Updates Surg DOI 10.1007/s13304-015-0342-z
ORIGINAL ARTICLE
Feasibility of unilateral parathyroidectomy in patients with primary hyperparathyroidism and negative or discordant localization studies Pietro Giorgio Calo`1 • Fabio Medas1 • Giulia Loi1 • Enrico Erdas1 Giuseppe Pisano1 • Angelo Nicolosi1
•
Received: 31 July 2015 / Accepted: 27 December 2015 Ó Italian Society of Surgery (SIC) 2016
Abstract The purpose of this study was to examine the feasibility of unilateral parathyroidectomy in patients with primary hyperparathyroidism and negative or discordant localization studies. We included in our study 72 patients with preoperative diagnosis of primary hyperparathyroidism who had negative or discordant preoperative studies. In 66 patients, studies were discordant while in six were both negative. In 40 (55.6 %) patients initial approach was a bilateral exploration. In 32 cases (44.4 %) initial surgery was a unilateral exploration: in 26 conservative approach was successful, in six mini-invasive surgery failed and a bilateral exploration was necessary due to IOPTH negative test (five cases) or to the impossibility to find a pathological gland during exploration (one case). Intra-operative PTH test showed a sensitivity of 93.2 %, a specificity of 92.3 %, and an accuracy of 93.1 %. Multiple gland disease was found in 8 (11.1 %) patients (two double adenoma and six multiple gland hyperplasia). Mean operative time was lower in unilateral exploration group & Pietro Giorgio Calo` [email protected]
(87.9 ± 43.8 min). Comparing unilateral surgery in negative or discordant studies with 77 consecutive patients who underwent focused surgery with positive and concordant studies, conversion to bilateral exploration rate was statistically significantly higher in the first group (15.6 %). We believe that unilateral parathyroidectomy can be safely performed also in patients with discordant localization studies with a high cure rate; in these cases, however, the use of intra-operative PTH is absolutely necessary. We suggest the need for referral of these patients to high-volume medical centers for thyroid and parathyroid surgery. Keywords Primary hyperparathyroidism Intra-operative PTH Sestamibi scintigraphy Parathyroidectomy Abbreviations PHP Primary hyperparathyroidism US Ultrasound MIBI Sestamibi scintigraphy PTH Parathyroid hormone IOPTH Intra-operative PTH HPT Hyperparathyroidism
Fabio Medas [email protected] Giulia Loi [email protected] Enrico Erdas [email protected] Giuseppe Pisano [email protected] Angelo Nicolosi [email protected] 1
Department of Surgical Sciences, University of Cagliari, S.S. 554, Bivio Sestu, Monserrato, 09042 Cagliari CA, Italy
Introduction The incidence of primary hyperparathyroidism (PHP) is increasing and surgical treatment remains the only curative therapy for this disease [1–4]. For many years in patients with PHP bilateral neck exploration with visualization of all four parathyroid glands and resection of enlarged parathyroid glands without any preoperative localization studies has resulted in a
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success rate exceeding 95 % and only minimal morbidity in the hands of an experienced endocrine surgeon [1, 3–7]. However, more than 80 % of patients are cured after removal of a solitary parathyroid adenoma, which is the most common cause of PHP [1, 3, 4, 8]. Introduction and improvement of the preoperative radiologic examination as ultrasound (US) and sestamibi scintigraphy (MIBI) allow for a focused exploration in at least 80 % of the patients [9]. The advantages of minimally invasive parathyroidectomy in comparison to a bilateral neck exploration are an equally high cure rates with low complication rates, lower incidence of hypocalcaemia, decreased pain, small incisions, improved cosmesis, shorter operation, shorter hospital stays, and lower hospital costs [1, 3, 4, 7, 10]. The success of a focal exploration depends on the accurate localization of parathyroid disease preoperatively [11, 12]. MIBI has a sensitivity of 69–100 % and US of 61–63 % [12, 13]. The sensitivity of MIBI is approximately 75 to 80 % for single gland disease, but it is lower, 60 % or less, for multi-glandular disease, and only 50 to 60 % for hyperplasia [5]; it has a specificity of 75–90 %, and a positive predictive value of 89–96 % [12–15]. Some authors have identified an association between localizing MIBI and heavier or larger volume glands, higher parathyroid hormone (PTH) level, higher calcium level, and/or greater oxyphil cell content [5]. Non-localizing MIBI are believed to be more frequently associated with small parathyroid adenomas and multi-glandular disease, with the expression of P-glycoprotein or multidrug resistance-related protein, and delayed washout from thyroid such as in multinodular goiter and Hashimoto’s thyroiditis [3, 5, 14]. Other coexistent benign or malignant thyroid disease has also been associated with false-positive results [5]. In particular, the association between thyroid nodules with PHP occurs frequently in iodine-deficient areas where the incidence of nodular goiter varies from 20 to 60 %, and this has been reported to reduce the diagnostic performance of MIBI to 60–70 % [3, 14, 16]. It has been suggested that, in parathyroidectomies for PHP patients with negative MIBI, results are worse [17], for the higher incidence of multi-glandular disease [6, 12]. Therefore, standard cervicotomy with bilateral exploration is still considered the procedure of choice in these cases [3, 9, 10, 18]. The use and accuracy of intra-operative PTH (IOPTH) have been challenged by several authors and deemed not to be cost-effective for patients with two positive localization tests [17, 19–23], but its use is recommended for patients with only one or no positive localization test [17]; to increase safe referrals for minimally invasive parathyroidectomy and offer this technique to all eligible patients with at least one positive localization study, IOPTH assay
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appears to be the only tool available at present to ensure high-standard surgical cure rates [1]. The purpose of this study was to examine the feasibility of unilateral parathyroidectomy in patients with PHP and negative or discordant localization studies.
