Addressing the challenges of missed parathyroid glands in ultrasonography for secondary hyperparathyroidism.

doi:10.21203/rs.3.rs-3970012/v1

Background

Preoperative localization plays an important role in secondary hyperparathyroidism (SHPT) surgery. The advantages of neck ultrasound (US) include high availability and low cost. However, the reported sensitivity of US is 54–76%, and the reason for missed PG on US has been rarely addressed.

Methods

Fifty-four patients who were diagnosed with renal SHPT from September 2020 to March 2022 were included in this retrospective study. Preoperative localization included surgeon-oriented US and technetium 99m-sestamibi single-photon-emission-computed tomography/computed tomography (SPECT/CT).

Results

A total of 212 parathyroid glands (PGs) were pathologically confirmed, resulting in success rate of 96.2% (52/54). Using echo, 193 (91.0%) PGs were accurately localized, while 19 (9.0%) glands were not identified, including those in ectopic positions (n = 12, at thymus or intra-thyroid or others), of a small size (< 1 cm, n = 6), or overlapping with an ipsilateral PG (n = 1). US accurately detected four PGs in 36 (66.7%) patients, while SPECT/CT localized four glands in 19 (35.2%) patients. Although the number of US-detectable PGs was not associated with success rate, it showed significant negative correlation with surgical time (r_s=-0.459, P = 0.002).

Conclusion

US detected four glands in 66% of SHPT patients with a sensitivity of 90% for localization. Ectopic position and small size were the most common reasons of failing to detect PG on US. Complete preoperative echo localization might shorten the operating time.

ultrasonography

renal hyperparathyroidism

secondary hyperparathyroidism

localization

Chronic kidney disease (CKD) is a major burden on global health. Patients with CKD stage III or higher often develop secondary parathyroid hyperplasia, caused by hyperphosphatemia and hypocalcemia [1]. Secondary hyperparathyroidism (SHPT) results in abnormal calcium deposition, osteoporosis, bone deformity, or fracture [2]. Surgical resection is the treatment option for severe SHPT when drug regimens fail. Several studies have confirmed that parathyroidectomy provides better quality of life, fewer major cardiovascular events, and lower risk of postoperative recurrence [3–5].

Currently, the success of parathyroidectomy relies on localization with imaging and the experience of surgeon [6, 7]. However, the incidence of surgical failure, defined as persistent and recurrent SHPT after operation, is estimated to be 10–30%, largely due to incomplete localization. Therefore, thorough localization by imaging might prevent surgical failure [6, 8, 9].

Ultrasound (US) localization for SHPT is commonly practiced in various centers due to its widespread availability, real-time imaging, lack of contrast requirement, absence of renal dysfunction risk, and cost-effectiveness [10]. Compared with normal PGs, four-gland hyperplasia in SHPT may be more easily detected because of enlarged size. However, the preoperative imaging modality did not have high sensitivity in the detection of all the glands. The sensitivity of US localization ranges from 54–76% [11–13]. The reported rate of ultrasound-detection of four parathyroid glands ranges from 7.8–47.5% [14, 15].

Our objective aimed to assess the use of US and determine the reason for echo-detection failure. We may improve our technique accordingly to reduce surgical time and surgical failure rate.

Patients and methods

We retrospectively reviewed all SHPT patients who underwent total parathyroidectomy ± auto-transplantation between September 2020 and March 2022 in Kaohsiung Chang Gung Memorial Hospital, Taiwan. The indications for surgery were SHPT with any of the following: (1) age > 18 years old; (2) serum intact parathyroid hormone (iPTH) ≥ 800 pg/mL; (3) associated symptoms (pruritis, bone pain, fracture, calciphylaxis); (4) refractory hypercalcemia (≥ 10.2 mg/dL) and/or hyperphosphatemia (≥ 6.0 mg/dL) despite pharmacologic therapy [16]. Initially, 63 SHPT patients were enrolled. Patients who had recurrent SHPT (n = 5), a history of thyroidectomy (n = 2), no preoperative US (n = 1), or were lost to follow-up (n = 1) were excluded, thus leaving 54 patients for the final analysis (Fig. 1).

This study was approved by the Change Gung Medical Foundation Institutional Review Board (number: 202300239B0). The need for informed consent from patients was waived because of the study’s retrospective design.

