Giant parathyroid adenoma and challenges with preoperative differentiation from malignancy

Abstract

Giant parathyroid adenomas are rare and underreported benign tumours of parathyroid gland. Preoperative differentiation between giant parathyroid adenoma (GPA) and parathyroid carcinoma can be challenging, as they both may present as a large parathyroid tumour with hyperparathyroidism. Very few GPAs had been described in the literature, with only 60 cases including our present case. We report a case of GPA and the preoperative diagnostic challenges we faced in differential diagnosis of a potential parathyroid malignancy. As a parathyroid malignancy could not be excluded preoperatively the parathyroid tumour was excised en bloc with surrounding thyroid lobe. The histology was contributory to exclude parathyroid malignancy confirming a benign GPA.

Background

Primary hyperparathyroidism (PHPT) is caused by autonomous secretion of parathyroid hormone (PTH), with single gland adenomas accounting for around 80% of all cases of hyperparathyroidism.¹ It has long been observed that there exists a significant variation in the size of glands excised for PHPT. Parathyroid adenomas weighing more than 3.5 g or with size >3 cm have been termed as ‘giant parathyroid adenomas’ (GPAs).² The preoperative differentiation from parathyroid carcinoma could be challenging due to similar clinical and biochemical findings.^{3 4} GPAs are rare and we aimed to add our experience in management of this clinical entity.

Case presentation

A 67-year-old man initially presented acutely with poor mobility, fatigue, cognitive impairment and bony aches. Other than history of renal stones, his medical history was unremarkable. On physical examination, there was a unilateral midline neck swelling at the level of right thyroid lobe, with deviation of trachea to the left. There were no palpable enlarged cervical lymph nodes. There was no change of voice or altered swallowing.

With regards to the patient’s family history, his sister had previous history of thyroid surgery in the 1980s for a thyroglossal cyst within which papillary thyroid carcinoma was found. She had a subsequent thyroidectomy which was reportedly free of malignancy. Our patient had no other family history of thyroid or parathyroid conditions. He did not present with any focal bone lesions such as brown tumours.

Investigations

Laboratory results on admission showed a high serum corrected calcium level of 4.57 mmol/L (reference range 2.2–2.6 mmol/L) and significantly raised serum PTH level of 233 pmol/L (reference range 1.2–7.2 pmol/L). An acute kidney injury was diagnosed with elevated serum creatinine level of 335 µmol/L (reference range 64–111 µmol/L), with reduced estimated glomerular filtration rate (eGFR) of 16 mL/min (reference range 60–120 mL/min); patient’s baseline renal function was normal. His complete blood count and liver function test were within normal limits. He also had mildly insufficient 25-hydroxy-vitamin D at 35.9 nmol/L (reference range 71–200 nmol/L) on presentation.

He was managed initially with intravenous fluid hydration for 3 days when his serum adjusted calcium levels remained high at 4.4–4.57 mmol/L. His renal function improved during the rehydration, with serum creatinine level down from 335 µmol/L to 286 µmol/L and his eGFR up to 19 mL/min. Intravenous pamidronate infusion was given subsequently on day 4 of hospitalisation to reduce the serum adjusted calcium level from 4.57 mmol/L to 3.57 mmol/L, while the acute kidney injury was still present. He was also given vitamin D 3200 IU oral tablets preoperatively.

Ultrasound of his neck showed a large heterogeneous mass in the region below the lower pole of right thyroid, measuring up to 6 cm with extension below the clavicle. There were multiple cystic areas within the lesion, and vascularity was predominantly peripheral with appearance of an extrathyroidal vessel feeding the upper pole of the lesion suggesting parathyroid origin. The tumour was seen displacing the right lobe of thyroid anteriorly with no obvious infiltrative features. Margins of the tumour were regular with no obvious soft-tissue infiltration. There were no enlarged lymph nodes in the neck region. A CT scan of his neck also identified this large nodule in contact with the right thyroid lobe, with size of 4 cm×3.8 cm×3.2 cm and displacing the trachea to the left (figures 1 and 2).

Figure 1.

Preoperative CT scan (axial view) of neck and thorax. The right neck tumour (red arrow) was demonstrated measuring 4.0×3.8×3.2 cm with adjacent thyroid tissue. The neck mass was deviating but not constricting the trachea.