Methods In this retrospective study, we reviewed 264 consecutive patients who underwent parathyroidectomy with preoperative diagnosis of PHP from October 2002 to December 2012 at our institution (Department of Surgical Sciences, University of Cagliari, Italy). We excluded 21 patients in which suspicion of PHP was due to intra-operative findings during neck surgery for other pathologies, nine patients who underwent re-exploration after unsuccessful initial surgery for PHP and 22 patients with incomplete data or lost at follow-up. Among the remaining 212 patients, we included in our study 72 patients who had negative or discordant preoperative studies. We defined a negative study when US and MIBI were both negative; a discordant study was defined when US was positive and MIBI negative (or vice versa), or when US and MIBI were both positive but for different side. Data recorded included age, sex, preoperative serum calcium and PTH levels, results of preoperative localization studies, surgical procedure, histopathological features and postoperative complications. The patients underwent parathyroidectomy with unilateral or bilateral exploration. Causes for initial bilateral exploration included other associated neck procedure, familial form of PHP, and discordant or negative studies with very low PTH levels. The unilateral access was carried out through a mid-line transverse cervical incision of about 3 cm, while the bilateral through an incision of approximately 5 cm. In case of one positive localization study, exploration was started from the side where it was described the suspected parathyroid; in case of discordant side, intervention was started from the side where MIBI positivity was reported, while in the case of negative localization studies intervention was started from the right side. IOPTH determination was routinely used during surgery to confirm removal of all pathological glands; we defined a positive test when PTH value 100 after excision of suspected pathological gland was 50 % or lesser than preoperative value and when it was within range values (10–65 pg/ml). In case of negative test another measurement was made 200 after excision and, if negative result was confirmed, a bilateral exploration was performed. We defined a persistent or recurrent hyperparathyroidism (HPT) if high PTH blood levels were found, respectively, within or after 6 months after surgery.
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Ethical approval for our study was obtained from University of Cagliari institutional ethical committee. Informed consent was obtained from patients for their inclusion in our study. Statistical analysis was based on the v2 test, the Student t test, or Fischer exact test. A p value \0.05 was considered significant.
Demographic data and preoperative calcium and PTH values are reported in Table 1. In 66 (91.7 %) patients, studies were discordant; in 6 (8.3 %) cases US and MIBI were both negative (Table 2). In 40 (55.6 %) patients initial approach was a bilateral exploration: reasons for not performing a unilateral surgery were in 34 cases the association with a thyroidectomy, in five patients negative preoperative studies, while in one case MIBI was suggestive for a bilateral disease with US negative (Table 3). Of the six patients with negative studies, in five cases a bilateral exploration was performed, in one case a pathologic parathyroid was found immediately exploring the right side and the intervention was considered successfully concluded on the basis of IOPTH. In 32 patients (44.4 %) initial surgery was a unilateral exploration: in 26 cases unilateral approach was successful, in six cases failed and a bilateral exploration was necessary due to IOPTH negative test (five cases) or to the impossibility to find a pathological gland during exploration (one case). In these 32 patients, the localization studies were discordant in 31, negative in 1. We performed IOPTH test in all the patients. Among the 40 bilateral explorations we had three false-negative and four true-negative results (in one case we were not able to find another suspected lesion after the excision of a parathyroid adenoma, and the patient had a persistent HPT). Among the 32 unilateral explorations we had one false-negative result, one false-positive result (the patient presented a persistent HPT), and eight true-negative results (in these patients another suspected pathologic parathyroid Table 1 Demographic data Patients (n = 72) 10 (13.9 %)
Female
62 (86.1 %)
Age (years)
59.7 ± 13.3
Preoperative calcium (mg/dl)
11.1 ± 0.9
Preoperative PTH (pg/ml)
239.4 ± 143.4
Continuous variables are expressed as mean ± SD
Patients (n = 72) Discordant studies
66 (91.7 %)
MIBI? US-
46
MIBI- US?
