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Case Report

Microwave ablation for recurrent primary hyperparathyroidism in four patients with multiple endocrine neoplasia type 1: a case series report

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Article: 2308056 | Received 19 Oct 2023, Accepted 15 Jan 2024, Published online: 05 Feb 2024

Abstract

Multiple endocrine neoplasia type 1 (MEN1), a rare tumor syndrome, is inherited in an autosomal dominant pattern, mainly manifested as primary hyperparathyroidism (PHPT). Surgery is preferred for patients with MEN1 and PHPT. Thermal ablation has been widely applied for PHPT but rarely for postoperative recurrent PHPT in MEN1 patients. Based on a series of cases, we aimed to investigate the clinical efficacy and safety of ultrasound-guided percutaneous microwave ablation in the treatment of MEN1 patients with postoperative recurrence of PHPT.

Introduction

Multiple endocrine neoplasia type 1 (MEN1), also known as Wermer syndrome, is an inherited endocrine disorder caused by mutations in the tumor suppressor gene MEN1. It is characterized by proliferative and/or neoplastic lesions that mainly involve the parathyroid glands, anterior pituitary, gastrointestinal tract and pancreas [Citation1]. Primary hyperparathyroidism (PHPT) is the most common clinical manifestation of MEN1, with a prevalence of 1:30,000 in the general population but higher in a specific population with associated diseases or complications. For example, the prevalence of MEN1 in PHPT patients diagnosed before the age of 30 years is 7–11% [Citation2,Citation3].

Surgery is currently preferred for MEN1 patients with hyperparathyroidism, although more than 50% of patients may experience persistent or recurrent PHPT after surgery [Citation4,Citation5]. Reoperation poses a high risk of complications, such as injuries to the recurrent laryngeal nerve [Citation6,Citation7]. Moreover, surgery is not recommended for patients with contraindications or refusal to undergo surgical treatment. Thermal ablation techniques, including ultrasound-guided microwave ablation (MWA) and radiofrequency ablation (RFA), have been recommended because of their acceptable efficacy and safety in thyroid diseases. We have previously reported a MEN1 patient with postoperative recurrence of hyperparathyroidism after parathyroidectomy, who was successfully managed by MWA, with parathyroid hormone (PTH) and serum calcium levels recovering to normal ranges [Citation8]. However, more evidence is needed to prove whether thermal ablation can effectively control recurrent hyperparathyroidism after parathyroidectomy in MEN1 patients. In this case series, we retrospectively analyzed the clinical data of four MEN1 patients with postoperative recurrence of PHPT after subtotal parathyroidectomy who were managed by MWA, with the aim of exploring the feasibility and safety of MWA in the treatment of recurrent PHPT in MEN1 patients.

Case presentation

Case 1

A 44-year-old female patient presented with a space-occupying lesion in the pancreas that was initially found on physical examination. Abdominal computed tomography (CT) revealed space-occupying lesions in the tail of the pancreas and right adrenal gland, and small stones in the right kidney. Plain and contrast-enhanced magnetic resonance imaging (MRI) visualized a space-occupying lesion in the tail of the pancreas, suggesting the possibility of a neuroendocrine tumor and adrenal adenoma in the right adrenal gland. The patient was surgically treated with resection of the pancreatic tail, and the lesion was finally diagnosed as a grade 2 neuroendocrine tumor based on pathological and immunohistochemical findings (). Postoperative reexamination at 1 month showed a blood calcium of 3.01 mmol/L and PTH of 2847.6 pg/mL. Prolactin level of 59.2–120.55 ng/mL, basal prolactin of 63.75 ng/mL and peak/baseline prolactin <1.5 detected by the metoclopramide test were suggestive of hyperprolactinemia. An uneven signal intensity was detected on the plain MRI scan of the pituitary gland, and no abnormal findings were detected on the contrast scan. The gastrin level was 28.43 pg/mL↓. Painless gastrointestinal endoscopy showed chronic superficial gastritis with erosions and colonic diverticulum. Thyroid function testing and ultrasound did not suggest any thyroid disorder. Z-score of the bone mineral density of L1-4 was below −2.0. CT scan of the chest showed micronodules in both lungs. The dual-phase 99mTc-MIBI parathyroid scan revealed a soft-tissue-density nodule behind the inferior pole of the right thyroid lobe, indicating the presence of a hyperfunctioning parathyroid mass. The patient was finally diagnosed as MEN1 by genetic testing (). Moreover, genetic testing was performed in the first-degree relatives of the patient, and the MEN1 gene mutation was detected in the patient’s father, eld brother and nephew.