The PGs were determined to be eutopic or ectopic during operation [9]. An intrathyroidal PG was defined as a gland that was completely surrounded by thyroid tissue [17]. The normal range for iPTH is 15–76 pg/ml. Early surgical success was defined as the iPTH ≤ normal range on the 5th postoperative day. Persistent SHPT was defined as the lowest iPTH exceeding the normal range within 6 months after parathyroidectomy. When initial postoperative iPTH was normal but returned to above normal range more than 6 months after successful surgery, the patient was defined as recurrent SHPT [16].

Patient demographics, imaging reports, laboratory values, and operative and pathological results were collected. Laboratory values included serum calcium, phosphorus, and iPTH, which were checked on 1st and 5th postoperative days and 6 months thereafter [18]. The primary endpoint of the study was the US detection rate of PG and analysis of the reason for missed PGs. The secondary endpoint was the association of the number of image-detectable PGs with surgery success rate and operating time.

As part of our evaluation protocol, electrocardiography, echocardiography, and thallium scans were conducted before operation. If positive or equivocal thallium scan results were obtained, patients were referred to cardiologists for percutaneous coronary intervention (PCI). For safety, parathyroid surgery was postponed for at least two months in patients who underwent PCI stenting followed by dual anti-platelet therapy. US and technetium 99m-sestamibi single-photon-emission-computed tomography/computed tomography (SPECT/CT) were used for preoperative localization, and both performed less than one month before surgery.

The US was performed by one of three experienced endocrine surgeons with ultrasound diagnostic instruments (LOGIQ S8; GE Healthcare; USA) and line array high-frequency probes (8–10 mHz). The typical parathyroid image showed an oval or multilobulated hypoechoic mass with peripheral vascular arch and a parathyroid vascular pedicle (Fig. 2) [19]. The patient was placed in supine position with neck mildly extended. We searched four common gland locations, including the right upper, right lower, left upper, and left lower positions of the neck (Fig. 3a to 3d). The size of PG was measured in axial and transverse views. If the number of detected PGs was less than four, the regions of the carotid sheath, thyro-thymic trunk, and upper mediastinum were focused on to search for ectopic PGs. We did not perform a routine biopsy to confirm parathyroid hyperplasia. When an incidental thyroid nodule was detected on US, fine needle aspiration (FNA) was conducted according to current guidelines [20].

^99mTc sestamibi SPECT/CT imaging was performed on a Siemens Symbia T SPECT/CT gamma camera (Siemens Medical Solutions, IL, USA). After intravenous administration of 1110 MBq (30 mCi) of ^99mTc sestamibi via a lower limb vein, each patient underwent early-phase planar imaging and delayed-phase planar imaging followed by SPECT/CT. The image was considered positive if it showed a focal area of increased uptake in the neck, mediastinum, or any potential ectopic site with either a progressive increase or a prolonged retention at the delayed phase.

Surgical techniques

US and parathyroidectomy were performed by the same surgical team. The results of US and SPECT/CT were read by surgeons at the time of surgery. Every patient underwent bilateral four-gland neck exploration via a transverse cervical incision under general anesthesia. When four or more enlarged PGs were removed, 100mg of the smallest gland was implanted into the subcutaneous layer of the limb. If fewer than three PGs were identified, no auto-transplantation would take place. We performed routine bilateral transcervical thymectomy. The location of PG was recorded during surgery (Fig. 3e) and each gland was classified as true positive, false positive, true negative, or false negative based on US findings and pathology. Additionally, the surgeon defined the ectopic location and cause of US-missed PGs intraoperatively. The size and weight of PGs were measured immediately after removal. Hemithyroidectomy or total thyroidectomy was conducted in some patients with a large nodular goiter (> 2 cm), or a nodule suspected or confirmed malignancy via US or FNA. The removed PGs and/or thyroid were examined by pathologists for the final diagnosis. Postoperative follow-up was longer than six months to define SHP recurrence or relapse.

Statistical analysis

Numerical data are expressed as the mean (standard deviation) and categorical data are expressed as rates or proportions. Logistic regression and Spearman correlation were used for statistical analysis. Results were considered significant if the p value < 0.05. Statistical analysis was performed using SPSS software v.20 (Chicago, Illinois, USA)

In all, 212 PGs of 54 uremic patients were removed with histological confirmation of parathyroid hyperplasia. The mean age of the patients was 58.7 ± 11.9 years. Male patients accounted for 61.1% (33/54) of this cohort. The mean duration of surgery was 83.5 ± 31.0 minutes (Table 1). Two patients (3.7%) were diagnosed with persistent SHPT after operation and no recurrent SHPT or permanent hypoparathyroidism after a mean follow-up period of 19.4 months.

