Parathyroid carcinoma. Mini-series of patients successfully treated with minimally invasive surgery using intra-operative PTH assays, and literature review.

OO Komolafe, AG McMinn, JC Doughty, CR Wilson

Corresponding author: Mr Segun Komolafe – segun.komolafe@ggc.scot.nhs.uk

 Department of SurgeryWestern Infirmary Dumbarton Road Glasgow G11 6NT

^{SMJ 2009 54(2): 58}

Abstract

Parathyroid cancer is a rare cause of primary hyperparathyroidism, with a surgeon anecdotally expected to see a single case in his/her entire career. In our unit, however, we have treated three patients recently. The accepted optimal treatment of parathyroid cancer is radical resection at the initial surgery, but a low index of suspicion means that most parathyroid cancers are not identified pre- or intra-operatively. This results in the majority of patients having inadequate surgery. All three patients were treated by minimally invasive surgery, with radical en bloc resection based on intra-operative suspicion of malignancy. Pre-operative imaging guides the neck exploration, and intra-operative PTH assays confirm excision of the source of excess PTH. All patients have remained well with no recurrence to date. We review the literature on parathyroid cancer, and suggest features that point to a parathyroid tumour being malignant.

Key phrases: parathyroid cancer, intra-operative PTH, hyperparathyroidism, hypercalcaemia, parathyroidectomy

Abbreviation: PTH – Parathyroid Hormone

A 51 year old female (A) presented to her GP with vague symptoms and general malaise. Investigations revealed a serum calcium of 3.47 mmol/L, but no palpable neck lumps. She was referred to our unit, where she had a technetium 99m (Sestimibi) scan. This showed an enlarged parathyroid at the lower pole of the right thyroid lobe. Surgery revealed a large right retrosternal parathyroid, with clinical appearance of carcinoma so en bloc resection was performed. Pre-operative venous PTH sampling was 80 pmol/L, and dropped by 78% to 18 pmol/L after excision of the mass. On pathological examination, the sample was confirmed as parathyroid carcinoma, with no evidence of vascular or capsular invasion.

A 55 year old lady (B) presented with a two week history of vomiting, thirst and lethargy. She also gave a three year background history of constipation, nausea, polydipsia, anorexia and low mood. Routine bloods revealed a serum calcium of 3.94 mmol/L and PTH of 57.4 pmol/L. A palpable mass was present in left hand side of her neck and an ultrasound scan showed a 3.5cm lesion inferior to the lower pole of the thyroid gland. Neck exploration revealed a large inferior parathyroid. En bloc dissection was carried out to remove the left thyroid lobe, strap muscles and all the tissue medial to the carotid sheath. Her pre-operative PTH had fallen by 86% from 57.4 to 8 pmol/L once the gland had been removed. Histology confirmed parathyroid carcinoma with capsular and vascular invasion.

A 31 year old lady (C) presented as an emergency with renal colic. She was found to have a small right ureteric stone with a serum calcium of 3.7mmol. On examination of her neck there were no palpable masses. An ultrasound and sestamibi scan showed a well defined 2.4cm low echo nodule posterior to the lower pole of the left lobe of the thyroid. Surgery revealed an enlarged inferior parathyroid. Her pre-operative PTH was 116.6 pmol/L, this dropped to 7.2 pmol/L (a 94% fall) after removal of the gland. Histology of the sample showed early cancerous change.

Discussion

Parathyroid carcinomas are extremely rare tumours and account for 1% to 2% of primary hyperparathyroidism¹. The first patient recorded as having a functioning parathyroid carcinoma was in 1933², and since then over 700 patients worldwide with the disease, have been noted in the available literature^3,4. Functioning cancers are slow growing tumours and produce excess amounts of PTH, which leads to hypercalcaemia and usually manifest as bone and renal disease. The carcinomas have an equal distribution between each gender, compared to benign parathyroid tumours which are more prevalent in females.  Most cancers clinically present between 40 and 60 years, which is a decade, on average, earlier than benign tumours⁵. There is a global variation in incidence: in Japan 5% of patients with primary hyperparathyroidism have parathyroid cancer, compared to rates of <1% in Europe and USA. Currently there are no explanations for these variations but suggest genetic and environmental influences^{6, 7}.

The aetiology of parathyroid carcinoma is an area of great debate and uncertainty. Benign tumours have been linked to inadequate sun exposure, but this can not be correlated to carcinomas^{8, 9}.There are weak associations with radiation exposure to the neck^1,7. There is an increased risk of carcinoma in patients who have familial hyperparathyroidism, with particular interest in hereditary hyperparathyroidism jaw tumour syndrome 4. This autonomic dominant disease is clinically associated with parathyroid and fibro-osseous tumours of the mandible and maxilla¹⁰. The tumour suppressor gene HRPT2 has been associated with this rare syndrome and may be of pathogenetic importance.  HRPT2 encodes the protein parafibromin, and it has been hypothesized that a loss of parafibromin may be a predictor of parathyroid carcinoma¹¹.