5
Side discordant studies
15
Negative studies
6 (8.3 %)
MIBI Sestamibi scan, US ultrasound
Results
Male
Table 2 Preoperative studies
Table 3 Surgical procedures Patients (n = 72) Initial unilateral exploration
32 (44.4 %)
Bilateral exploration
40 (55.6 %)
Causes of bilateral exploration Other neck procedure associated
34
Negative preoperative studies
5
Discordant preoperative studies
1
Table 4 Intra-operative intact PTH test Patients (n = 72) True-positive result
55 (76.4 %)
True-negative result
12 (16.7 %)
False-positive result
1 (1.4 %)
False-negative result
4 (5.5 %)
Sensitivity
93.2 %
Specificity
92.3 %
Accuracy
93.1 %
gland was excised, requiring bilateral exploration in five cases; one patient had a persistent HPT due to multiple gland disease). Overall, IOPTH test showed a sensitivity of 93.2 %, a specificity of 92.3 % and an accuracy of 93.1 % (Table 4). Histopathological examination demonstrated a single gland disease in 63 (87.5 %) cases (51 single adenoma, 10 single gland hyperplasia, two carcinomas). Multiple gland disease was found in 8 (11.1 %) patients (two double adenoma and six multiple gland hyperplasia). In one case (1.4 %) no pathological glands were found in the specimen (a normal parathyroid gland was found in association to a thyroid adenoma) (Table 5). Full comparison between unilateral and bilateral surgery is reported in Table 6. Mean operative time was lower in unilateral group; we had a surgical failure in two cases (6.3 %) in unilateral and 1 (2.5 %) in bilateral surgery, but this difference was not statistically significant. Overall, we had 3 (4.2 %) surgical failures: two patients had persistent HPT, and one patient presented a recurrent PHP 11 months
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after surgery. Transient postoperative hypoparathyroidism was found in 14 (19.4 %) patients and permanent in 1 (1.4 %) patient. Finally, we have compared unilateral surgery in negative or discordant studies with 77 consecutive patients who underwent focused surgery with positive and concordant studies at our institution (Table 7). Obviously these are purely indicative data, just to get an idea of the numerical differences, since the two groups are totally different and hard to compare. Conversion to bilateral exploration rate was statistically significantly higher in negative and Table 5 Histopathological features Patients (n = 72) Single adenoma Double adenoma
51 (70.8 %) 2 (2.8 %)
Single gland hyperplasia
10 (13.9 %)
Multi-gland hyperplasia
6 (8.3 %)
Carcinoma
2 (2.8 %)
Non-pathological gland
1 (1.4 %)
discordant group (5 case, 15.6 % vs 1 case, 1.3 %) (Table 7). Surgical failure rate was higher in the first group (2 patients, 6.3 % vs 1 patient, 1.3 %) but not statistically significant. No other significant differences were found between the two groups. Cases of mini-invasive approach failure are reported in Table 8.
Discussion In the medical literature, most of the authors believe that unilateral parathyroidectomy has many advantages over the traditional bilateral 4-gland parathyroid exploration, including decreased pain, small incisions, improved cosmetic results, lower morbidity, and decreased length of hospital stay [10]. Accurate preoperative localization of the abnormal parathyroids is required for a focused, minimally invasive parathyroidectomy [5, 10, 11]. False-negative neck US results may be rarely found in cases with small, ectopic, intrathyroidal parathyroids, or undescended hyperfunctioning parathyroids situated along the common carotid artery or recurrent laryngeal nerve,
Table 6 Unilateral vs bilateral surgery Unilateral surgery (n = 32)
Bilateral surgery (n = 40)
P
Female/male ratio Age (years)
28/4 58.7 ± 15.7
34/6 60.5 ± 11.2
0.9696 0.5591
Preoperative calcium (mg/dl)
11.4 ± 0.7
10.8 ± 0.9
0.1934
Preoperative PTH (pg/ml)
247.4 ± 167.9
233.4 ± 123.6
0.6967
Operative time (minutes)
87.9 ± 43.8
120.4 ± 35.9
0.0014
Postoperative stay (days)
2.4 ± 1.2
2.6 ± 0.6
0.5810
Surgical failure (persistent/recurrent PHP)
2 (6.3 %)
1 (2.5 %)
0.8431
Transient hypoparathyroidism
4 (12.5 %)
10 (25 %)
0.3020
Persistent hypoparathyroidism
0
1 (2.5 %)
0.9103
Continuous variables are expressed as mean ± SD
Table 7 Discordant or negative vs concordant studies in unilateral surgery Discordant studies (n = 32)
Concordant studies (n = 77)
P
Female/male ratio
28/4
61/16
0.4560
Age (years)
58.7 ± 15.7
54.2 ± 11.9
0.1053 0.6816
Preoperative calcium (mg/dl)
11.4 ± 0.7
11.6 ± 1.54
Preoperative PTH (pg/ml)
247.4 ± 167.9
367.1 ± 462.8
0.1786
Surgical time (minutes)
87.9 ± 43.8
77.04 ± 31.1
0.1527
Postoperative stay (days)
2.4 ± 1.2
2.2 ± 1
0.5105
Conversion to bilateral exploration
5 (15.6 %)
1 (1.3 %)
0.0115
Surgical failure (persistent/recurrent PHP)
2 (6.3 %)
1 (1.3 %)
0.4259
Transient hypoparathyroidism
4 (12.5 %)
4 (5.2 %)
0.3530
Persistent hypoparathyroidism
0
0
–
Continuous variables are expressed as mean ± SD
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Ectopic adenoma Preop preoperative, bilat bilateral, Ca Calcium, inf inferior, sup superior, parathyr parathyroidectomy, histopathol histopathological
No Single adenoma (ectopic gland) normal lymphatic tissue (left gland) 29 Ectopic mediastinic parathyr 116 Inf left parathyr 131 10.5 F, 74 238
MIBI? (left) US? (right)
Discordant localization studies No Single adenoma (right gland) normal lymphatic tissue (left gland) 65 Bilat exploration, inf right parathyr 74 Sup left parathyr 153 9.9 F, 66 191
MIBI? (bilat) US? (left)
Multiple gland disease No Multiple gland hyperplasia 24 Bilat exploration, sup right parathyr 118 Sup left parathyr 149 10.9 F, 53 135