There were 28 (13.1%) ectopic PGs in this study. The locations of these ectopic PGs were as follows: thymus (n = 15, 7.0%), intrathyroid (n = 3, 1.4%), and others (n = 10, 4.7%). Eleven patients underwent concurrent lobectomy (n = 5, 9.3%) or total thyroidectomy (n = 6, 11.1%) for nodular goiter (n = 7, 13.0%) or thyroid cancer (n = 4, 7.4%).

There were 2 surgical failures. We excised four extrathyroid nodules, but pathology proved that only three nodules were parathyroid hyperplasia and the other one was nodular goiter. The patient had persistent SHP (postoperative iPTH 261 pg/ml). In another case, we also excised four extrathyroid nodules, which all confirmed to be parathyroid hyperplasia. However, the postoperative iPTH was 665 pg/ml, therefore supernumerary PGs were suspected. The two patients did not undergo imaging evaluation after first operation.

Table 1

Basic characteristics of the 54 ESRD patients with secondary hyperparathyroidism
	Total (n = 54)
Age (year)	58.7 ± 11.9
Male sex, n (%)	33 (61.1%)
Type of dialysis, n (%)
Hemodialysis	40 (74.1%)
Peritoneal dialysis	14 (25.9%)
Years of dialysis (year)	7.6 ± 5.0
Pre-op iPTH level (pg/mL)	1797.9 ± 998.4
Post-op iPTH level (pg/mL)	19.7 ± 47.0
Pre-op Ca level (mg/dL)	10.4 ± 0.8
Concurrent thyroidectomy, n (%)	11 (20.4%)
Lobectomy/total thyroidectomy	5 (9.3)/6 (11.1)
Nodular goiter/thyroid cancer	7(13.0)/4(7.4)
Eutopic PG	184 (86.8%)
Ectopic PG	28 (13.2%)
Thymus	15 (7.1%)
Intrathyroid	3 (1.4%)
Others*	10 (4.7%)
US-missed ectopic PG	12 (5.7%)
Small PG (< 1 cm)	12 (5.7%)
US-missed small PG	6 (2.8%)
Duration of surgery^# (minutes)	83.5 ± 31.0
Postoperative follow-up (months)	19.4 ± 9.6
Recurrent or persistent SHP, n (%)	2 (3.7%)

Values are expressed as means ± SD or numbers (percent)

iPTH = intact parathyroid hormone, PG = parathyroid gland, SHP = secondary hyperparathyroidism

* Parathyroid glands in mediastinum, retroesophageal, retropharyngeal locations

^# Exclude patients who underwent concurrent thyroidectomy

In Table 2, US showed all four PGs in 36 patients (66.7%), three PGs in 15 patients (27.8%), two PGs in 1 patient (1.9%), and only one PG in 2 patients (3.7%). SPECT/CT detected all four PGs in 19 patients (35.2%), three PGs in 23 patients (42.6%), and two PGs in 12 patients (22.2%). When analyzed by lesion number, the sensitivity of US, SPECT, and combination was 91.0% (193/212), 79.3% (169/212), and 95.8% (203/212), respectively. The specificity of US, SPECT, and combination was 75.0% (3/4), 33.3% (1/3), and 25.0% (1/4), respectively. The accuracy of US, SPECT, and combination was 90.7% (196/216), 78.7% (170/216), and 94.4% (204/216), respectively (Table 3).

Table 2

Total number of parathyroid glands accurately identified on ultrasound and ^99mTc-MIBI SPECT/CT
Numbers of glands identified*	US, n (%)	^99mTc-MIBI SPECT/CT, n (%)
4	36 (66.7)	19 (35.2)
3	15 (27.8)	23 (42.6)
2	1 (1.9)	12 (22.2)
1	2 (3.7)	0 (0.0)

* Exclude false positive parathyroid glands

Table 3

Results of parathyroid glands localized on ultrasound and ^99mTc-MIBI SPECT/CT FP = false positive, FN = false negative, TP = true positive, TN = true negative
	TP	FN	TN	FP	Sensitivity (%)	Specificity (%)	Accuracy (%)
US	193	19	3	1	91.0	75.0	90.7
^99mTc-MIBI SPECT/CT	169	44	1	2	79.3	33.3	78.7
US + ^99mTc-MIBI SPECT/CT	203	9	1	3	95.8	25.0	94.4