Table 1. Clinical data of the four MEN1 patients with postoperative recurrence of PHPT.

Table 2. MEN1 genetic detecting analysis.

On 11 February 2022, the patient underwent parathyroidectomy of the right inferior parathyroid gland at another hospital, and postoperative pathology confirmed the presence of parathyroid hyperplasia (). The postoperative blood calcium and PTH were 2.72 mmol/L and 215 pg/mL, respectively. Three months after parathyroidectomy, reexamination of blood calcium level (2.78 mmol/L) and PTH level (294.3 pg/mL) were suggestive of unrelieved PHPT. In May 2022, reexamined ultrasonography of the thyroid showed: (1) resection of the inferior pole of the right parathyroid gland; (2) a hypoechoic nodule (3.1 cm × 0.9 cm) posterior to the inferior pole of the right thyroid gland; (3) a hypoechoic nodule (0.93 cm × 0.46 cm) posterior to the left thyroid gland. The hypoechoic nodules were parathyroid lesions. Other examinations showed a 25-hydroxyvitamin D3 (25(OH)D3) level of 10.1 ng/mL, and the Z-score of bone mineral density (BMD) at L1-L4 was less than 2.0. Parathyroid emission computerized tomography (ECT) showed localization in two adjacent hyperfunctioning parathyroid tissues on the dorsal side of the right thyroid gland and a suspected hyperfunctioning parathyroid tissue on the dorsal side of the superior pole of the left thyroid gland ().

Figure 1. Postoperative pathological images of Case 1 (A), Case 3 (B) and Case 4 (C) after the first time of subtotal parathyroidectomy.

Figure 1. Postoperative pathological images of Case 1 (A), Case 3 (B) and Case 4 (C) after the first time of subtotal parathyroidectomy.

Figure 2. Representative imaging scans of cases 1–4 before and after thermal ablation.

Figure 2. Representative imaging scans of cases 1–4 before and after thermal ablation.

The patient was intervened by MWA for supplementary therapy after being fully informed of therapeutic efficacy and potential risks. The MWA for bilateral parathyroid glands was guided by intraoperative ultrasound, as previously reported [Citation9]. The MWA system (KY-2000) was produced by Canyon Medical Inc. (Nanjing, China). Briefly, normal saline was injected and maintained surrounding the parathyroid adenoma to create a barrier that prevents thermal damage to the trachea, esophagus and recurrent laryngeal nerve. The ablation antenna was inserted into the parathyroid lesion through the previously determined path, and MWA was initiated at 35 W output power. The operation was sustained until the entire gland was hyperechoic. After the ablation, color Doppler ultrasound and contrast-enhanced ultrasound were performed to confirm no blood flow in the nodule and remaining lesions (). The MWA procedure lasted 170 s, and intraoperative heart rate, blood pressure and blood oxygen level were 77 beats/min, 136/79 mmHg and 79%, respectively. The patient only complained of mild pain. PTH level immediately returned to normal at 10 min postoperatively, and remained normal at 20 min, 4 h, 24 h, 1 month, 2, 3, 6, 12 and 18 months postoperatively, suggesting the complete remission of hyperparathyroidism (). The patient developed hypocalcemia at 1 month postoperatively due to the irregular supplement of vitamin D and calcium. Serum calcium and PTH levels both returned to normal after treatment. Postoperative adverse events like obvious hoarseness and hemorrhage were not reported.