MIBI? (left) US? (bilat)
Ectopic adenoma No Single adenoma 13 Ectopic mediastinic parathyr – Initial negative exploration 150 11.4 F, 61 61
MIBI? (left) US-
Multiple gland disease No Multiple gland hyperplasia 32 Bilat exploration, inf right parathyr 95 Sup left parathyr 248 11.1 F, 80 49
MIBI? (left) US-
Multiple gland disease Recurrent PTH Multiple gland hyperplasia 130 Bilat exploration, inf right parathyr 360 Inf left parathyr 760 10.9 F, 78 27
MIBI? (left) US-
Basal Ca Preop localization studies Sex, age Patient
Table 8 Unilateral approach failure
Basal PTH
Initial surgical approach
100 IOPTH
Following surgical procedure
Following IOPTH
Histopathol features
Persistent or recurrent HPT
Cause of failure
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while false-negative MIBI have been observed in the presence of small size, low oxyphil cell content, and morphological changes (cystic degeneration, apoptosis, or necrosis) of hyperfunctioning parathyroids [3, 14]. On the other hand, difficulty in neck US and MIBI interpretation have been described in the presence of thyroid nodules or nodular goiters [14]. When preoperative localization studies are negative, the risk of multi-glandular disease is high (22–40 %) [3, 6, 9]. Patients with negative MIBI have smaller adenomas, lower serum and urinary calcium, lower PTH levels, and a lower cure rate than patients with positive MIBI results [7, 8]; for these reasons, they have a higher risk of persistent hyperparathyroidism [7, 24]. Patients with discordant or negative localization studies are not uncommon. In our experience of 212 patients with PHP, we observed 72 cases with negative or discordant localization studies (33.96 %). On the other hand, the incidence of multi-glandular disease was not as high as reported in literature (11.1 %). These results could be related to the high frequency of nodular thyroid disease in our region that could be the most important cause of negative or discordant localization studies rather than the parathyroid features themselves. At present, patients with negative preoperative localization studies represent an important subset of patients with PHP in whom traditional 4-gland operative exploratory surgery remains the optimal management because of the increased frequency of multi-glandular disease [6, 9, 12, 23]. However, in the opinion of some authors [7, 25], unilateral procedure can be performed safely in these patients with better cosmetic results, shorter operation time, and less early hypocalcemia with the aid of IOPTH. We performed a unilateral approach in 32/72 patients (44.4 %). Conversion to bilateral intervention was necessary in six patients (18.75 %) (in five cases on the basis of IOPTH results). So, unilateral approach was successful in 26 patients (81.25, 36.11 % of all patients). In these patients, mean operative time was significantly lower, while surgical failures were 2 (6.3 %) without statistically significant differences with bilateral surgery. However, in our experience, patients with discordant or negative localization studies had a statistically significant higher risk of conversion to bilateral surgery than those with concordant studies (15.6 vs 1.3 %). In short, if it is true that 18.75 % of conversions was a very high rate, it is also true that in 81.25 % of patients the surgery was concluded with a favorable unilateral intervention. The use of IOPTH allowed to recover also the other patients, performing a conversion by simply extending slightly the incision. IOPTH monitoring can help to confirm a successful operation, leaving little to no suspicion of multi-glandular disease and thereby avoiding bilateral neck exploration [10,
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21]. In our experience, IOPTH test showed a high sensitivity (93.2 %), specificity (92.3 %), and accuracy (93.1 %). In five patients IOPTH led to change the unilateral to bilateral approach (15.62 %). Our results seem to be very interesting and encouraging, although our study presents several limitations: the number of patients is small, the study is retrospective, and therefore we had no randomized control group. In conclusion, we believe that unilateral parathyroidectomy can be safely performed also in patients with discordant or even, in particular and selected cases, negative localization studies with a high cure rate; in these cases, however, the use of IOPTH is absolutely necessary. We suggest the need for referral of these patients to high-volume medical centers for thyroid and parathyroid surgery.
4.
5.
6.
7.
8. Author contribution PGC: study conception and design, analysis and interpretation of the data, drafting and critical revision of manuscript. FM: study conception and design, acquisition of data, analysis and interpretation of the data, drafting of manuscript. GL: acquisition of data. FP: acquisition of data. EE: analysis and interpretation of the data. GP: critical revision of manuscript. AN: critical revision of manuscript.
9.
Acknowledgments We thank Lucia Barca and Francesco Podda who provided IOPTH determination.
10.
Conflict of interest of interest.
The authors declare that they have no conflict
Ethical approval All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
11.
12.
13. Research involving human participants and/or animals This article does not contain any studies with animals performed by any of the authors. Informed consent Informed consent was obtained from all individual participants included in the study.
