Abstract
Parathyroid carcinoma is a rare form of cancer, which can be initially a diagnostic challenge and once diagnosed, there is lack of clinical evidence for its management. Its predominant manifestation is symptomatic hypercalcemia, but incidental diagnoses can also occur. Here, we report two cases but each with its own clinical nuances—one presents with asymptomatic hypercalcemia and the other presents with long-standing debilitating manifestations of hypercalcemia. We detail our extensive pre-operative evaluation and the perioperative management. Both are treated surgically, requiring radical excision, and both had unilateral level VI neck dissections. Radiological and biochemical surveillance is performed in both cases and in each case is essential in long-term management. Both patients remain disease free on one-year postoperative follow-up.
Introduction
Parathyroid carcinoma is an exceedingly rare form of cancer, which can pose both a diagnostic and therapeutic challenge. It’s incidence has been reported as 5.7–10.2 per 10,000,000, accounting for less than 0.005% of all cancers, with an five-year overall survival ranging from 82–100% [Citation1–4]. Most often it presents with symptoms of primary hyperparathyroidism, but still only accounts for less than 1% of cases of primary hyperparathyroidism [Citation5]. In contrast, parathyroid adenomas account for 85% of primary hyperparathyroidism [Citation5].
Here, we report two cases of parathyroid carcinoma treated at our institution. Interestingly, both presented differently. Multiple imaging modalities were utilized preoperatively, which along with a high clinical index of suspicion of malignancy, given the markedly elevated PTH levels, guided our management of these cases. As this is a rare clinical entity with as yet a paucity of clinical guidelines available, a detailed multi-disciplinary approach is required, which included input from Otorhinolaryngology, Endocrinology, Anaesthesia, Radiology and Histopathology. The goal of this case report is to document our management approach to parathyroid carcinoma and to guide management for other institutions who are faced with this rare clinical entity.
Case presentation
Patient 1
An otherwise fit and healthy 47-year-old gentleman was admitted with a varicella zoster infection. On routine admission bloods, his corrected calcium was 3.19 (reference range 2.20 to 2.60 mmol/L). A corresponding PTH level was 88.0 (reference range 1.6 to 6.9 pmol/L) with a vitamin D level of 88 nmol/L.
A subsequent technetium-99m (Tc-99m) sestamibi single photon emission computed tomography/computed tomography (SPECT/CT) scan performed at 2 h following radiotracer administration demonstrated focally retained activity at the inferior aspect of the right lobe of the thyroid gland, with indentation along the inferior margin of the lower pole of the right thyroid lobe. A neck ultrasound demonstrated a 3 × 2.5 × 2.4 cm hypoechoic nodule in the region of the lower pole of the right thyroid, with internal vascularity and calcifications.
He was commenced on cardiac monitoring and his hypercalcemia was treated with intravenous fluids and a bisphosphonate.
Two weeks following admission he proceeded to theatre. Based on his markedly elevated PTH, there was a high index of suspicion for malignancy, and as such he was counselled pre-operatively about the potential need for a more extensive resection.
At operation, a mass was seen at lower pole of the thyroid, which was contiguous with the thyroid with complete absence of a surgical plane. A right hemithyroidectomy and level VI neck dissection was performed. The recurrent laryngeal nerve was identified and preserved. Intra-operative PTH was 14.1 pmol (decreased from 109.5 pmol/L). A 1/8 drain was placed and the wound was closed in layers.
Histology returned as a completely excised 35 mm parathyroid carcinoma, with negative margins. All six excised lymph nodes were negative for malignancy.
Post-operatively his PTH (1.7 pmol/L) and corrected calcium (2.42 mmol/L) returned to normal. He was discharged well on post-operative day 3.
On follow-up, three weeks post-operatively, his calcium remained within normal limits but his PTH was elevated at 22.2 pmol/L.
After post-operative MDT discussion, a surveillance CT thorax, abdomen and pelvis was performed to assess for metastases. This suggested several potential bony metastases which were further assessed on a technetium-99m-methylene diphosphate (MDP) bone scan (Figures –). Increased uptake was seen at the left acromioclavicular joint, cervicothoracic junction, anterior ribs bilaterally, left iliac bone and right patellofemoral joint. Subsequent radiographs of the left shoulder and right knee demonstrated distal clavicular osteolysis and a large lytic lesion in the patella respectively. CT of the chest showed a pathological fracture through T1 spinous process and expansion of the anterior left 5th rib, with underlying soft tissue lesions in each. A further MRI spine was performed which revealed bone marrow lesions within T10 and S1. A CT-guided biopsy of his iliac crest lesion was performed, and histology returned as regenerative changes with hemosiderin. No tumour was identified, and these lesions were most consistent with brown tumours (bony lesion due to fibrous growth secondary to excess osteoclast activity).