Patients with parathyroid cancer commonly present with clinical features which are secondary to hypercalcaemia, rather than direct expansion of the tumour leading to compressive symptoms. However, patients with benign parathyroid disease also have non-specific features such as anorexia, weight loss, fatigue^12,13. Parathyroid carcinomas are palpable in 30% to 76% of cases¹³. Benign parathyroid adenomas are typically non-palpable, and arguably, one feature that ought to raise suspicions about parathyroid malignancy, is a palpable neck lump in the presence of primary hyperparathyroidism. Another pathognomonic feature is primary hyperparathyroidism with recent voice changes, due to tumour invasion of laryngeal nerves.

Although there have been reports of multi-glandular involvement¹⁴ parathyroid cancer is usually limited to a single gland. The inferior glands are the most commonly affected with ongoing debate as to whether the right or left side has a greater dominance¹³. Carcinomas appear irregular, firm tumours with a pale grey to dirty white colour while adenomas are regular, oval appearance and light reddish brown in colour with a well defined capsule. Carcinomas may however invade the adjacent thyroid gland, strap muscles, recurrent laryngeal nerve, oesophagus and trachea. On microscopic examination carcinoma cells can be arranged in trabecular, solid or acinar patterns. Histological cell types include chief cell (most common), transitional clear cell, and mixed cell types. The cell type is not known to be of prognostic significance.

In order to differentiate between parathyroid carcinomas and adenomas a histopathological criterion was defined in 1973 by Schantz and Castleman¹⁶. The following features are observed in carcinomas: fibrous trabeculae, mitotic figures, capsular or vascular invasion, and the presence of mitoses in parrenchymal cell, which is thought to be the single most pathognomic feature. However, mitotic activity can also be seen in adenomas and hyperplastic glands, and even in carcinoma, mitotic activity can be low.  Higher levels of mitotic activity are associated with poorly differentiated tumours and poor prognosis¹⁷. Inactivation of the retinoblastoma tumour-suppressor gene has been reported in malignant tumours, but not in benign adenomas¹⁸.This finding may prove to be of diagnostic and prognostic value in the future.

It is notoriously difficult to preoperatively diagnose parathyroid carcinoma. It is preferable therefore to suspect parathyroid carcinoma rather than fail to diagnose it, in patients who present with adverse features.  Diagnosis has been reportedly missed in up to 86% of cases at the time of initial surgery¹⁹. Fine needle aspiration cytology of the suspected cancer is not advised as it can be difficult, sampling errors can lead to false negatives, and there is a risk of track seeding^20,21. Imaging such as ultrasound, CT, MRI and sestamibi scanning are not diagnostic, but are useful to investigate suspected carcinomas with a view to planning curative resection. Ultrasound and sestamibi scanning are the recommended means of assessing the first presentation of a parathyroid lesion. Sestamibi in particular has a high sensitivity and specificity rate at localizing abnormal parathyroid tissue^{21, 22}.

The most effective treatment of parathyroid carcinoma is en bloc resection of the primary lesion – removal of the parathyroid gland along with the ipsilateral thyroid lobe and adjacent structures. Patients who have en bloc resection have a longer disease-free period and overall survival than those who have a lesser procedure^{7, 23}. Since the majority of patients undergo the surgery with the presumption that they have benign hyperparathyroid disease, the surgeon must be vigilant about the distinguishing macroscopic features of parathyroid carcinomas. After surgery all patients require long-term biochemical surveillance to monitor serum calcium and PTH levels for recurrence. Although parathyroid carcinoma is a slow growing tumour, it has a propensity to recur, both locally and distally, with a recurrence rate as high as 50% in some series⁸. Metastatic disease is most commonly found in the regional lymph nodes, with distant metastases following a haematogenous route, to the lungs, bones, and liver²⁴.

Those most at risk of recurrence are patients who present with either multiple endocrine adenomatosis type I or familial hyperparathyroidism. The majority of recurrences occur within 3-5 years (with a range of 1-20 years) of initial surgery^{25, 23}. Earlier recurrence carries a poorer prognosis. As with the initial presentation of parathyroid carcinoma, the most effective treatment is surgery ²⁵. The goal of salvage surgery is to decrease the tumour burden, aiming to control hypercalcaemia as most deaths are caused by hypercalcaemic crisis. Aggressiveness of surgery has been shown to be an independent prognostic factor for outcome: patients treated with more extensive surgery have a longer survival and a longer relapse-free period than patients treated with tumour resection alone²⁶. In a series of 286 patients, the overall survival at 5 years and 10 years was 85% and 49% respectively¹⁹. There is little evidence to prescribe a definite role for adjuvant chemotherapy or radiotherapy, although post-operative radiotherapy may reduce the risk of recurrence ²⁷.

In our unit, a minimally invasive method is used for parathyroid surgery: all three patients had a small collar incision, through which en bloc resection was performed. As PTH has half life of minutes, intra-operative assays confirm excision of the source of excess hormone. Histology of the specimen confirmed complete excision in all three. The patients have remained well with no recurrence to date at 33 (A), 37 (B), and 65 (C) months follow-up (table I). 

Table I: Summary of the three cases.

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