14.
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ORIGINAL ARTICLE
Feasibility of unilateral parathyroidectomy in patients with primary hyperparathyroidism and negative or discordant localization studies Pietro Giorgio Calo`1 • Fabio Medas1 • Giulia Loi1 • Enrico Erdas1 Giuseppe Pisano1 • Angelo Nicolosi1
•
Received: 31 July 2015 / Accepted: 27 December 2015 Ó Italian Society of Surgery (SIC) 2016
Abstract The purpose of this study was to examine the feasibility of unilateral parathyroidectomy in patients with primary hyperparathyroidism and negative or discordant localization studies. We included in our study 72 patients with preoperative diagnosis of primary hyperparathyroidism who had negative or discordant preoperative studies. In 66 patients, studies were discordant while in six were both negative. In 40 (55.6 %) patients initial approach was a bilateral exploration. In 32 cases (44.4 %) initial surgery was a unilateral exploration: in 26 conservative approach was successful, in six mini-invasive surgery failed and a bilateral exploration was necessary due to IOPTH negative test (five cases) or to the impossibility to find a pathological gland during exploration (one case). Intra-operative PTH test showed a sensitivity of 93.2 %, a specificity of 92.3 %, and an accuracy of 93.1 %. Multiple gland disease was found in 8 (11.1 %) patients (two double adenoma and six multiple gland hyperplasia). Mean operative time was lower in unilateral exploration group & Pietro Giorgio Calo` [email protected]
(87.9 ± 43.8 min). Comparing unilateral surgery in negative or discordant studies with 77 consecutive patients who underwent focused surgery with positive and concordant studies, conversion to bilateral exploration rate was statistically significantly higher in the first group (15.6 %). We believe that unilateral parathyroidectomy can be safely performed also in patients with discordant localization studies with a high cure rate; in these cases, however, the use of intra-operative PTH is absolutely necessary. We suggest the need for referral of these patients to high-volume medical centers for thyroid and parathyroid surgery. Keywords Primary hyperparathyroidism Intra-operative PTH Sestamibi scintigraphy Parathyroidectomy Abbreviations PHP Primary hyperparathyroidism US Ultrasound MIBI Sestamibi scintigraphy PTH Parathyroid hormone IOPTH Intra-operative PTH HPT Hyperparathyroidism
Fabio Medas [email protected] Giulia Loi [email protected] Enrico Erdas [email protected] Giuseppe Pisano [email protected] Angelo Nicolosi [email protected] 1
Department of Surgical Sciences, University of Cagliari, S.S. 554, Bivio Sestu, Monserrato, 09042 Cagliari CA, Italy
Introduction The incidence of primary hyperparathyroidism (PHP) is increasing and surgical treatment remains the only curative therapy for this disease [1–4]. For many years in patients with PHP bilateral neck exploration with visualization of all four parathyroid glands and resection of enlarged parathyroid glands without any preoperative localization studies has resulted in a
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success rate exceeding 95 % and only minimal morbidity in the hands of an experienced endocrine surgeon [1, 3–7]. However, more than 80 % of patients are cured after removal of a solitary parathyroid adenoma, which is the most common cause of PHP [1, 3, 4, 8]. Introduction and improvement of the preoperative radiologic examination as ultrasound (US) and sestamibi scintigraphy (MIBI) allow for a focused exploration in at least 80 % of the patients [9]. The advantages of minimally invasive parathyroidectomy in comparison to a bilateral neck exploration are an equally high cure rates with low complication rates, lower incidence of hypocalcaemia, decreased pain, small incisions, improved cosmesis, shorter operation, shorter hospital stays, and lower hospital costs [1, 3, 4, 7, 10]. The success of a focal exploration depends on the accurate localization of parathyroid disease preoperatively [11, 12]. MIBI has a sensitivity of 69–100 % and US of 61–63 % [12, 13]. The sensitivity of MIBI is approximately 75 to 80 % for single gland disease, but it is lower, 60 % or less, for multi-glandular disease, and only 50 to 60 % for hyperplasia [5]; it has a specificity of 75–90 %, and a positive predictive value of 89–96 % [12–15]. Some authors have identified an association between localizing MIBI and heavier or larger volume glands, higher parathyroid hormone (PTH) level, higher calcium level, and/or greater oxyphil cell content [5]. Non-localizing MIBI are believed to be more frequently associated with small parathyroid adenomas and multi-glandular disease, with the expression of P-glycoprotein or multidrug resistance-related protein, and delayed washout from thyroid such as in multinodular goiter and Hashimoto’s thyroiditis [3, 5, 14]. Other coexistent benign or malignant thyroid disease has also been associated with false-positive results [5]. In particular, the association between thyroid nodules with PHP occurs frequently in iodine-deficient areas where the incidence of nodular goiter varies from 20 to 60 %, and this has been reported to reduce the diagnostic performance of MIBI to 60–70 % [3, 14, 16]. It has been suggested that, in parathyroidectomies for PHP patients with negative MIBI, results are worse [17], for the higher incidence of multi-glandular disease [6, 12]. Therefore, standard cervicotomy with bilateral exploration is still considered the procedure of choice in these cases [3, 9, 10, 18]. The use and accuracy of intra-operative PTH (IOPTH) have been challenged by several authors and deemed not to be cost-effective for patients with two positive localization tests [17, 19–23], but its use is recommended for patients with only one or no positive localization test [17]; to increase safe referrals for minimally invasive parathyroidectomy and offer this technique to all eligible patients with at least one positive localization study, IOPTH assay
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appears to be the only tool available at present to ensure high-standard surgical cure rates [1]. The purpose of this study was to examine the feasibility of unilateral parathyroidectomy in patients with PHP and negative or discordant localization studies.