Compared with intraoperative findings and final pathology, one gland on US and two glands on SPECT/CT were false positives (Table 3). Meanwhile, 19 PGs (9.0%) were not shown on US and were categorized as false negatives. Table 4 summarizes the reason for US-missed PGs. The most common cause was an ectopic position (n = 12, 3.2%), including thymus (n = 6, 2.8%) (Fig. 4a), intrathyroid (n = 1, 0.5%) (Fig. 4b), and others (located at mediastinum, retroesophageal, and retropharyngeal area; n = 5, 2.4%). The second most common cause was small size (n = 6, 2.8%), which all was less than 1 cm in maximal length and weighed less than 200 µg. One upper PG overlap with the ipsilateral lower PG (n = 1, 0.5%) (Fig. 4c) also led to a missed US cause.

Table 4

Causes of US-missed parathyroid glands
Causes	n (%*)
Ectopic location	12 (5.7)
Thymus	6 (2.8)
Intrathyroid	1 (0.5)
Others^#	5 (2.4)
Small size (< 1 cm)	6 (2.8)
Overlap with ipsilateral parathyroid gland	1 (0.5)
Overall	19 (9.0)

* Divided by total parathyroid glands identified by pathology (n = 212)

^# Ectopic parathyroid glands at upper mediastinum, retroesophageal, and retropharyngeal area

The analysis of the association between the number of US, SPECT/CT, or US + SPECT/CT detected PGs and the surgical success rate showed no significance (p = 0.671, 0.625, and 0.335, respectively) (Table 5). The number of SPECT/CT detected PGs was not correlated with surgical time (rs= -0.225, p = 0.147), but the number of US- or US + SPECTCT-detected PGs was negatively associated with surgical time (rs= -0.459 and − 0.519, p = 0.002 and < 0.001, respectively), as shown in Table 6.

Table 5

Correlation between number of image-detected parathyroid glands with surgical success rate
Imaging modality	Odds ratio	P value
US-detectable PG number	NA	0.671
^99mTc-MIBI SPECT/CT detectable PG number	NA	0.625
US + ^99mTc-MIBI SPECT/CT detectable PG number	NA	0.335

NA = not available

Table 6

Correlation between number of image-detected parathyroid glands with surgical time*
Imaging modality	rs	P value
US-detectable PG number	-0.459	0.002
^99mTc-MIBI SPECT/CT-detectable PG number	-0.225	0.147
US + ^99mTc-MIBI SPECT/CT detectable PG number	-0.519	< 0.001

* Exclude patients who underwent concurrent thyroidectomy

Ultrasonography is one of the most common modalities for localization of hyperfunctioning PGs. However, several studies have noted that the sensitivity of US varies greatly, and the reason for missed gland has not been discussed in detail. In this study, we found that US for preoperative localization had 90% sensitivity and accuracy. Visualizing all four parathyroid hyperplasia can be achieved in 66.7% and 35.2% of SHPT patients by US and SPECT/CT, respectively. PGs located in an ectopic position or of a small size (< 1 cm) might cause negative results on US. Furthermore, if we could completely map the hyperplastic glands, the surgical time could be reduced.

Ectopic position was the most common cause of US-missed localization. In our study, the incidence of ectopic glands was 13.2%, 42.9% of which could not be recognized on US. The study by Andrade et al. corroborated these findings [15]. They recruited 166 secondary and tertiary HPT patients. Thirteen percent of hyperfunctioning PGs were located in ectopic positions, and 61.5% of these ectopic PGs failed to be localized by US and Tc99m-Sestamibi scintigraphy (MIBI). A study by Alkhalili et al. concluded that half of ectopic PGs were not detected by US or MIBI [14]. Several different definitions of ectopic glands have led to variation in the incidence. The most common ectopic sites included the thymus, retroesophageal, retropharyngeal, intrathyroid, mediastinum, and carotid sheath [9, 14, 15]. Hyperfunctioning PGs within the mediastinum or in retroesophageal locations where bone and air, respectively, prevent visualization of deeper structures. Because missed PGs in ectopic positions were the leading cause of failed surgery, awareness of the disadvantages of US is important for surgical planning.