Figure 1. (A) Delayed axial technetium-99m sestamibi single photon emission computed tomography (SPECT) fused with axial CT shows focally retained activity at the inferior aspect of the right lobe of the thyroid gland, with indentation along the inferior margin of the lower pole of the right thyroid lobe. (B) Transverse colour doppler ultrasound of the right thyroid lobe demonstrates a hypoechoic extrathyroidal nodule posterior to the lower pole of the right thyroid with internal vascularity and calcifications, correlating to the abnormality on SPECT/CT.
Figure 2. (A) Anterior and posterior whole-body planar images from a technetium-99m-methylene diphosphate (MDP) bone scan show increased tracer uptake secondary to hyperparathyroidism, at the left acromioclavicular joint (black asterisk), cervicothoracic junction (grey arrowhead), costochondral junctions bilaterally (black arrowhead), left iliac bone (grey arrow, biopsy-confirmed brown tumour) and right patellofemoral joint (black arrow). (B) Anteroposterior radiograph of the left shoulder showing osteolysis of the distal clavicle. (C) Axial CT of the spine showing a pathological fracture of the T1 spinous process, secondary to a brown tumour. (D) Axial CT through the chest showing an expansile lytic lesion of the anterior left 5th rib, in keeping with a brown tumour. The increased uptake on bone scan along the remaining costochondral junctions was non-specific. (E) Anteroposterior radiograph of the right knee showing a large lucent lesion in the patella, consistent with a brown tumour.
Following multi-disciplinary discussion (Otorhinolaryngology, Endocrinology, Oncology, Radiology) it was decided that no systematic therapy was required and he should remain under clinical surveillance.
At his most recent follow-up, 18 months post-operative period, his calcium and PTH remain normal, and both neck ultrasound and sestamibi scan showing no evidence of recurrence.
Patient 2
Our second patient was a 67-year-old male who was referred to ENT outpatient department with symptomatic hypercalcemia and biochemical primary hyperparathyroidism despite being on Cinacalcet (corrected calcium 2.67 mmol/L, PTH 28 pmol/L). He suffered from prolonged fatigue, malaise, abdominal pain and had recurrent nephrolithiasis, requiring operative intervention.
On examination, no focal head and neck abnormalities were identified, and he had no palpable neck masses.
His medical history was significant for an unprovoked pulmonary embolism, and he was on long-term Warfarin.
Initially a neck ultrasound was performed which demonstrated a 3.1 cm complex cyst centred on the left lobe of the thyroid, with a moderately thick wall, central cystic components and a hypervascular mural nodule protruding intraluminally (Figure ). Due to his persistently raised PTH, an initial Tc-99m sestamibi scan and subsequent four-phase CT neck were ordered. Technetium-99m sestamibi images demonstrated focal uptake corresponding to the hypervascular nodule identified on US in the left lobe of the thyroid gland, which was further characterized as a 3.3 cm mixed solid-cystic lesion posterior to the left lobe of the thyroid gland on multi-phasic CT images. He had no evidence of laryngeal nerve paresis pre-operatively.
Figure 3. (A) Ultrasound of the thyroid demonstrates a 3.1 cm complex cyst centred on the left lobe of the thyroid, with a moderately thick wall, central cystic components and a hypervascular mural nodule protruding intraluminally (white arrowhead). (B) Technetium-99m sestamibi early and delayed images demonstrate focal uptake corresponding to the hypervascular nodule identified on US in the left lobe of the thyroid gland (black arrow). There is retention of radiotracer uptake on delayed images within the nodule (black arrowhead) with washout of the background thyroid activity. (C-F) Multiphasic CT images of the neck with initial non-contrast phase followed by 30, 60 and 90 second post-contrast delays, demonstrate a 3.3cm mixed solid-cystic lesion posterior to the left lobe of the thyroid gland, containing a solid nodule which demonstrates hyperenhancement and washout (white arrow), with Hounsfield Units of 36, 131, 104 and 97 respectively.
After multi-disciplinary team discussion, the decision to proceed to surgery was made. At operation, a left inferior parathyroid mass was identified which was adherent into the left inferior thyroid lobe and invading the left recurrent laryngeal nerve (RLN), the RLN was resected en bloc along with a central neck dissection.
Post-operative histology confirmed parathyroid carcinoma with positive margins at the resection plane between the parathyroid carcinoma and thyroid gland.
