In 1947 Petit and Clark successfully treated a patient suffering from GPHPT
. Under local anaesthesia and supplemented only by nitrous oxide and oxygen, they were able to remove a palpable parathyroid adenoma weighting 13 g
. Since then, no more than 200 similar cases have been reported
[1–3]. Because the incidence of GPHPT is so low, the literature is comprised almost exclusively of case reports with few reviews and only a large series
[1–3]. Its rarity accounts for missing guidelines supporting physicians in the decision making process.
The low albumin levels, typically associated with pregnancy, are responsible for the low sensitivity of serum total calcium screening tests and may explain why up to 90% of GPHPT cases are undiagnosed until after a miscarriage
[1, 11, 12]. GPHPT can have dramatic negative effects on both mother and foetus. Maternal complications occur in up to 67% of pregnancies, with most those common being hyperemesis, polyuria and nephrolithiasis
[13, 14]. Untreated GPHPT may also lead to preeclampsia and miscarriage in up to 25% and 50% of cases, respectively
[1, 2]. More severe complications (such as pancreatitis and hypercalcaemic crisis) occur rarely. The rate of foetal complications in untreated GPHP is as high as 53%, with neonatal death occurring in up to 30% of cases
. Calcium is actively transported across the placenta and, when pregnancy results in a live birth, cases of profound foetal PTH suppression (with hypocalcaemia and tetany requiring intravenous calcium therapy) have been reported
. Permanent hypoparathyroidism and growth retardation has also been documented
In non-pregnant individuals, hyperplasia and multiple adenomas occur in 10-12% and 2%, respectively. Carcinoma occurs in less then 1% of PHPT cases
. There are simply not enough patients reported in the literature to correctly estimate the prevalence of multiple gland disease in GPHPT. On the other hand, few cases of hyperplasia or multiple adenomas are still reported in the above-mentioned series
[1–3]. The management of GPHPT is linked to peculiar problems, which we will try to discuss individually.
Indications for surgery
The cases best managed by surgical treatment have been best demonstrated by Norman et al.
. A case series of 32 women (who had a total of 77 pregnancies with elevated serum calcium levels due to GPHPT) showed that even a mild elevation of calcium (as moderate as 2.67 mmol/l) was associated with a 12% risk of pregnancy loss
. Parathyroidectomy is indicated for all GPHPT patients, with or without symptoms, even in mild hypercalcaemia
Timing of surgery
Surgical intervention in general, and parathyroidectomy specifically, has always been considered more acceptable during the second trimester
. According to the largest series of patients with GPHPT, the majority of pregnancy losses occur during the late first or early second trimester. The Authors therefore recommend to time parathyroidectomy in the late first trimester (instead of waiting until the mid-second trimester)
. Even in case of a delayed diagnosis of GPHPT, surgery should not be delayed any further, nor performed after delivery
. The increased foetal and maternal risks of delayed parathyroidectomy compare negatively with the most common and easily treatable postoperative complications (namely hypocalcaemia, which happens in up to 60% of patients following bilateral neck exploration)
. Given the favourable benefit-to-risk ratio, parathyroidectomy should be performed as early as possible and, in case of late diagnosis, even during the third trimester
Accurate preoperative localization of parathyroid adenomas allows the targeting of suspicious glands and has sparked the development of MIP techniques. The most commonly employed preoperative imaging techniques are parathyroid radionuclide imaging (Sestamibi) and US.
Sensitivities of Sestamibi vary widely from 39% to over 90%. The discrepancies reported relate to both differences in technique and patient cohorts, as Sestamibi uptake is influenced by PTH levels and the presence, or absence, of thyroid nodules
. Unfortunately during pregnancy, Sestamibi is not an ideal option due to the risks linked to foetal irradiation. Sestamibi should be reserved only for patients with persistent GPHPT following non-curative cervical explorations, as recently reported on a series of 7 patients
In experienced and dedicated hands, high frequency US is a highly sensitive technique (sensitivity of 89% and PPV 98%); especially in patients without thyroid nodules
. The absence of ionizing radiation explains why US is the most commonly used diagnostic tool for many pathologies during pregnancy. The primary limitation of US resides on the fact that optimal results are exquisitely operator dependent and not easily reproducible in less experienced hands
Although computed tomography (CT) scanners use high doses of ionizing radiation, the foetus can be efficiently screened. Despite newer equipment and algorithms (such as four-dimensional CT) that improve overall parathyroid adenoma detection rate, CT sensitivity and specificity remain lower than either Sestamibi or US
[17, 19]. Similar considerations apply to magnetic resonance tomography, which although a promising option (especially when fused with Sestamibi), lacks sensitivity especially for smaller adenomas
. Venous sampling is recommended only before revision surgery
In practical terms the only preoperative localization study suitable for GPHPT patients is a dedicated US.