Table 3. Changes in blood calcium and PTH levels after thermal ablation.

Case 2

A 48-year-old male patient, who was the elder brother of Case 1, had increased blood calcium 10 years ago and was subsequently diagnosed with parathyroid adenoma. He then underwent left inferior parathyroid gland at another hospital. The patient had not been diagnosed with MEN1 at the time of ingle gland resection of parathyroid gland, and only single gland lesion as the initial treatment of PHPT. Moreover, the pathological data and postoperative follow-up data were unavailable. An increased PTH level, pituitary microadenoma, and pancreatic tumor were detected one year ago, and the patient was finally diagnosed with MEN1 by genetic testing (). However, the patient did not receive any clinical management. On 19 April 2023, relevant examinations in the Outpatient Department of our hospital showed prolactin levels > 10,000.000 μIU/mL, and bromocriptine was administered. Further examinations revealed the following: (1) PHT, 154.2 pg/mL; (2) blood calcium, 2.7 mmol/L; (3) hypoechoic nodules in the inferior pole of the thyroid glands on ultrasound scans, with a suspected origin from the parathyroid glands; and (4) abnormal radioactivity concentration was not found on parathyroid ECT scans (). Additionally, PRL was measured as > 10,000.000 μIU/m. The CT scan of the chest showed glass nodules of upper lobe of right lung.

After being fully informed, the patient was treated by MWA. Eventually, the MWA procedure lasted 152 s. The patient only complained of mild pain. After the ablation, color Doppler ultrasound and contrast-enhanced ultrasound were performed to confirm that no blood flow in the nodule and remaining lesions (). PTH level immediately returned to normal at 10 min postoperatively, and remained normal at 20 min, 1 day, 1 month, 2, 3 and 6 months postoperatively, suggesting the complete remission of hyperparathyroidism (). Postoperative adverse events like obvious hoarseness and hemorrhage were not reported.

Case 3

A 47-year-old male patient presented with a space-occupying lesion in the pancreas on chest CT scan four years ago. He was treated with spleen-preserving distal pancreatectomy on 29 August 2019 and was pathologically diagnosed with a low-grade neuroendocrine tumor. Oxaliplatin plus capecitabine was given three months later and terminated after confirmation of non-metastatic lesions by 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT). Further examination revealed pituitary microadenoma (prolactinoma). The patient was treated with oral bromocriptine. Reexaminations in July 2020 showed: (1) increased blood calcium and PTH levels; (2) color Doppler ultrasound suggested a suspected parathyroid adenoma in the right parathyroid gland; and (3) single-photon emission computed tomography (SPECT) showed a positive lesion in the right inferior parathyroid gland, considering the possibility of a parathyroid adenoma. On 13 December 2021, somatostatin receptor PET/CT (SSTR PET/CT) showed: (1) a significantly increased uptake of somatostatin receptor (SSTR) was not detectable in the previously resected region of the low-grade neuroendocrine tumor in the pancreas; (2) a similar visualization of the soft-tissue nodule on the left side of the pituitary fossa to that of the previous imaging, and the low uptake of SSTR was suggestive of a pituitary adenoma; (3) a focal increased uptake of SSTR in the duodenal bulb, and abnormal shadows were not detectable on CT scans; (4) hyperplasia of the right adrenal gland, suggesting a suspected adrenal adenoma in the right adrenal gland; (5) absence of the left testicle (cryptorchidism), and (6) multiple nodules in the right kidney, and endoscopic ultrasonography showed duodenal bulb and descending segment protrusion lesions (originating from submucosa). On 25 August 2022, the adenoma in the right parathyroid gland was resected and finally diagnosed as a thyroid adenoma by postoperative pathology (). The postoperative blood calcium and PTH were hormone levels gradually increased. The blood calcium level was maintained within the normal range during the administration of cinacalcet, which was withdrawn after six months of medication by the patient. However, the increased blood calcium (2.63 mmol/L) and PTH (194.5 pg/mL) measured on 4 February 2023, were suggestive of unrelieved PHPT. On 13 February 2023, parathyroid MIBI showed a small nodule on the dorsal side of the inferior pole of the left thyroid gland with a weakly positive parathyroid scintigraphy scan, indicating the possibility of parathyroid adenoma or parathyroid hyperplasia (). A bone density scan revealed a normal bone mass.

