Case report
Simultaneous presentation of parathyroid carcinoma, papillary thyroid cancer and ACTH-independent hypercortisolism due to benign cortical adenoma
Ovie Edafe,1 Miguel Debono,2 Fawzia Tahir,3 Sabapathy P Balasubramanian® 2,4
1ENT, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
2Oncology and Metabolism, University of Sheffield, Sheffield, UK
3Histopathology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK 4General Surgery, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
Correspondence to Sabapathy P Balasubramanian, s.p.balasubramanian@sheffield. ac.uk
Accepted 3 August 2019
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To cite: Edafe O, Debono M, Tahir F, et al. BMJ Case Rep 2019;12:e230438. doi:10.1136/bcr-2019- 230438
SUMMARY
A 46-year-old woman presented with hypertension and renal disease. Investigations showed severe hypercalcaemia due to primary hyperparathyroidism. Imaging demonstrated renal calculi and an incidental left adrenal lesion. Additional biochemistry confirmed adrenocorticotropic hormone-independent hypercortisolism. Ultrasound and sestamibi scan found an enlarged right-sided parathyroid gland and a suspicious right thyroid nodule, biopsy of which suggested papillary carcinoma. The right parathyroid mass, right thyroid lobe and right central compartment tissue along with a segment of the right recurrent laryngeal nerve was resected en-bloc. Completion thyroidectomy and left adrenalectomy were performed 6 months later. Histology showed parathyroid cancer, multifocal papillary thyroid cancer and adrenal clear cell cortical adenoma. Genetic tests were normal. There was no evidence of recurrence at 12 months follow-up. Parathyroid cancer should be suspected in the presence of significant hypercalcaemia, very high parathyroid hormone and end organ damage. Suspicious thyroid nodules on imaging should be appropriately investigated.
BACKGROUND
Parathyroid carcinoma is rare.1 Synchronous presentation of thyroid and benign parathyroid pathology are well documented2; however, simul- taneous parathyroid cancer and thyroid cancer are extremely rare.3 The synchronous presentation of parathyroid carcinoma, papillary thyroid carcinoma (PTC) and cortisol-secreting adrenal adenoma has not been previously reported.
CASE PRESENTATION
A 46-year-old woman initially presented to the nephrology unit with longstanding hypertension and progressive chronic renal impairment. She was referred to the endocrine surgical unit after severe hypercalcaemia was detected as part of initial workup. There was no history of neck surgery or exposure to radiation. There was no history of thyroid dysfunction, hyperlipidaemia, diabetes mellitus or osteoporosis. There was no family history of endocrine disease. She was taking rami- pril for hypertention. Clinical examination of her neck was normal. There were no clinical features of Cushing’s disease.
INVESTIGATIONS
Following presentation, the patient was detected to have severe hypercalcaemia (corrected calcium >3 mmol/L) due to primary hyperparathy- roidism (parathyroid hormone (PTH) 65 pmol/L). Further assessment included a 24 hour urine collec- tion for catecholamines and metanephrines, thyroid function tests and vitamin D levels, which were all normal.
Ultrasound of the renal tract showed bilateral renal cyst and calculi. A CT scan of the urinary tract for further evaluation found an incidental 16mm left adrenal lesion (figure 1). A low dose overnight dexamethasone suppression test confirmed adreno- corticotropic hormone (ACTH)-independent hyper- cortisolism (cortisol 412 nmol/L (reference range: 133-537), ACTH <5 (reference range: < 46 ng/L)).
Sestamibi scan demonstrated uptake in a large right-sided parathyroid gland. Ultrasound neck showed a large right-sided parathyroid gland (maximum diameter of 3.34cm) (figure 2), a malignant appearing in the right thyroid nodule (maximum diameter of 1.82cm) and another nodule in the left thyroid lobe (maximum diameter of 1.28 cm). Fine needle aspiration and cytology were done on the right thyroid nodule which confirmed PTC (Thy5). Preoperative laryngoscopy showed normal bilateral vocal cord movement.