Like the case reported here, the majority of thyroid and parathyroid surgery performed today is carried out under general anaesthesia
. Alternatively, local anaesthetic use in thyroid surgery has been described and recommended by many authors
[20–22]. Spanknebel and colleagues reported on a series of 1,025 patients who underwent regional C2-C4 superficial cervical and local field block for thyroidectomy by the same surgeon, at the same major tertiary referral center, over 16 years
. They concluded that performing thyroidectomy using local anaesthesia appeared safe for most patients, including those who had a general anaesthetic risk or required more complex procedures, when performed by an experienced surgeon.
Of the 1,025 patients who received local anaesthesia, 3.3% (34) had to be converted to a general anaesthetic during the procedure. Two-thirds of these patients had either sub-sternal goiter or extensive cancer, hence the authors recommend careful selection of patients for local anaesthesia with the caveat that regardless of the requirement to convert, they were done so safely, both electively and urgently.
Thyroidectomy under local anaesthesia, specifically using a minimally invasive video-assisted technique, has been reported by Lombardi et al.
. Five cases were described. There were no reported conversions to either general anesthesia or to conventional surgery; neither were there postoperative complications. All of the patients were reported to be satisfied with both their surgical experience and cosmetic outcomes.
Choice of surgical technique
MIP techniques have proven in randomized controlled trials to reduce pain, improve cosmesis and achieve a similar cure rate when compared to the golden standard: open bilateral neck exploration with identification of the four parathyroid glands
[4–6, 23]. Different minimally invasive techniques have been described to remove a preoperatively well-localized parathyroid adenoma. These are the options:
1) Open focused parathyroidectomy, through a 20-30 mm incision performed over the adenoma, is an option favoured by many
[8, 24–26]. This is a logistically simple and straightforward procedure that uses open surgery instruments to remove the localized adenoma. It is recommended for cases with concordant imaging, or at least with a positive Sestamibi scan. To ensure complete removal of pathologic tissue, the use of iPTHa is recommended by many but not all authors, especially in case of concordant localization
[24, 27, 28]. Norman used intraoperative nuclear mapping, which is not an option during pregnancy
. The main limitations of this technique are: longer scar, poor visualization of RLN, limited (if not impossible) visualization of the ipsilateral parathyroid gland and above all, missing a further pathologic parathyroid gland
2) Fully endoscopic procedures rely on neck insufflation with CO2 and 3 mini-trocars. The procedure is technically challenging, it risks spreading CO2 through tissues and increasing carbonaemia, but it allows exploration of both ipsilateral parathyroid glands and a clear visualization of the RLN. On the other hand it requires replacement of all the 3 trocars to explore the contralateral side
3) Video-assisted MIP is definitely the most versatile MIP technique. It relies on external retractors, endoscopic magnification and dedicated spatulas. Through a single 15 mm incision it allows bilateral neck exploration, total or subtotal parathyroidectomy, and total or hemi-thyroidectomy
[9, 30, 31]. Each RLN is typically well and easily localised and does not require neck insufflation. Despite being technically more challenging than open focused MIP, the logistics are quite simple as all is needed is the usual endoscopic towers, a conventional 30 degree 5-mm laparo-endoscope and a few non-disposable instruments.
4) Other fully endoscopic techniques have been described that use periareolar and axillary ports. These involve large subcutaneous dissection and gas insufflation. These latest techniques may offer some cosmetic advantage, but are technically and logistically very challenging. Most importantly, due to the large dissections they cannot be considered minimally invasive options
When dealing with GPHPT, the importance of achieving cure in a timely and efficient fashion cannot be overemphasized. Traditional bilateral neck exploration achieves a cure rate of at least 95%. To guarantee comparable cure rates with MIP, the latest propositional statements recommend the use of iPTHa during targeted parathyroidectomy for patients with a single (or two non concordant) preoperative localisation study
. When preoperative Sestamibi and US localisation do concord for single-gland disease, iPTHa may not be necessary
. Following that, Sestamibi is not a safe preoperative localisation option in pregnancy; the use of iPTHa is therefore recommended to safely perform a targeted MIP for GPHPT. As iPTHa was not available to us (as is the case in many institutions), we offered to our patient the only MIP option that allows bilateral 4-gland exploration: the video-assisted MIP.