After being fully informed, the patient was treated by MWA. The MWA procedure lasted 86 s. After the ablation, color Doppler ultrasound and contrast-enhanced ultrasound were performed to confirm no blood flow in the nodule and remaining lesions (). PTH level significantly decreased to normal at 10 min postoperatively, but slightly higher than the upper limit of the normal during follow-up. At 12 months, serum PTH and calcium became normal (). Again, postoperative adverse events like obvious hoarseness and hemorrhage were not reported.

Case 4

An 18-year-old female patient, who was the daughter of Case 3, presented with a lesion occupying the pituitary and a prolactin level higher than 10,000 mIU/mL detected in another hospital due to 6 months of amenorrhea three years ago. The patient underwent endoscopic skull base surgery at another hospital and was pathologically diagnosed with pituitary adenoma. Oral bromocriptine and femoston recovered menstruation, although the menstrual periods were irregular. Reexaminations in February 2022 showed: (1) blood calcium, 2.87 mmol/L; (2) PTH, 382.9 pg/mL; (3) color Doppler ultrasound suggested a parathyroid tumor (details were not available); (4) parathyroid MIBI showed soft tissue nodules in the inferior pole of the left thyroid gland, and behind the inferior pole of the right thyroid gland, with positive parathyroid scintigraphy scans. The patient was later diagnosed with MEN1 via genetic testing (). In May 2022, parathyroidectomy of the inferior pole of the bilateral parathyroid glands was performed in another hospital, and parathyroid adenoma was finally confirmed by postoperative pathology (). Two months after parathyroidectomy, reexamination of the blood calcium level (2.75 mmol/L) and PTH level (215.9 pg/mL) were suggestive of unrelieved PHPT. On 3 July 2023, repeated color Doppler ultrasound showed a hypoechoic nodule (0.34 cm × 0.28 cm) in the right superior parathyroid gland and another hypoechoic nodule (0.5 cm × 0.31 cm) in the left superior parathyroid gland, suggesting the possibility of parathyroid nodules. Abnormal radioactivity concentrations were not found on parathyroid ECT scans (). Laboratory test showed a gastrin of 172.87 pmol/L. The CT scan of the chest showed old lesions in both lungs.

The patient was treated by MWA after being fully informed. The MWA procedure lasted 149 s. After the ablation, color Doppler ultrasound and contrast-enhanced ultrasound were performed to confirm no blood flow in the nodule and remaining lesions (). PTH level returned to the upper limit of the normal at 10 min and 20 min postoperatively, but then unfortunately elevated slightly higher than the normal after 1 month and decreased in the following visit at 6 months (). But the blood calcium levels remained normal. Postoperative adverse events like obvious hoarseness and hemorrhage were not reported.

Discussion

MEN1 is a rare autosomal dominant disease caused by germline mutations in the tumor suppressor gene MEN1. MEN1 encodes a 610-amino acid protein Menin that maps to chromosome 11q13. Loss of heterozygosity (LOH) at 11q13 of MEN1 results in biallelic inactivation [Citation10]. Multiple endocrine glands are affected by MEN1, manifesting proliferative and/or neoplastic lesions [Citation11]. Consistent with the previous finding that PHPT is the most common manifestation of MEN1 (88–97%), all four patients in the present case series reported PHPT and pituitary microadenomas. Except for Case 4, space-occupying lesions were detected in the remaining patients.

