Parathyroid Carcinoma Presenting as Recurrent Primary Hyperparathyroidism and Neck Mass: A Case Report

Parathyroid carcinoma is a rare endocrine neoplasm that accounts for <1% of cases of primary hyperparathyroidism. The management of parathyroid carcinoma is a challenge due to the high rate of local recurrence of the tumour. We report the case of a middle-aged north Indian woman who presented with recurrent primary hyperparathyroidism due to parathyroid carcinoma. She presented with a recurrent palpable hard neck mass and underwent radical dissection of the neck six times. At the time of writing this report, she was referred for external beam radiotherapy to the neck. Parathyroid carcinoma is a rare malignancy with an indolent but tenacious course. Complete resection at the time of initial surgery determines the prognosis of the neoplasm. Chemotherapy and radiotherapy are usually ineffective. Hypercalcaemia needs to be aggressively managed. A multidisciplinary team is required to effectively manage parathyroid carcinoma.


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arathyroid carcinoma is a rare endocrine neoplasm that accounts for <1% of cases of primary hyperparathyroidism.The management of parathyroid carcinoma is a challenge due to the high rate of local recurrence of the tumour.We report the case of a middle-aged north Indian woman who presented with recurrent primary hyperparathyroidism due to parathyroid carcinoma.She presented with a recurrent palpable hard neck mass and underwent radical dissection of the neck six times.At the time of writing this report, she was referred for external beam radiotherapy to the neck.Parathyroid carcinoma is a rare malignancy with an indolent but tenacious course.Complete resection at the time of initial surgery determines the prognosis of the neoplasm.Chemotherapy and radiotherapy are usually ineffective.Hypercalcaemia needs to be aggressively managed.A multidisciplinary team is required to effectively manage parathyroid carcinoma.
Parathyroid carcinoma is a rare endocrine neoplasm with an incidence of 0.5-2.0% of all cases of primary hyperparathyroidism (PHPT). 1 It was first described in 1904 by de Quevain, when it was found in a patient presenting with a non-functioning parathyroid mass. 2 Around 26 years later, Sainton and Millot described the first functioning parathyroid carcinoma. 3ere is no known predisposing factor for parathyroid carcinoma.
Patients usually present in their 50s, which is a decade earlier than is usual for benign parathyroid adenomas. 1Men and women are equally affected by parathyroid carcinoma, unlike in benign PHPT, which is 3-4 times more common in women. 1 Parathyroid carcinoma may occur sporadically or may be a result of a genetic syndrome such as autosomal dominant isolated familial hyperparathyroidism. 4 It can also be seen in 15% of cases of hyperparathyroidism-jaw tumour syndrome due to mutation in the hyperparathyroidism 2 (HRPT2) gene encoding the protein parafibromin. 5In addition, other chromosomal abnormalities identified are reciprocal translocation between chromosomes 3 and 4, trisomy 7, loss of chromosome 13q, pericentric inversion of chromosome 9, and somatic mutations of genes such as cyclin D1 (CCND1), retinoblastoma (RB) and tumour protein P53 (TP53). 5The genetic syndromes of multiple endocrine neoplasia type 1 (MEN1) and type 2A (MEN2A) are usually not associated with parathyroid carcinoma. 5rathyroid carcinoma may mimic benign cases of PHPT and cause diagnostic challenges. 6Preoperatively, it may be difficult to distinguish between benign and malignant cases based on history and imaging.Even in histopathology, it may be difficult to distinguish parathyroid carcinoma from atypical parathyroid adenoma.Managing parathyroid carcinoma is also difficult, since there is a high recurrence rate with no definitive role for radiotherapy or chemotherapy.
In this case report, we describe a patient with a history of recurrent PHPT due to parathyroid carcinoma.We aim to increase awareness of the DOI: http://doi.org/10.17925/EE.2023.19.2.6  touchREVIEWS in Endocrinology challenges encountered in parathyroid carcinoma and to highlight the importance of a thorough and individualized approach.This report also contributes to the limited medical literature on parathyroid carcinoma and provides valuable insights for healthcare professionals, who may encounter similar cases in their practice.