Figure 2.

Preoperative CT scan (coronal view) of neck and thorax; red arrow at the right neck tumour.

Differential diagnosis and treatment

Because of the acute condition, he underwent an urgent neck exploration and removal of right neck tumour under general anaesthesia. Following a midline horizontal neck incision, strap muscles were divided on the right. A large parathyroid tumour adherent to a hypoplastic thyroid gland was identified. As a malignancy could not be excluded in preoperative planning, the oversized parathyroid tumour was excised en bloc with the attached right thyroid lobe (figure 3). Intraoperative PTH monitoring confirmed the excision of the parathyroid adenoma as the PTH level dropped from a baseline pre-excision level of 265 pmol/L to 32.4 pmol/L 20 min after removal of the parathyroid tumour. The recurrent laryngeal nerve was preserved with with good signal on neuromonitoring. A size 10 Redivac drain was placed and a layered wound closure was performed.

Figure 3.

Demonstrating the specimen from the en bloc excision of right giant parathyroid adenoma (GPA) and thyroid lobe: well-circumscribed nodule (71 mm×46 mm×38 mm, weight 52 g) with a solid and cystic appearance. The GPA was abutting a hypotrophic right thyroid lobe. Short marking stitch is at superior pole of parathyroid tumour, long marking stitch is placed at thyroid isthmus.

Histopathology of the surgical specimen reported a nodular tissue with dimensions of 71 mm×46 mm×38 mm and weight of 52 g (figure 3). Microscopically, the nodule was composed of cellular parathyroid tissue with a thin fibrous capsule. There was prominent intralesional haemorrhage resulting in cystic degeneration. The cells showed moderate nuclear pleomorphism. Occasional mitotic figures were identified. There was no evidence of direct extension beyond the capsule into adjacent connective tissue. Occasional fibrous bands were seen within the lesion, but these were not particularly prominent. No evidence of vascular invasion was identified. Connective tissue between the parathyroid neoplasm and the thyroid gland was seen, mainly composed of skeletal muscle, with no evidence of invasive disease and normal thyroid tissue (figures 4 and 5). The overall appearances were suggestive of a parathyroid neoplasm, with a differential diagnosis between adenoma and carcinoma. The patient’s serum PTH level normalised and decreased to 7 pmol/L 24 hours after tumour removal. This case was discussed in multidisciplinary team meeting, with conclusion that the histological features met the criteria for a benign GPA rather than carcinoma despite the high calcium and PTH levels.

Figure 4.

H&E staining staining of parathyroid adenoma with circumscription, thin fibrous capsule (arrow), cellular nature and extensive central haemorrhage (*). Low-power (×40 magnification) photomicrograph.

Figure 5.

H&E staining staining of parathyroid adenoma with relatively uniform nature of the chief cells (arrow) with a predominantly microfollicular architecture (*). High-power (×200 magnification) photomicrograph.

Outcome and follow-up

The patient recovered well from the surgery and was discharged on the third postoperative day with normal serum PTH and calcium levels. The patient was discharged on vitamin D 400 IU oral tablets twice daily, and his vitamin D level was normalised to 80.8 nmol/L (reference range 71–200 nmol/L) 4 months after the operation. The adjusted calcium levels remain within normal range up to present 10 months postoperation. The preoperative significantly elevated PTH serum level normalised after tumour removal; however, it was slightly elevated and remained at 12.5 pmol/L (reference range 1.2–7.2 pmol/L) during the follow-up period.

Although hungry bone syndrome could have been an expected postoperative side effect,⁵ given the high level of the parathyroid hormone preoperatively, it was not observed in this case.

Genetic test for the HRPT2 (CDC73) gene was offered to the patient in the outpatient setting and results are still pending.

Discussion

In view of the rarity of GPA, in this report we highlight the clinical and biochemical aspects of GPA with diagnostic challenges in differentiating GPA from parathyroid carcinoma.