The patient was screened for multiple endo- crine neoplasia (MEN)1, MEN2 and hyperpara- thyroidism-jaw tumour (HPT-JT) syndromes. The following genes were analysed by gene sequencing and dosage analysis: AIP, CASR, CDC73, CDKN1B, MEN1, PRKAR1A and RET. No pathogenic muta- tion was identified. Whole genome sequencing as part of the 100, 000 Genome Project did not iden- tify any underlying genetic cause.
DIFFERENTIAL DIAGNOSIS
The differential diagnosis of the enlarged parathy- roid gland includes parathyroid cancer and a large parathyroid adenoma or atypical adenoma.
TREATMENT
At neck exploration, a densely fibrotic, infiltrating right-sided parathyroid mass was found adjacent to a dominant thyroid nodule in the right lobe with no discernable planes between the two. The right recurrent laryngeal nerve was seen extending into the mass and was clearly involved. Continuous
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intraoperative nerve monitoring was used, and signal was lost during dissection. An en-bloc resection of the lesion along with the right hemithyroid and ipsilateral central compartment lymph nodes was performed. The proximal and distal ends of the right recurrent laryngeal nerve were brought together and an end-to-end anastomosis of the free ends was done. The left side was not explored at this stage in view of the uncertain nature of the underlying pathology and the expected right vocal cord paresis. The patient recovered uneventfully after surgery and was discharged on the second postoperative day. Histology demonstrated classical PTC (pT3N1a) and parathyroid carci- noma with soft tissue invasion beyond capsule (figure 3) and perineural invasion (figure 4). Both tumours were fully excised. Postoperatively, the patient had a weak voice and flexible laryn- goscopy showed right vocal cord palsy.
Left completion thyroidectomy and left adrenalectomy were performed 6 months later to allow time for nerve palsy to improve. Intraoperative nerve monitoring was used. Histology revealed another focus of PTC in the contralateral lobe and a clear cell cortical adenoma in the left adrenal gland. There was an immediate postoperative neck haematoma after extubation which was promptly re-explored and evacuated. The patient subsequently made an uneventful recovery and was discharged 3 days after surgery. Her voice was normal following surgery. There was no sign of aspiration. Flexible laryngoscopy 2 months after surgery showed persistent right vocal cord palsy, normal left vocal cord movement and good glottic closure. Histology demonstrated another focus of PTC in the contralateral lobe and a clear cell cortical adenoma in the left adrenal gland. Radio-io- dine ablation was done 4 months after the second operation.
OUTCOME AND FOLLOW-UP
At 12 months after radio-iodine ablation, the patient is clinically well and asymptomatic. Her renal function was stable with an estimated glomerular filtration rate of 37mL/min/1.73 m2 (32 at presentation). A post ablation follow-up ultrasound of the
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neck showed no evidence of recurrence. Thyroglobulin antibody levels, adjusted serum calcium and PTH were all normal.
From an adrenal perspective, the patient required steroid replacement for contralateral adrenal suppression for around 1 year after surgery. She was subsequently weaned off the steroid successfully and had a normal short Synacthen test 12 months after adrenal surgery.
DISCUSSION
To our knowledge, this combination of conditions is not consis- tent with any known genetic syndrome.
MEN1 classically presents with tumours in the parathyroid, pancreas and pituitary glands but can involve other endocrine organs.
ACTH secreting pituitary adenoma is the most common cause of hypercortisolism in patients with MEN1.4 Most adrenocor- tical tumours in MEN1 are non-functioning. Hypercortisolism as a result of adrenal tumour has been reported in MEN1.5 Primary hyperparathyroidism due to secreting parathyroid tumours occurs in around 95% of patients with MEN1.6 Parathyroid carcinoma in MEN1 is rare.6 The combination of parathyroid carcinoma and non-functioning adrenal adenoma has also been reported in a patient with MEN1.7 In addition, PTC has been reported to occur in patients with MEN1.68 Given the relatively high prevalence of thyroid disorders in the general population, it has been suggested that this association is incidental.6
MEN 2A is characterised by medullary thyroid cancer (MTC), phaeochromocytoma and hyperparathyroidism. Some patients also develop skin lesions (cutaneous lichen amyloidosis), promi- nent corneal nerves or Hirschsprung’s disease.9 MEN2B is char- acterised by MTC, phaeochromocytoma, Marfanoid appearance, typical facies, widespread ganglioneuromatosis, musculoskeletal and ocular abnormalities.9 HPT-JT syndrome is characterised by
Learning points
A very high serum calcium, parathyroid hormone with significant end organ damage should raise the suspicion of parathyroid carcinoma.