Case report
A 55-year-old woman from north India presented to our endocrine clinic with a history of recurrent neck mass for the past 6 years.It started as a small hard nodule in the front of her neck that rapidly progressed in size.There was no pain, redness, fever, difficulty in swallowing, difficulty in breathing, stridor or hoarseness of voice.The mass did not move with deglutition or with the movement of the tongue.Laboratory investigations suggested PHPT with elevated serum calcium of 3.62 mmol/L (normal range [N]: 2.12-2.62mmol/L) and elevated serum intact parathyroid hormone (iPTH) of 142.21 pmol/L (N: 1.59-6.89pmol/L).She underwent the first surgical resection of the mass 6 years ago, and the histopathology confirmed a diagnosis of parathyroid carcinoma.
Around a year after the first surgery, the mass recurred in the same region of the neck.It again progressed rapidly in size and was hard in consistency.Biochemically, she again had PHPT.She underwent a second surgery, which was followed by a relapse 6 months later.In this manner, over the course of 6 years, she underwent five neck surgeries, which involved radical neck dissection with the removal of the entire mass, the thyroid with both its lobes and isthmus, and all the parathyroid glands along with lymph node dissection.
The current presentation was the recurrence of the neck mass for the sixth time (Figure 1a and b).On examination, it was a large mass of 5 × 4 cm that involved the anterior aspect of the mid and left side of the neck and extended inferiorly into the anterior part of the sternum.It was hard in consistency and did not move with deglutition or protrusion of the tongue.It was non-tender and there was no redness or ulceration of the skin over the mass.Scars from previous surgeries were evident and were clean.Systemic examination was normal with no localized bone tenderness.Her height was 172.7 cm and weight was 85.0 kg with a body mass index of 28.8 kg/m 2 .
In this presentation, the patient also reported a loss of appetite for 2 months.She had multiple episodes of vomiting during the 2 weeks prior to admission, along with vague abdominal pain and constipation.For the past 6 years, she experienced diffuse musculoskeletal pain and low backache.There was no history of weight loss, fracture, bone deformity or proximal myopathy.She had a history of recurrent renal stones and had undergone percutaneous nephrolithotomy three times previously.1).Urine routine examination was normal, while 24 h urinary calcium was 15.0 mmol/24 h (N: 2.5-7.5 mmol/24 h).Thyroid function tests were normal: thyroxine was 104.One week after surgery, the patient's serum calcium was 1.97 mmol/L and iPTH was 8.64 pmol/L (Table 1).She was started on calcium supplements with 1 g of elemental calcium and 60,000 IU of cholecalciferol once a week for 8 weeks.At the time of writing this report (four weeks after surgery), after discussion with a multidisciplinary team, the patient was planned for external-beam radiotherapy to prevent local regrowth of the tumour.