Small PGs (< 1 cm) were determined to be a limitation for US detection. Perie et al. found that false-negative results on ultrasonography correlated with low gland weight [19]. A small gland was considered equally as low weight. Although we found that not all small glands are undetectable on US, all the missed PGs that was in eutopic positions were smaller than one centimeter. In a prospective study of 1000 consecutive patients with primary HPT, body mass index and gland size independently predicted the accurate detection of PGs by US and MIBI [21]. Furthermore, when the maximal length was smaller than 1 cm, more than half of PGs were undetectable [21]. Either in primary or secondary HTP, abnormal PG with less than 1 cm in length were associated with false negatives on US.

The overwhelming majority of individuals have 4 PGs, 2 superiors and 2 inferiors, whereas between 2.5–13.0% have supernumerary glands, and 3% have fewer than 4 glands [22, 23]. We did not find any supernumerary PGs, but there was one suspicious case because of persistent HPT after excision of four parathyroid hyperplasia. Our protocol for parathyroid US consisted of searching four common positions for PGs, and supernumerary glands would therefore miss. Furthermore, surgical failure is mainly due to resect not all the PGs, coming from the existence of ectopic or supernumerary PGs [12, 24, 25]. To improve the surgical success rate, precise preoperative imaging localization is crucial. Andrade et al. noted that US and MIBI could not detect supernumerary PGs [15]. EI-Sageer et al. recommended that neck exploration was the best reliable method for localization than imaging modalities [7]. However, from our experience, ectopic PGs in the thyroid, carotid sheath or mediastinum were difficult to detect during operation and the searching of neck prolonged the operative time. Preoperative mapping for parathyroid surgery is rational and recommended.

Recent studies have found that concurrent nodular goiter or thyroid cancer was not uncommon in SHP patients, and the prevalence of incidental nodular goiter and thyroid cancer were approximately 20–30% and 6–8%, respectively [14, 26–28], both of which corresponded with our results. The prevalence of concurrent papillary carcinoma (PTC) was higher in SHP patients than in general population. Although most of those concomitant PTCs were microcarcinomas (> 70%), they may express more aggressive tumor features [27]. Therefore, it is necessary to perform a thorough examination to avoid missing the coexistence of malignancy.

Limitations of the study

The study has several limitations. First, ^99mTc-MIBI SPECT/CT provided additional information for preoperative localization. Second, the judgement of US-missed PG was decided by endocrine surgeons who were not blinded. Third, two surgical failure cases with persistent HPT did not undergo imaging survey and reoperation until now. Finally, the study was a retrospective design with a small sample size. More prospective studies with larger groups are needed.

Our findings demonstrated that US localization was accurate in 90% of our patients. Awareness of the limitations of US is important for surgeons searching for hyperplastic PGs, especially those situated in ectopic positions and small sizes. US provided a useful guide for localization, and therefore, shortened the operation time.

CKD – chronic kidney disease

ESRD – end-stage renal disease

FNA – fine needle aspiration

HPT – hyperparathyroidism

iPTH – intact parathyroid hormone

MIBI – Tc99m-Sestamibi scintigraphy

PCI – percutaneous coronary intervention

PG – parathyroid gland

PTC – papillary thyroid carcinoma

SHPT – secondary hyperparathyroidism

SPECT/CT – single-photon-emission-computed tomography/computed tomography

US – ultrasound

Funding

This study was supported by National Science and Technology Council, Taiwan (111-2314-B-182A-158 -)

Conflict of interest statement

The authors have declared that no conflicts of interests exist.

Ethical approval

The study was approved by Change Gung Medical Foundation Institutional Review Board (number: 202300239B0)

Informed consent

The need for informed consent from patients was waived because of the retrospective design of the study

Acknowledgements

We thank the Biostatistics Center, Kaohsiung Chang Gung Memorial Hospital, for their statistics work.

Availability of data and materials

The dataset supporting the conclusions of this article are included within the article and files. The dataset used during the current study are available from the corresponding author on reasonable request.

Authors contribution:

YCC, SEC, and SYC designed this project. SEC and YCC analyzed data and wrote the manuscript. FFC and YJW analyzed the data and modified this paper. YCC, SYC, and YHC recruited patients and revised the paper. All authors read and approved the final manuscript.

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No competing interests reported.

Addressing the challenges of missed parathyroid glands in ultrasonography for secondary hyperparathyroidism.

Status:

Version 1

Abstract

Background

Methods

Results

Conclusion

Figures

Introduction

Methods

Patients and methods

Surgical techniques

Statistical analysis

Results

Discussion

Limitations of the study

Conclusions

Abbreviations

Declarations

References

Additional Declarations

Status:

Version 1