Surgery is the first-line treatment for MEN1-associated PHPT. Subtotal parathyroidectomy (SPTX) plus bilateral cervical thymectomy or total parathyroidectomy (TPTX) plus bilateral cervical thymectomy and parathyroid autotransplantation is recommended for MEN1 patients with PHPT [Citation4]. The rate of persistent and recurrent PHPT in MEN1 patients ranges from 14% to 69%, which is significantly higher than that in sporadic PHPT [Citation12]. However, both SPTX and TPTX are associated with a high risk of permanent hypoparathyroidism, especially the latter [Citation13]. A meta-analysis showed that the possibility of PHPT recurrence is 3.11 times higher in patients treated with less than subtotal parathyroidectomy (<SPTX, resection of less than 3 parathyroid glands) than in those treated with SPTX (resection of 3–3.5 parathyroid glands) or TPTX (resection of 4 parathyroid glands plus parathyroid autotransplantation) (95% CI 2.00–4.84; p = 0.0001) [Citation14]. Moreover, the risk of permanent hypoparathyroidism in patients treated with < SPTX was significantly lower than that in patients treated with SPTX or TPTX (OR 0.24, 95% CI 0.12–0.48; p = 0.0001), which was significantly lower in patients treated with SPTX than in those treated with TPTX (OR 0.25, 95% CI 0.11–0.54; p = 0.0004). The risk of recurrent PHPT, however, was similar between patients treated with SPTX or TPTX (OR 2.15, 95% CI 0.82–5.61; p = 0.12). A recent meta-analysis consistently suggested that STPH is an alternative to PHPT in MEN1 patients [Citation15]. Collectively, SPTX is a promising surgical procedure for MEN1 patients with PHPT, which provides a similar risk of recurrent PHPT to that of TPTX but a lower risk of persistent PHPT. In the present case series, all four patients had been previously treated with < SPTX and developed postoperative recurrent PHPT with unclear causes. Pieterman et al. [Citation16] reported that MEN1 patients with PHPT carrying nonsense or frameshift mutations in exons 2, 9, and 10 have a significantly lower risk of persistent or recurrent PHPT after < SPTX than those carrying other mutations. Mutations in exon 3 of MEN1 are also correlated with the risk of recurrent PHPT [Citation17]. We did not perform genetic testing in these four patients, and the exact cause of postoperative PHPT in these patients should be further analyzed.

Reoperation, percutaneous ethanol ablation (PEA), and calcimimetic agents, such as cinacalcet, are common therapeutic strategies for MEN1 patients with recurrent PHPT. Reoperation is recommended for MEN1 patients with severe hypercalcemia (blood calcium > 2.75 mmol/L), symptomatic urinary stones, or osteoporosis. The recovery of blood calcium within the normal range after the second surgery was only detected in 50% of MEN1 patients who were initially treated with < SPTX or SPTX [Citation18]. Nevertheless, reoperation greatly increases the risk of persistent PHPT and injuries to the inferior laryngeal nerve [Citation6,Citation7]. Cinacalcet medication requires a long period that may cause severe adverse events, and it is unable to cure the cause of MEN1-associated PHPT. EA has been applied for the treatment of MEN1-associated recurrent PHPT, and its efficacy is comparable to that of reoperation. In a cohort of 37 MEN1 patients with recurrent PHPT who had been treated with 80 treatment episodes of PEA, recovery of blood calcium within the normal range was observed after 54 (73.0%) treatment episodes and maintains for 24.8 months. High postoperative blood calcium (>10.0 mg/dl) and hypocalcemia occurred after 14 (18.9%) and 6 (8.1%) treatment episodes, respectively. Transient hoarseness was reported in 4 (5.0%) of the treatment episodes, and severe adverse events were not reported [Citation19].