Discussion
The current case represents a unique clinical presentation of recurrent PHPT due to parathyroid carcinoma.A palpable neck mass has been reported in 30-76% of patients with parathyroid carcinoma. 1Clinically, there is no definitive symptom or sign that can differentiate between benign PHPT and parathyroid carcinoma.Usually, patients with parathyroid carcinoma tend to have more severe skeletal and renal symptoms due to a more severe degree of hypercalcaemia. 7case series has reported a prevalence of nephrolithiasis in 56% and renal insufficiency in 84% of patients with parathyroid carcinoma. 8The classical radiological manifestations of skeletal involvement like osteitis fibrosa cystica, salt and pepper appearance of the skull, subperiosteal resorption of phalanges, and loss of lamina dura of the teeth are more commonly seen in parathyroid carcinoma, although they may be present in severe benign PHPT, particularly in developing countries. 7In our patient, renal involvement was predominant with recurrent renal stones,  9 It is recommended to measure mitotic activity per high power field and Ki-67 labelling index in parathyroid carcinomas. 9In our patient, the mass invaded adjacent structures, although there was no distant metastasis.The tumour specimen also demonstrated a high mitotic index, suggestive of its malignant potential.
The management of parathyroid carcinoma is an arduous task. 10mplete surgical resection with tumour-free margins offers the best possible cure.Certain intra-operative findings may arouse suspicion of parathyroid carcinoma, such as large size, greyish to whitish colour and adherence to adjacent structures like the strap muscles, thyroid gland, recurrent laryngeal nerve, trachea or oesophagus. 10Upon recognizing malignant features during surgery, the surgeon should perform en bloc resection of all the tissues involved by the tumour, taking great care not to breach the tumour capsule. 10It has been recommended to remove the adjacent thyroid lobe; however, previous studies show that this does not improve survival in parathyroid carcinoma. 11,12 the immediate post-operative period, if the histopathology suggests parathyroid carcinoma and the patient remains hypercalcaemic, re-exploration of the neck may be required. 10If the patient attains normal serum calcium levels in the post-operative period and parathyroid touchREVIEWS in Endocrinology carcinoma is diagnosed based on microscopic features, immediate re-exploration may not be required, rather it becomes imperative to frequently monitor serum calcium. 10In the current case, we do not have records of post-operative calcium after the initial surgery.The patient's history shows that she had persistent disease and could have benefitted from immediate re-exploration after histopathology confirmed the diagnosis.
Hungry bone syndrome is more commonly seen in parathyroid carcinoma, due to more severe skeletal disease and profound hypercalcaemia.In the immediate post-operative period, patients may require intravenous calcium infusion and calcitriol.As the other parathyroid glands recover, the requirement of calcium and calcitriol reduces.Our patient did not have hungry bone syndrome, which might be attributed to less severe skeletal presentation prior to surgery.
The management of recurrent or metastatic parathyroid carcinoma is primarily surgical.Unlike other cancers, it has an indolent nature and is mostly associated with local recurrence and involvement of contiguous structures in the neck rather than distant metastasis.The latter, if present, is mostly observed in the lymph nodes, lungs or liver. 6Tumour deposits at any site, even though small, can produce sufficient parathyroid hormone (PTH) to cause significant hypercalcaemia.In most cases, surgical removal of the metastatic deposits can ameliorate hypercalcaemia considerably, providing a window of opportunity for medical therapies to control remaining hypercalcaemia. 10 patients with recurrence of parathyroid carcinoma, careful localization should be done with 99m Tc sestamibi scan, computed tomography or magnetic resonance imaging of the neck and chest.Biopsy or fine needle aspiration cytology should not be done to avoid seeding of the tumour. 10current parathyroid carcinoma in the neck should be managed with wide local excision, removing regional lymph nodes and all the adjacent involved structures.Distant metastatic deposits, if accessible, should be resected. 10diotherapy in parathyroid carcinoma is ineffective in the majority of cases, as it is not a radio-sensitive tumour. 10A few case series have, however, found that radiotherapy to the neck post-surgery prevented tumour regrowth in the local areas. 7,13Wynne et al. reported a tumourfree state for 10 years following adjuvant radiotherapy after surgery for parathyroid carcinoma. 14Usually, the decision for radiotherapy should be made on an individual basis.In our patient, radical neck dissection had been done six times.However, re-surgery is rarely curative and relapse is likely, as has been observed in our patient.Such patients usually have a 60% lifetime accumulated surgical risk from all subsequent surgical interventions. 11,15Therefore, in our multidisciplinary team meeting, it was decided to offer radiotherapy to the patient based on previous anecdotal reports. 7,13,14e role of chemotherapy in parathyroid carcinoma is a matter of debate.The results of chemotherapy in parathyroid carcinoma have been disappointing.[18] Bukowski et al. reported a single patient with pulmonary metastases responding to a chemotherapy regimen of dacarbazine, 5-fluorouracil and cyclophosphamide with normalization of serum calcium for 13 months. 16e management of hypercalcaemia in parathyroid carcinoma can be difficult due to the severity of hypercalcaemia.Management of touchREVIEWS in Endocrinology hypercalcaemia includes saline infusion to replenish volume status followed by loop diuretics to increase urinary calcium excretion.Such measures are usually not sufficient and agents inhibiting osteoclastic bone resorption, such as bisphosphonates, denosumab and calcitonin, are usually required. 19Among bisphosphonates, the most potent agent, 4 mg zoledronic acid by intravenous infusion, is usually administered.
It may cause transient side effects such as fever, chills, exacerbation of bone pain, and very rarely, cardiac arrhythmias. 20Denosumab, a monoclonal antibody against receptor activator of nuclear factor κΒ ligand (RANKL), inhibits osteoclastic bone resorption and is used to manage hypercalcaemia in parathyroid carcinoma. 21,22Calcitonin inhibits osteoclast-mediated bone resorption and increases urinary calcium.However, the reduction in calcium is transient due to the development of tachyphylaxis. 23Cinacalcet is a calcimimetic agent that is an allosteric modulator of the calcium-sensing receptor protein, which lowers serum PTH and calcium levels in PHPT.Cinacalcet has been tried in cases of parathyroid carcinoma, with a transient reduction in serum calcium level. 24,25One case report has described the efficacy of octreotide, a long-acting somatostatin analogue, in a woman with parathyroid carcinoma and metastatic bone disease, where they show a transient decrease in PTH levels. 26Synthetic oestrogen has been found to be successful in a single case. 27Immunization with human and bovine PTH peptides with booster doses at 4 and 11 weeks helped lower serum calcium levels for 6 months in a patient with parathyroid carcinoma. 28,29rathyroid carcinoma has a variable prognosis.Hypercalcaemia seems to be the primary cause of mortality and morbidity in these patients. 30e single most important factor affecting prognosis is the extent of resection at the time of initial surgery. 31Usually, a gap of 3 years is noted between the initial surgery and the first recurrence, although it can occur even after 20 years. 1 Once there is a recurrence, palliative surgery can be of considerable benefit, although a complete cure is unlikely.

