We retrospectively analyzed the records of a consecutive cohort of patients treated for sPHPT in one geographical region of The Netherlands between 1994 and 2009, comprising one academic center and three affiliated hospitals. All patients were symptomatic. The diagnosis PHPT was established biochemically by a serum calcium level greater than 10.20 mg/dL (>2.55 mmol/L) and/or a serum ionized calcium greater than 5.28 mg/dL (>1.32 mmol/L) combined with an increased, greater than 65 pg/mL (>6.5 pmol/L), or not suppressed plasma parathyroid hormone (PTH) level. In a few patients calcium levels were normal, but an increased renal calcium excretion combined with an elevated PTH level was affirmative for PHPT [12
]. In addition, all patients with PHPT from the MEN1 and MEN2 database at the University Medical Center Utrecht (UMCU), The Netherlands were analyzed. The MEN1 database includes patients diagnosed with PHPT between 1967 and 2009. Patients were included in the MEN1 database if they had genetically proven MEN1, or three out of five manifestations of MEN1 or one out of five manifestations and a first-degree family member. Gene testing (mutation analysis) was performed in very young patients with PHPT, PHPT in combination with possible MEN1 manifestations, or a MEN- positive family history [15
]. From the MEN2 database, patients diagnosed with PHPT between 1979 and 2009 were selected. MEN2A was defined in case of a MEN2A germline mutation. Patients with MEN1 and MEN2A were included if they had biochemical evidence of PHPT as stated above or enlarged parathyroid glands while undergoing a total thyroidectomy. Since the UMCU is a tertiary referral center, also patients who were initially treated at another institution and later referred to our institution were included. All patients gave ethical consent for their information to be held anonymously in our database and to be used for future retrospective analysis.
Preoperative localizing studies were used in sPHPT and MEN2A patients and included ultrasonography (US), computed tomography (CT) and/or technetium-99m-sestamibi-scintigraphy (MIBI). The preoperative diagnostic work up differed between hospitals and evaluated over time. Presently, our preferential preoperative work up consists of MIBI and US. Depending on the results of the preoperative localization studies, sPHPT and MEN2A patients were subsequently operated in a preferentially minimally invasive approach [16
]. MIP was defined as a small (3cm) incision over the suspected adenoma as guided by preoperative localization (two concordant preoperative imaging techniques), whereas a unilateral approach involves a larger incision and exposure plus systematic exploration of the entire area of interest on one side (based on one positive preoperative imaging). Both inferior and superior parathyroid glands will have to be identified using this approach. In case of no visualization of an enlarged gland or discordant imaging techniques a conventional neck exploration (CNE) was performed. Preoperative imaging for MEN1 patients is not part of our policy, although many patients underwent preoperative imaging studies prior to referral to our surgical department. In subtotal parathyroidectomy (SPTX), 3–3½ parathyroid glands were resected during a CNE after identification of all parathyroid glands. In total parathyroidectomy (TPTX), four glands were resected and one (partial) gland was used as a graft for autotransplantation into the brachioradial muscle of the nondominant forearm. The autotransplantation was performed during the same operation, using fresh parathyroid tissue.
Intraoperative PTH measurements (IOPTH) and/or intraoperative frozen section analysis, to verify removal of aberrant parathyroid tissue, were carried out in a routine fashion whenever a minimally invasive parathyroidectomy (MIP) was performed. A significant drop of more than 50% from the highest of either preoperative baseline or preexcision level at 10 minutes after hyperfunctioning parathyroid gland(s) excision indicates surgical cure and predicts postoperative normocalcemia [17
Surgical cure was defined as a normalization of serum (ionized) calcium and PTH levels for a period of at least six months after the surgical procedure. Persisting hypercalcemia or renewed hypercalcemia within the first six months after surgery was considered indicative of surgical failure. Hypercalcemia after a period of six month of postoperative normocalcemia was defined as recurrent disease. The findings of all operations necessary to achieve normocalcemia were taken into account when determining the cause of PHPT. Extirpation of a single enlarged parathyroid gland with subsequent normalization of serum calcium was defined as single gland disease. Retrieval of more than one enlarged parathyroid gland leading to normocalcemia was defined as multiglandular disease (MGD). Multiglandular hyperplasia was defined as the situation when all four glands appeared abnormal. Hypoparathyroidism and nerve damage were considered complications of surgery. Permanent hypoparathyroidism was defined as a serum ionized calcium of less than 4.60 mg/dL (<1.15 mmol/L) and/or total calcium of less than 8.48 mg/dL (<2.12 mmol/L), persisting beyond the first six months after surgery and requiring substitution with calcium and an active form of vitamin D.
To get insight into PHPT in MEN1 and MEN2A and their difference with respect to sPHPT, we evaluated clinical and biochemical parameters, differences in preoperative workup, operative strategies, and findings.
All continuous variables were reported as median (range). Mann–Whitney U test and Independent-Samples T Test were used for two-group comparison of continuous variables and Chi squared test for analysis of categorical data. Statistical analysis was performed using SPSS version 15.0 (SPSS, Inc., Chicago, IL). Statistical significance was established at p<0.05.