In primary hyperparathyroidism, serum calcium is increased due to various mechanisms: osteoclastic bone resorption, increase in renal tubular reabsorption of calcium and stimulation of the formation of 1,25-dihydroxyvitamin D which increases intestinal calcium absorption. Bisphosphonates that inhibit osteoclast activity affect one of the many sites of PTH action, in some patients leading to a poor response in serum calcium levels.^{6 7} However, in our patient, his preoperative serum adjusted calcium levels only dropped slightly after administration of pamidronate.

On the other hand, vitamin D (25-hydroxyvitamin D) insufficiency is common in primary hyperparathyroidism⁸ and is more commonly seen in patients with larger parathyroid adenomas. It is postulated to be associated with accelerated catabolism of 25 hydroxyvitamin D by increased concentrations of PTH and 1,25-dihydroxyvitamin D.^{9 10} Our patient had vitamin D deficiency preoperatively; however, it was unlikely to be the main contributor to his presentation.

After the operation, our patient had mildly elevated PTH during the follow-up period; this phenomenon was reported to occur in 27% of patients following a curative parathyroidectomy and was usually a transient phenomenon more common in patients with musculoskeletal symptoms.¹¹ It was not a manifestation of persistent disease but was most likely a secondary response to bone remineralisation. Persistently elevated PTH levels with normocalcaemia had previously been documented following parathyroidectomy for primary hyperparathyroidism. It had been referred to as postoperative secondary hyperparathyroidism, implying that it occurs as a result of a compensatory response to an abnormality in calcium homeostasis. However, the pathogenesis of this phenomenon had not been clearly elucidated.

Preoperative differentiation between GPA and parathyroid carcinoma (PC) could be challenging, as they both may present as a large parathyroid tumour with hyperparathyroidism and hypercalcaemia.^{3 4} There had been controversy on the relationship between tumour size and hyperparathyroidism.^12–14 Furthermore, non-functional GPA or PC had been reported; however, these are rare entities.^{4 15–19} Histological differentiation between PC and GPA can be challenging without obvious invasion of adjacent structures.³ Preoperative parathyroid fine-needle aspiration is not recommended and is associated with risks of tumour seeding, histological alteration and parathyromatosis,^20–22 especially in clinically suspected parathyroid carcinoma. Current surgical recommendation for parathyroid carcinoma is en bloc resection of the tumour with removal of the ipsilateral hemi-thyroid and any other involved tissues.

The diagnosis of PC defined by WHO is a H&E stain diagnosis. The features that would indicate a carcinoma are (1) unequivocal invasion into adjacent soft tissues, muscle or other adjacent organs; (2) lymphovascular invasion; (3) perineural invasion; and/or (4) presence of distant metastases. Parathyroid neoplasms that show more histologically worrisome features but do not fulfil the more robust criteria of invasion or metastases are classified as atypical parathyroid adenomas or parathyroid neoplasm of uncertain malignant potential.^23–25 Removal of parathyroid tumour and subsequent histology are therefore contributory to diagnosis and treatment. Ancillary immunohistochemistry tests have been tested for diagnosis of PC. The loss of staining for parafibromin, a product of the HRPT2 gene involved in the pathogenesis of PC has a sensitivity of 67%–96% and a specificity of 99% for the diagnosis of PC. However, parafibromin immunohistochemistry is not widely available and was regarded as technically difficult to perform and interpret.²⁶ Parafibromin staining of the specimen was not performed for this patient but HRPT2 (CDC73) genetic testing was offered to the patient. For the patient’s family history, his sister had previous thyroid surgery for a thyroglossal cyst rather than calcium related disorder and thus was not deemed to be linked to the patient’s disease.

Finally, the distinction of GPAs as a separate clinical entity had not been much investigated. Several case series had supported the hypothesis that GPAs might represent a distinct clinical entity² with specific genomic aberrations.²⁷ Further cases need to be reported to understand the clinical and biochemical presentation of this rare parathyroid tumour.

Learning points.

• Giant parathyroid adenomas (GPAs) are rare and underreported benign tumours of parathyroid gland.

• Preoperative differentiation between GPAs and parathyroid carcinoma can be challenging.

• Removal of parathyroid tumour and subsequent histology are contributory to diagnosis and treatment.

• Fine-needle aspiration for parathyroid lesion is associated with several innate risks; it is not recommended especially when parathyroid carcinoma is suspected.