Conclusion
We have described a case of recurrent PHPT due to parathyroid carcinoma in a woman with a recurrent neck mass.She underwent palliative surgery multiple times and, at the time of writing this report, was referred for external radiotherapy.Parathyroid carcinoma imposes a considerable challenge in terms of diagnosis and management.

Figure 1 :
Figure 1: Clinical images of the patient showing a neck mass (arrows) with previous surgical scars from the front (a) and left side (b) Figures 3 and 4.
while florid skeletal disease was absent.Pathologically, parathyroid carcinoma poses a diagnostic challenge.The World Health Organization 2022 classification of parathyroid tumours requires one of the following findings to be present for histological diagnosis of parathyroid carcinoma: (i) angio-invasion, characterized by a tumour invading the vessel wall, and associated thrombus or intravascular tumour cells admixed with thrombus; (ii) lymphatic invasion; (iii) perineural invasion; (iv) local malignant invasion into adjacent structures; or (v) histologically/cytologically documented metastatic disease.

Figure 2 :
Figure 2: Contrast-enhanced computed tomography images (sagittal view) showing an oval-shaped heterogeneously enhancing lesion on the left side of the neck (arrow).Two adjacent heterogeneously enhancing lymph nodes are seen in the left supraclavicular region (star)

Figure 3 :Figure 4 :
Figure 3: Intra-operative images showing a large neck mass adhering to adjacent structures

Figure 5 :
Figure 5: Histopathology images showing tumour cells separated by broad fibrotic bands (a).The tumour cells were uniform with mild to moderate nuclear atypia and macro-nucleoli with 10-15 mitosis/10 high power field.Atypical mitotic figures and capsular and vascular invasion were also observed (b)

Table 1 :
Biochemical parameters of the patient before and after surgery

Normal range Pre-operative Post-operative after 1 week
N/A = Not applicable.Parathyroid Carcinoma Presenting as Recurrent Primary Hyperparathyroidism and Neck Mass: A Case Report touchREVIEWS in Endocrinology