of cure, and of minimising the associated morbidity. Noninvasive imaging using a stepwise approach is now established as the optimal preoperative localisation strategy, with invasive investigations reserved to the select few with otherwise unlocalised disease. This shift has not compromised the outcomes of reoperative parathyroidectomy.