Methods In this retrospective study, we reviewed 264 consecutive patients who underwent parathyroidectomy with preoperative diagnosis of PHP from October 2002 to December 2012 at our institution (Department of Surgical Sciences, University of Cagliari, Italy). We excluded 21 patients in which suspicion of PHP was due to intra-operative findings during neck surgery for other pathologies, nine patients who underwent re-exploration after unsuccessful initial surgery for PHP and 22 patients with incomplete data or lost at follow-up. Among the remaining 212 patients, we included in our study 72 patients who had negative or discordant preoperative studies. We defined a negative study when US and MIBI were both negative; a discordant study was defined when US was positive and MIBI negative (or vice versa), or when US and MIBI were both positive but for different side. Data recorded included age, sex, preoperative serum calcium and PTH levels, results of preoperative localization studies, surgical procedure, histopathological features and postoperative complications. The patients underwent parathyroidectomy with unilateral or bilateral exploration. Causes for initial bilateral exploration included other associated neck procedure, familial form of PHP, and discordant or negative studies with very low PTH levels. The unilateral access was carried out through a mid-line transverse cervical incision of about 3 cm, while the bilateral through an incision of approximately 5 cm. In case of one positive localization study, exploration was started from the side where it was described the suspected parathyroid; in case of discordant side, intervention was started from the side where MIBI positivity was reported, while in the case of negative localization studies intervention was started from the right side. IOPTH determination was routinely used during surgery to confirm removal of all pathological glands; we defined a positive test when PTH value 100 after excision of suspected pathological gland was 50 % or lesser than preoperative value and when it was within range values (10–65 pg/ml). In case of negative test another measurement was made 200 after excision and, if negative result was confirmed, a bilateral exploration was performed. We defined a persistent or recurrent hyperparathyroidism (HPT) if high PTH blood levels were found, respectively, within or after 6 months after surgery.
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Ethical approval for our study was obtained from University of Cagliari institutional ethical committee. Informed consent was obtained from patients for their inclusion in our study. Statistical analysis was based on the v2 test, the Student t test, or Fischer exact test. A p value \0.05 was considered significant.
Demographic data and preoperative calcium and PTH values are reported in Table 1. In 66 (91.7 %) patients, studies were discordant; in 6 (8.3 %) cases US and MIBI were both negative (Table 2). In 40 (55.6 %) patients initial approach was a bilateral exploration: reasons for not performing a unilateral surgery were in 34 cases the association with a thyroidectomy, in five patients negative preoperative studies, while in one case MIBI was suggestive for a bilateral disease with US negative (Table 3). Of the six patients with negative studies, in five cases a bilateral exploration was performed, in one case a pathologic parathyroid was found immediately exploring the right side and the intervention was considered successfully concluded on the basis of IOPTH. In 32 patients (44.4 %) initial surgery was a unilateral exploration: in 26 cases unilateral approach was successful, in six cases failed and a bilateral exploration was necessary due to IOPTH negative test (five cases) or to the impossibility to find a pathological gland during exploration (one case). In these 32 patients, the localization studies were discordant in 31, negative in 1. We performed IOPTH test in all the patients. Among the 40 bilateral explorations we had three false-negative and four true-negative results (in one case we were not able to find another suspected lesion after the excision of a parathyroid adenoma, and the patient had a persistent HPT). Among the 32 unilateral explorations we had one false-negative result, one false-positive result (the patient presented a persistent HPT), and eight true-negative results (in these patients another suspected pathologic parathyroid Table 1 Demographic data Patients (n = 72) 10 (13.9 %)
Female
62 (86.1 %)
Age (years)
59.7 ± 13.3
Preoperative calcium (mg/dl)
11.1 ± 0.9
Preoperative PTH (pg/ml)
239.4 ± 143.4
Continuous variables are expressed as mean ± SD
Patients (n = 72) Discordant studies
66 (91.7 %)
MIBI? US-
46
MIBI- US?
