Challenges and Pitfalls in the Management of Parathyroid Carcinoma: 17-Year Follow-Up of a Case and Review of the Literature

A 29-year-old man presented to his primary care physician with a 2-month history of severe weight loss (20 kg) associated with polyuria, polydipsia, nausea, muscle weakness, difficulty in concentrating and debilitating tiredness. On physical examination, he was clinically dehydrated and had a palpable hard, fixed swelling in the left side of the neck. He was using no medication and had no significant past or family history. Laboratory investigations revealed a severe hypercalcaemia of 4.9 mmol/l (normal range 2.15–2.55 mmol/l), a decreased creatinine clearance of 45 ml/min (normal >120 ml/min) and a 10-fold increased serum intact parathyroid hormone (PTH) concentration: 88 pmol/l (normal <8 pmol/l). These findings suggested a diagnosis of severe primary hyperparathyroidism probably due to parathyroid carcinoma. No further investigations were requested; the patient was intensively rehydrated and referred for parathyroidectomy. At neck exploration, an enlarged parathyroid gland (3.5 × 3 × 3.5 cm) invading the ipsilateral thyroid lobe was found and removed from the left side of the neck (Fig. 1). A left hemithyroidectomy was also performed. The diagnosis of parathyroid carcinoma was confirmed histologically by the finding of capsular and vascular invasion. Serum calcium and PTH concentrations normalised within a few days of surgery associated with a significant improvement in renal function. A second surgery was performed within 1 month of the first surgery to ensure complete removal of all malignant tissue and provide a negative surgical margin. The patient was started on a course of radiotherapy, which had to be discontinued before completion because of severe pharyngitis and oesophagitis.

A recurrence of hyperparathyroidism was documented on routine laboratory control 3 years after parathyroidectomy. This was mild, with a serum calcium concentration of 2.74 mmol/l, a PTH concentration of 8.4 pmol/l and a stable creatinine clearance of 75 ml/min. The patient was completely asymptomatic. Tc99m-MIBI-SPECT and ultrasonography identified a lesion in the left side of the neck, which was found to be a local recurrence of the primary tumour at extensive bilateral neck exploration. The recurrent tumour had invaded the oesophagus, part of which was excised and reconstructed using tissue from the sternocleidomastoid muscle. The edges of the excised specimen were tumour free and resected draining lymph nodes were clear of tumour tissue. DNA analysis of the resected recurrent tumour demonstrated a somatic HRPT2 mutation, c.165delC located on exon 2 [22]. Despite the radical nature of the surgery, mild hyperparathyroidism persisted post-operatively, suggesting the presence of residual probably metastatic tumour tissue. No further localisation studies or surgery were planned principally because of the patient’s reluctance to undergo further surgery but also because of the mild nature of the hyperparathyroidism. Closer clinical monitoring was arranged.

Over the following 4 years, serum calcium and PTH concentrations and bone turnover markers slowly increased, and periods of dehydration were associated with transient worsening of renal function, which remained, however, on the whole stable despite persistent hypercalciuria and development of nephrocalcinosis. Progressive bone loss, predominantly cortical, was also documented and treatment with the non-nitrogen-containing bisphosphonate clodronate was started, resulting in normalisation of bone turnover and stabilisation of BMD measurements. Rehydration and treatment with bisphosphonates eventually failed in controlling hypercalcaemia and bone loss. Localisation studies were undertaken to identify the source of PTH production. Ultrasound (US), selective venous sampling for PTH (SVS) and CT scan of the neck succeeded in localising a small dense lesion in the left supraclavicular region. CT scan of the thorax also revealed a small solitary lesion of 1-cm radius in the inferior lobe of the right lung (Fig. 2a). The patient refused to undergo a thoracotomy, but did agree to a fourth neck exploration at which a lymph node metastasis was excised from the left supraclavicular region (Fig. 1). Although less severe, hyperparathyroidism persisted post-operatively, as expected due to the unresected lung metastasis. Two attempts at embolisation of the lung metastasis failed to reduce tumour load. In contrast, radiofrequency ablation (RFA) of the lesion, although complicated by an episode of severe pleuritis, was very successful in achieving biochemical remission, with serum PTH concentrations decreasing from 265 pmol/l to <1 pmol/l (Fig. 2), suggesting that the metastasis targeted with RFA was the only source of PTH secretion. However, remission was not permanent and PTH levels started to rise within 9 months of RFA. The patient finally agreed to undergo a right inferior lobectomy (Fig. 3), which was complicated by multiple small cerebral infarcts resulting in right haemianopia, dysphasia, acalculia and transient epilepsy. Disappointedly, there was also only partial improvement in serum calcium and PTH concentrations, which continued to increase within 2 months of lobectomy (Fig. 3).