At present, thermal ablation techniques such as RFA, MWA, laser ablation (LA), and high-intensity focused ultrasound (HIFU) ablation have been applied for the treatment of PHPT with acceptable efficacy and safety [Citation20–22]. In our previous study, two patients with persistent PHPT involving 21 parathyroid adenomas were treated with MWA. During the postoperative follow-up period of 3–12 months, patients present significant decreases in serum PTH, calcium, and phosphorus levels, and a median volume reduction rate of up to 89.0% [Citation9]. The technique and clinical success rates were 100% and 63.6%, respectively. A meta-analysis demonstrated that thermal ablation effectively ablates parathyroid lesions and reduces PTH and blood calcium levels. Notably, MWA provides a shorter operation time for a single lesion and a higher rate of complete ablation for a large lesion than RFA [Citation23]. However, the treatments for hyperparathyroidism vary among MEN1 patients, because the development of parathyroid adenomas is driven by mutated genes. After the parathyroid adenoma is ablated, other parathyroid glands may be still driven by the mutated gene, and functional adenomas may form again. Meanwhile, recurrent hyperparathyroidism in MEN1 patients is somewhat similar to secondary hyperparathyroidism, in that the recurrences of both diseases are driven by underlying factors. However, the treatment goals and success criteria for secondary hyperparathyroidism are different from those for primary hyperparathyroidism. Our report showed that all four patients in this case series were managed by MWA, with significantly decreased postoperative blood calcium levels that remained normal during the follow-up period. Postoperative PTH levels significantly decreased in all patients, including three patients with normal PTH levels during the follow-up period, one with a slight increase, and one with a decreased PTH level but higher than that of the normal range.

The recovery of blood calcium within the normal range but with elevated PTH levels after surgery is defined as normocalcemic parathormone elevation (NPE) [Citation24]. The incidence of NPE in surgically treated PHPT patients during short-term (3–18 months) and long-term (10 years) postoperative follow-up is approximately 11.0% and 44.0%, respectively [Citation25,Citation26]. NPE has also been observed in patients with PHPT after thermal ablation [Citation9]. Although NPE cannot predict the recurrence of PHPT, it is a potential marker reflecting the unrelieved condition in MEN1 patients [Citation24]. The long-term follow-up of NPE in MEN1 patients with PHPT is lacking; therefore, its optimal management requires further exploration.

Collectively, this series report indicates that MWA may be an alternative for recurrent PHPT in selected MEN1 patients. However, due to a small sample size and short follow-up time, the long-term efficacy of MWA for recurrent PHPT in patients with MEN1 has not been validated yet. Subtotal parathyroidectomy still serves as the first-line treatment, although it poses the risk of recurrent PHPT. Our findings may encourage the advent of further research on thermal ablation in MEN1 patients with recurrent hyperparathyroidism. Larger, multi-center prospective and long-term follow-up studies should be conducted to investigate the potential benefit of microwave ablation in these patients.

Ethical approval

The study was conducted in accordance with the Declaration of Helsinki, and approved by the Ethics Committee of Jiangsu Province Hospital of Integrated Traditional and Western Medicine (protocol code 2023-LWKYZ-070).

Informed consent

Written informed consent for publication of patients’ details was obtained from them or their parent.

Authors contributions

Jie Tan, Yuzhi Zhang, and Shuhang Xu were responsible for data collection and analysis. Guofang Chen, Chao Liu, and Shuhang Xu participated in this study. Shuhang Xu performed the microwave ablation. Xue Han, Yaofu Fan, and Juan Xu were responsible for the perioperative management. Jie Tan drafted the manuscript. Shuhang Xu critically revised the manuscript for intellectual content. All authors agreed to take responsibility for the integrity of the data and the accuracy of data analysis, and approved the final version of the manuscript.

Acknowledgements

We appreciate Qing Guo, Yalin Wang, and Yang Xu for their assistance with the ablation and data collection.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

All data are made available by the authors on request without undue reservation.

Additional information

Funding

This study was funded by the Jiangsu Provincial Key Research and Development Program [BE2020726] and Medical Scientific Research Foundation of Jiangsu Province of China [M2020102].

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