5
Side discordant studies
15
Negative studies
6 (8.3 %)
MIBI Sestamibi scan, US ultrasound
Results
Male
Table 2 Preoperative studies
Table 3 Surgical procedures Patients (n = 72) Initial unilateral exploration
32 (44.4 %)
Bilateral exploration
40 (55.6 %)
Causes of bilateral exploration Other neck procedure associated
34
Negative preoperative studies
5
Discordant preoperative studies
1
Table 4 Intra-operative intact PTH test Patients (n = 72) True-positive result
55 (76.4 %)
True-negative result
12 (16.7 %)
False-positive result
1 (1.4 %)
False-negative result
4 (5.5 %)
Sensitivity
93.2 %
Specificity
92.3 %
Accuracy
93.1 %
gland was excised, requiring bilateral exploration in five cases; one patient had a persistent HPT due to multiple gland disease). Overall, IOPTH test showed a sensitivity of 93.2 %, a specificity of 92.3 % and an accuracy of 93.1 % (Table 4). Histopathological examination demonstrated a single gland disease in 63 (87.5 %) cases (51 single adenoma, 10 single gland hyperplasia, two carcinomas). Multiple gland disease was found in 8 (11.1 %) patients (two double adenoma and six multiple gland hyperplasia). In one case (1.4 %) no pathological glands were found in the specimen (a normal parathyroid gland was found in association to a thyroid adenoma) (Table 5). Full comparison between unilateral and bilateral surgery is reported in Table 6. Mean operative time was lower in unilateral group; we had a surgical failure in two cases (6.3 %) in unilateral and 1 (2.5 %) in bilateral surgery, but this difference was not statistically significant. Overall, we had 3 (4.2 %) surgical failures: two patients had persistent HPT, and one patient presented a recurrent PHP 11 months
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after surgery. Transient postoperative hypoparathyroidism was found in 14 (19.4 %) patients and permanent in 1 (1.4 %) patient. Finally, we have compared unilateral surgery in negative or discordant studies with 77 consecutive patients who underwent focused surgery with positive and concordant studies at our institution (Table 7). Obviously these are purely indicative data, just to get an idea of the numerical differences, since the two groups are totally different and hard to compare. Conversion to bilateral exploration rate was statistically significantly higher in negative and Table 5 Histopathological features Patients (n = 72) Single adenoma Double adenoma
51 (70.8 %) 2 (2.8 %)
Single gland hyperplasia
10 (13.9 %)
Multi-gland hyperplasia
6 (8.3 %)
Carcinoma
2 (2.8 %)
Non-pathological gland
1 (1.4 %)
discordant group (5 case, 15.6 % vs 1 case, 1.3 %) (Table 7). Surgical failure rate was higher in the first group (2 patients, 6.3 % vs 1 patient, 1.3 %) but not statistically significant. No other significant differences were found between the two groups. Cases of mini-invasive approach failure are reported in Table 8.
Discussion In the medical literature, most of the authors believe that unilateral parathyroidectomy has many advantages over the traditional bilateral 4-gland parathyroid exploration, including decreased pain, small incisions, improved cosmetic results, lower morbidity, and decreased length of hospital stay [10]. Accurate preoperative localization of the abnormal parathyroids is required for a focused, minimally invasive parathyroidectomy [5, 10, 11]. False-negative neck US results may be rarely found in cases with small, ectopic, intrathyroidal parathyroids, or undescended hyperfunctioning parathyroids situated along the common carotid artery or recurrent laryngeal nerve,
Table 6 Unilateral vs bilateral surgery Unilateral surgery (n = 32)
Bilateral surgery (n = 40)
P
Female/male ratio Age (years)
28/4 58.7 ± 15.7
34/6 60.5 ± 11.2
0.9696 0.5591
Preoperative calcium (mg/dl)
11.4 ± 0.7
10.8 ± 0.9
0.1934
Preoperative PTH (pg/ml)
247.4 ± 167.9
233.4 ± 123.6
0.6967
Operative time (minutes)
87.9 ± 43.8
120.4 ± 35.9
0.0014
Postoperative stay (days)
2.4 ± 1.2
2.6 ± 0.6
0.5810
Surgical failure (persistent/recurrent PHP)
2 (6.3 %)
1 (2.5 %)
0.8431
Transient hypoparathyroidism
4 (12.5 %)
10 (25 %)
0.3020
Persistent hypoparathyroidism
0
1 (2.5 %)
0.9103
Continuous variables are expressed as mean ± SD
Table 7 Discordant or negative vs concordant studies in unilateral surgery Discordant studies (n = 32)
Concordant studies (n = 77)
P
Female/male ratio
28/4
61/16
0.4560
Age (years)
58.7 ± 15.7
54.2 ± 11.9
0.1053 0.6816
Preoperative calcium (mg/dl)
11.4 ± 0.7
11.6 ± 1.54
Preoperative PTH (pg/ml)
247.4 ± 167.9
367.1 ± 462.8
0.1786
Surgical time (minutes)
87.9 ± 43.8
77.04 ± 31.1
0.1527
Postoperative stay (days)
2.4 ± 1.2
2.2 ± 1
0.5105
Conversion to bilateral exploration
5 (15.6 %)
1 (1.3 %)
0.0115
Surgical failure (persistent/recurrent PHP)
2 (6.3 %)
1 (1.3 %)
0.4259
Transient hypoparathyroidism
4 (12.5 %)
4 (5.2 %)
0.3530
Persistent hypoparathyroidism
0
0
–
Continuous variables are expressed as mean ± SD
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Ectopic adenoma Preop preoperative, bilat bilateral, Ca Calcium, inf inferior, sup superior, parathyr parathyroidectomy, histopathol histopathological
No Single adenoma (ectopic gland) normal lymphatic tissue (left gland) 29 Ectopic mediastinic parathyr 116 Inf left parathyr 131 10.5 F, 74 238
MIBI? (left) US? (right)
Discordant localization studies No Single adenoma (right gland) normal lymphatic tissue (left gland) 65 Bilat exploration, inf right parathyr 74 Sup left parathyr 153 9.9 F, 66 191
MIBI? (bilat) US? (left)
Multiple gland disease No Multiple gland hyperplasia 24 Bilat exploration, sup right parathyr 118 Sup left parathyr 149 10.9 F, 53 135