Parathyroid carcinoma is often suspected during or diagnosed after surgery.
Intraoperative suspicion of parathyroid cancer should lead to an en-bloc resection at the first operation to ensure optimum outcomes.
hyperparathyroidism (parathyroid adenoma or carcinoma), ossi- fying fibromas of the jaw, renal lesions and uterine tumours.10
A review of literature demonstrated that at least 23 other cases of synchronous parathyroid carcinoma and non-medullary thyroid carcinoma have been reported.3 11-17 Reported patients have been mostly women (75%) with a mean age of 52 years. Most patients presented with elevated serum calcium and PTH. The diagnosis of parathyroid cancer was often made based on intraoperative suspicion or postoperative histology. Most patients underwent resection of the parathyroid mass with bilateral thyroidectomy (as one or two-staged procedures). Some patients (n=10) also under- went central neck dissection. Synchronous thyroid cancer was often found incidentally on postoperative histology. One patient had persistent hypercalcaemia and one had recurrent parathy- roid disease 4 years following treatment.12 18 Three deaths were reported as a result of metastatic parathyroid carcinoma and treat- ment-resistant hypercalcaemia.
In the present patient, the parathyroid tumour involved the right recurrent laryngeal nerve and this was sacrificed to facilitate an en-bloc resection to achieve clear margins. Resection of the recur- rent laryngeal nerve due to tumour involvement was reported in another patient.3 However, recurrent laryngeal nerve involvement or function was not reported in the other published reports.
Hypercalcaemia may be persistent following en-bloc resection of the parathyroid mass due to persistent local or metastatic disease or associated contralateral multigland disease.3
Adrenal incidentaloma is found in 4% of CT scans not done for suspected adrenal disease.19 It occurs more often with increasing age; peak incidence at the fifth to seventh decades.20 The pres- ence of hypercortisolism varies depending on the definition used may be seen in up to 47% of cases of adrenal incidentaloma.21 A complete adrenal workup includes assessment of cortisol, aldo- sterone, catecholamine and metanephrine levels.22
This present case shows an unusual combination of parathy- roid cancer, clinically significant multifocal thyroid cancer and adrenal tumour. To our knowledge, this has not been reported previously.
Patient presenting with significant hypercalcaemia, very high PTH with significant end organ damage should raise a clinical suspicion of parathyroid cancer. Parathyroid cancer is rare and often suspected intraoperatively by an experienced surgeon. Intraoperative suspicion of parathyroid cancer should lead to an en-bloc resection (including ipsilateral lobectomy ± level VI dissection) even in the absence of a definitive histological diagnosis, as surgery is currently the only effective treatment and complete resection at the first operation is associated with improved disease-free survival and lower recurrence rates.23 A detailed discussion in a multidisciplinary setting is essential for optimum management of these patients.
Contributors OE: acquisition, analysis, interpretation of data; drafting the paper; approving the submitted version; agreed accountability to all aspect of the work. MD: interpretation of data; revising paper critically; approving the submitted version; agreed accountability to all aspect of the work. FT: analysis, interpretation of data; revising paper critically; approving the submitted version; agreed accountability to all aspect of the work. SPB: conception of work; interpretation of data; revising paper critically; approving the submitted version; agreed accountability to all aspect of the work.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient consent for publication Obtained.
Provenance and peer review Not commissioned; externally peer reviewed.
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