Further localisation studies, in the form of Tc99m-MIBI-SPECT and a CT scan of the neck and thorax, were unable to localise any residual pathological parathyroid tissue suggesting the presence of (micro)metastasis. The now available calcimimetic cinacalcet was prescribed eventually at a maximum dose of 90 mg twice daily, which decreased PTH concentrations from 120 pmol/l to 85 pmol/l, stabilised calcium concentrations to about 2.80 mmol/l and stabilised creatinine clearance at 51 ml/min. In the course of the following year, serum calcium and PTH concentrations further increased, however, despite maximal doses of cinacalcet and intermittent intravenous bisphosphonates.

Repeat Tc99m-MIBI-SPECT and CT scan of the thorax, now demonstrated a new large (4 × 3 × 2 cm) subcarinal mediastinal metastasis, which was successfully excised using a transpericardial approach (Fig. 4). The elimination of the source of PTH secretion was associated with a very severe hungry bone syndrome for which the patient needed intensive care for over 2 months, requiring very large doses of iv administered calcium (up to 14 g/day) and maximal doses of active vitamin D metabolites. Remission lasted for more than 1 year, after which PTH levels started to rise again and a new metastatic lesion was localised pretracheally in the upper mediastinum on CT scan of the thorax. There was also suggestion of a second subcarinal lesion at the site of the previously excised metastasis.

In view of the complications associated with his previous surgeries, the patient was at that stage again reluctant to undergo any further surgery. Within the next few months, PTH steadily increased associated with uncontrollable hypercalcaemia and deteriorating renal function eventually requiring haemodialysis using a very-low-dialysate calcium concentration. Localisation studies confirmed the two previously identified pretracheal and subcarinal mediastinal lesions. The pretracheal lesion was accessible from the neck and was radically removed by a cervical approach (Fig. 1). There were no post-operative complications and serum PTH concentration decreased from 590 pmol/l to 155 pmol/l, as expected due to the remaining subcarinal mediastinal metastasis. Surgical removal of this metastasis would have required a third thoracotomy, which would be associated with too high an operative risk, especially in view of the patient’s poor clinical condition. Excision of the metastasis by mediastinoscopy was also not considered to be an option because of multiple scarring due to previous surgeries. The patient remains on haemodialysis and is still treated with cinacalcet, with intermittent courses of intravenous bisphosphonates. The patient was not considered to be a candidate for PTH immunisation [23, 24] because of surgical clearance of cervical and mediastinal lymph nodes, poor general immune status and recurring infections.

Sixty-two new cases have been reported in the literature since the last published review in 2001 [3], and data of these cases are summarised in Table 1. The median age of the reported patients was 50 years (21–79) and there was an equal number of men and women reported. Data on initial presentation were available in 43 of the 62 patients (69%), 37 of which were symptomatic (86%). Polyuria and polydipsia were reported in nine patients (21%), constipation in seven (16%), tiredness in 13 (30%), bone and joint pain in 17 (40%), muscle weakness in seven (16%), nausea and vomiting in 10 (23%) and weight loss in seven patients (16%). Seventeen patients (40%) had renal stones and six patients (14%) had sustained a documented fracture. A palpable neck mass was reported in 22 of 27 patients in whom this was checked (81%).

Similar to the review of 2001, surgery is still the most frequently chosen therapy for the initial treatment of parathyroid carcinoma but also for the treatment of recurrent or metastatic parathyroid carcinoma (Table 1). It is of note that the use of both chemotherapy and radiotherapy has decreased over the last 10 years, likely due to several reports and reviews which showed disappointing results [2‐5]. The last case report on the use of chemotherapy and radiotherapy dates from 2005 and 2008, respectively (Table 1). In contrast to the review of 2001, reports on the use of the newer techniques embolisation (n = 1), radiofrequency ablation (n = 3) and PTH immunisation (n = 1) have been recently published, although the number of cases reported is still very limited. Use of the calcimimetic, cinacalcet, has increased over the last few years after the first report in 2007, while the use of bisphosphonates has remained stable.

The median follow-up reported in the 62 cases is relatively short at 3 years (range 0.5–20 years), considering that the average time to a first recurrence is also approximately 3 years [1, 3]. This could explain why only 27 of the 62 patients (44%) developed a local recurrence and/or distant metastasis and nine patients (15%) died as a result of parathyroid carcinoma during the reported follow-up period.