After further multi-disciplinary discussion, a completion ipsilateral thyroid lobectomy was performed for local control. Intra-operative assessment of contralateral level VI identified no pathological lymph nodes. Systematic therapy (chemoradiotherapy) was not indicated in either case.
On surveillance imaging (PET-CT) at 6 months post-operative period, no metastatic disease or local recurrence was evident.
Discussion
Parathyroid carcinoma is a rare form of head and neck malignancy, with an incidence reported as 5.7-10.2 per 10,000,000 [Citation1–3]. There is currently no prognostic staging system.
Primary hyperparathyroidism is the most common manifestation, but parathyroid carcinoma is the cause for less than 1% of cases of primary hyperparathyroidism [Citation5]. The pathogenesis of parathyroid carcinoma remains unclear; however, there have been reported genetic links, such as CDC-73 and MEN-1 and 2 [Citation6–8].
The predominant manifestation of parathyroid carcinoma are symptoms associated with hyperparathyroidism, and more specifically hypercalcemia [Citation9]. Excessively elevated serum calcium and PTH may indicate parathyroid carcinoma. Other manifestations include dysphagia and neck pain [Citation2]. In a smaller proportion of patient, asymptomatic hypercalcemia is found incidentally on routine investigations. Metastatic spread is predominantly local to cervical lymph nodes, but distant metastases can occur in the lungs, liver and bone [Citation9]. As parathyroid adenomas also present in a similar manner, it can be challenging to differentiate the two pre-operatively and commonly parathyroid carcinoma is diagnosed on post-operative histology. It has been reported that intra-operatively, parathyroid lesions are more likely to be solitary and arise from the lower parathyroid glands [Citation9].
As of yet, there are no diagnostic criteria for parathyroid carcinoma, with pre-operative definitive diagnose only made in the presence of metastatic disease. Tissue sampling in the form of fine-needle aspirate is avoided due to the risk of seeding and procedural complications. After obtaining serum parathyroid hormone and calcium levels, radiological imaging is required is for localization and operative planning. A neck ultrasound is most commonly used for initial localization, followed by a technetium-99m Sestamibi scan to further aid localization [Citation10]. There is limited radiological capability to differentiate malignancy, or malignant potential on localizing imaging, but CT may help in identifying local or distant metastasis [Citation11]. Carcinoma may be larger on imaging, without typical benign features (solid and homogenous) [Citation12]. PET-CT can be used both pre- and post-operatively in combination with other imaging modalities to further guide treatment and surveillance [Citation13]. Both cases demonstrate key radiological indicators for pre-operative parathyroid carcinoma diagnosis. In Case 1, internal calcifications are seen, which have been shown to be the only radiological parameter to be 100% specific for parathyroid carcinoma [Citation12]. Interestingly, in Case 2 cystic changes are seen which have been noted to be 82% sensitive, but only 62% specific for tumour differentiation [Citation12]. However there remains a paucity of evidence on the radiological features required to diagnose recurrence. When laboratory results indicant suggest recurrence, the most recent guidelines recommend two concordant localization studies prior to re-do surgery which can include any combination of sestamibi, ultrasound, CT, PET-CT or MRI [Citation9,Citation14]. In Case 1, we detail rare systematic radiological features, which raise the index of suspicion for metastases but in the clinical context, and the histological features benign brown tumours are diagnosed.
Surgery remains the mainstay of treatment. As of yet, there is no proven benefit to adjuvant chemotherapy or radiotherapy in the management of parathyroid carcinoma [Citation9]. While radical surgery (including parathyroidectomy, ipsilateral thyroidectomy and central lymph node dissection) is still considered the standard treatment for parathyroid carcinoma, there is now debate about the optimal surgical approach [Citation15,Citation16]. Recent studies have found no difference in overall survival when a local resection was performed rather than a more invasive lymph node dissection [Citation4]. We advocate for central neck dissection for two reasons. Firstly, lymph node dissection provides more accurate staging and thus prognostic information to guide post-operative management. Secondly, as it may be difficult to identify malignancy pre and intra-operatively, and combined with the knowledge that disease recurrence is most commonly locoregional (which can lead to re-operation and harbours a greater risk of complications), en bloc resection at initial operation remains the recommended treatment. Further work needs to be done to ensure this is the optimal approach.
Contributions
Writing: NJM, CM
Concept and editing: FOD, TM
Images: DTR, RK
Informed consent
This study was completed in accordance with standards of Ethics in Publishing. Informed consent to share case information and images was obtained from the patient.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Funding
The authors have no funding and financial relationships.
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