MIBI? (left) US? (bilat)
Ectopic adenoma No Single adenoma 13 Ectopic mediastinic parathyr – Initial negative exploration 150 11.4 F, 61 61
MIBI? (left) US-
Multiple gland disease No Multiple gland hyperplasia 32 Bilat exploration, inf right parathyr 95 Sup left parathyr 248 11.1 F, 80 49
MIBI? (left) US-
Multiple gland disease Recurrent PTH Multiple gland hyperplasia 130 Bilat exploration, inf right parathyr 360 Inf left parathyr 760 10.9 F, 78 27
MIBI? (left) US-
Basal Ca Preop localization studies Sex, age Patient
Table 8 Unilateral approach failure
Basal PTH
Initial surgical approach
100 IOPTH
Following surgical procedure
Following IOPTH
Histopathol features
Persistent or recurrent HPT
Cause of failure
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while false-negative MIBI have been observed in the presence of small size, low oxyphil cell content, and morphological changes (cystic degeneration, apoptosis, or necrosis) of hyperfunctioning parathyroids [3, 14]. On the other hand, difficulty in neck US and MIBI interpretation have been described in the presence of thyroid nodules or nodular goiters [14]. When preoperative localization studies are negative, the risk of multi-glandular disease is high (22–40 %) [3, 6, 9]. Patients with negative MIBI have smaller adenomas, lower serum and urinary calcium, lower PTH levels, and a lower cure rate than patients with positive MIBI results [7, 8]; for these reasons, they have a higher risk of persistent hyperparathyroidism [7, 24]. Patients with discordant or negative localization studies are not uncommon. In our experience of 212 patients with PHP, we observed 72 cases with negative or discordant localization studies (33.96 %). On the other hand, the incidence of multi-glandular disease was not as high as reported in literature (11.1 %). These results could be related to the high frequency of nodular thyroid disease in our region that could be the most important cause of negative or discordant localization studies rather than the parathyroid features themselves. At present, patients with negative preoperative localization studies represent an important subset of patients with PHP in whom traditional 4-gland operative exploratory surgery remains the optimal management because of the increased frequency of multi-glandular disease [6, 9, 12, 23]. However, in the opinion of some authors [7, 25], unilateral procedure can be performed safely in these patients with better cosmetic results, shorter operation time, and less early hypocalcemia with the aid of IOPTH. We performed a unilateral approach in 32/72 patients (44.4 %). Conversion to bilateral intervention was necessary in six patients (18.75 %) (in five cases on the basis of IOPTH results). So, unilateral approach was successful in 26 patients (81.25, 36.11 % of all patients). In these patients, mean operative time was significantly lower, while surgical failures were 2 (6.3 %) without statistically significant differences with bilateral surgery. However, in our experience, patients with discordant or negative localization studies had a statistically significant higher risk of conversion to bilateral surgery than those with concordant studies (15.6 vs 1.3 %). In short, if it is true that 18.75 % of conversions was a very high rate, it is also true that in 81.25 % of patients the surgery was concluded with a favorable unilateral intervention. The use of IOPTH allowed to recover also the other patients, performing a conversion by simply extending slightly the incision. IOPTH monitoring can help to confirm a successful operation, leaving little to no suspicion of multi-glandular disease and thereby avoiding bilateral neck exploration [10,
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21]. In our experience, IOPTH test showed a high sensitivity (93.2 %), specificity (92.3 %), and accuracy (93.1 %). In five patients IOPTH led to change the unilateral to bilateral approach (15.62 %). Our results seem to be very interesting and encouraging, although our study presents several limitations: the number of patients is small, the study is retrospective, and therefore we had no randomized control group. In conclusion, we believe that unilateral parathyroidectomy can be safely performed also in patients with discordant or even, in particular and selected cases, negative localization studies with a high cure rate; in these cases, however, the use of IOPTH is absolutely necessary. We suggest the need for referral of these patients to high-volume medical centers for thyroid and parathyroid surgery.
4.
5.
6.
7.
8. Author contribution PGC: study conception and design, analysis and interpretation of the data, drafting and critical revision of manuscript. FM: study conception and design, acquisition of data, analysis and interpretation of the data, drafting of manuscript. GL: acquisition of data. FP: acquisition of data. EE: analysis and interpretation of the data. GP: critical revision of manuscript. AN: critical revision of manuscript.
9.
Acknowledgments We thank Lucia Barca and Francesco Podda who provided IOPTH determination.
10.
Conflict of interest of interest.
The authors declare that they have no conflict
Ethical approval All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
11.
12.
13. Research involving human participants and/or animals This article does not contain any studies with animals performed by any of the authors. Informed consent Informed consent was obtained from all individual participants included in the study.
14.
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15.
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