Previously unreported deletion of CDC73 involving exons 1–13 was detected in a patient with recurrent parathyroid carcinoma

Abstract

Parathyroid carcinoma (PC) is a rare malignancy, presenting sporadically or as part of a genetic syndrome. Diagnosis of PC includes the histopathological diagnosis based on capsular, perineural, or vascular invasion or metastasis. High suspicion for malignancy includes hypercalcaemia greater than 14 mg/dL, extremely high serum parathyroid hormone (PTH) levels, as well as large masses. Given the rarity of PC, it is challenging to design clinical trials for newer therapy. Currently, complete initial surgical excision of the tumour in high-risk patients offers the best chance of cure and prolonged disease-free survival in PC. In the absence of definite data, non-surgical therapies such as radiation and chemotherapy are not routinely recommended. For early detection of recurrence; long-term clinical follow-up with interval measurements of serum calcium and PTH is recommended. Localising studies of PC are helpful. Early screening for CDC73 mutation and multidisciplinary treatment by an endocrine/ENT/surgical oncology team is recommended.

Background

Primary hyperparathyroidism (HPT) is a disorder of the parathyroid glands that affects many individuals, where one or more of the parathyroid glands are overactive. HPT is usually caused by benign parathyroid adenomas, parathyroid hyperplasia and, rarely, parathyroid carcinoma (PC). PC accounts for less than 5% of all reported cases of HPT, which is approximately 0.5% of endocrine cancers overall.¹ PC is one of the rarest of all human cancers. The mean age at diagnosis is between 44 and 54 years.² PC manifests with equivalent incidence in men and women, whereas in primary HPT there is a threefold higher incidence in women.³ The aetiology of PC is unknown; however, in rare cases the occurrence of PC in patients with multiple endocrine neoplasia 1 (MEN1) and autosomal dominant familial isolated HPT has been observed.⁴ The molecular pathogenesis involves CDC73 gene mutation. Fewer patients have metastasis at initial presentation, either involving regional lymph nodes or to distant sites. A higher proportion invades locally. The likelihood of recurrence is high with studies reporting up to 40%–60% of patients having experienced a postsurgical recurrence.⁵ The postsurgical scar tissue makes it challenging to identify local recurrences. Use of sestamibi–thallium scanning and positron emission tomography (PET)/CT are useful tools in identification of difficult to detect recurrent disease.⁶ Distant metastases primarily involve the lungs, but are also found in the liver and bone.⁷ Because of its relative indolence, the mortality and morbidity associated with PC primarily results from the metabolic consequences rather than the malignant spread of the disease. In the National Cancer Institute database series of 286 patients, it was reported that the 10-year survival rate was approximately 49%.⁸ Parathyroid cancers are hyperfunctional, unlike some endocrine tumours which become hormonally inactive when malignant.⁹ There is a higher prevalence of renal and overt skeletal (non-metastatic) involvement present simultaneously at diagnosis in up to 50% cases of PC, which is unusual in primary HPT,^{10 11} in which diagnostic evaluation is typically initiated because of the serendipitous discovery of hypercalcaemia.

Currently, the highest chance of cure is offered by adequate en bloc excision of the PC including microscopically negative margins, at the initial surgery.

Recurrent or persistent disease has been observed in more than 50% of patients with PC. Even for recurrent disease, surgery is the mainstay of therapy. Reducing the disease burden can offer significant improvement in metabolic derangement caused by HPT, thereby making hypercalcaemia easier to manage medically. Adequate control of hypercalcaemia can prolong survival. Reoperation is not always curative and there exists a likelihood of eventual relapse.

Germline CDC73 mutations are present in 15%–30% of patients with sporadically presenting PC and the risk of PC in families with HPT-jaw tumour syndrome (HPT-JT) has been reported to be as high as 37%. In contrast, in the context of MEN1 families, PC is exceedingly rare.

This is an interesting case of a sporadically presenting PC patient with germline CDC73 mutation who lacks evidence of familial and/or syndromic disease and such mutations have implications in the further management of the patient and early detection of PC in family members. The genetic diagnosis indicates an increased risk for developing entirely new tumours, potentially malignant, in the remaining parathyroid glands.

Genetic testing of family members is recommended and for those relatives, who did inherit the mutation, biochemical testing for HPT, followed by surgery if diagnostic of HPT. For members who carry the mutation without biochemical evidence of HPT, we recommend prospective surveillance by measurement of serum calcium and parathyroid hormone (PTH) every 6 months.

The benefit of genetic testing of family members is the reassurance provided to those who have not inherited the mutation, thereby reducing their anxiety and the cost of ongoing disease surveillance.

For the surgical approach of CDC73 mutation carriers, bilateral exploration is advised, to identify all parathyroid glands. Any grossly abnormal or suspicious-appearing glands should be resected, as they bear the potential of malignancy. In addition, exploration can identify non-functional or poorly functional glands which could have evaded detection on preoperative imaging.

While some clinicians advocate prophylactic total parathyroidectomy for CDC73 mutation carriers, it has been associated with considerable morbidity and management of lifelong hypoparathyroidism (with less affordable PTH replacement therapy). Alternatively, prospective surveillance can help identify tumours early to prevent metastatic disease.

Case presentation

A 43-year-old woman was referred to endocrinology clinic for HPT after routine laboratories revealed a serum calcium level of 14.7 mg/dL as well an intact PTH level that was significantly increased at 2847 pg/mL, with reference range (15.0–68.3 pg/mL) with a serum 25-OH vitamin D level of 20 ng/mL (30–100). The patient presented with fatigue and generalised aches and pain. She had no history of nephrolithiasis or fractures. She also denied any radiation exposure or any personal or family history of cancer. On physical examination, a firm mass was palpable on the right side of her neck. Subsequent workup included a sestamibi scan which demonstrated an increased uptake on the right inferior side. On surgical exploration, the right-sided parathyroid mass (5×3×2 cm) was found to be grossly fibrotic and irregular, so the mass was excised along with adjacent thyroid tissue. Histopathological examination revealed PC with capsular and intracapsular vascular invasion (figures 1 and 2). Vascular invasion is only a feature of parathyroid malignancy if it affects vessels either within or beyond the capsule, NOT vessels within the gland (WHO criteria). In the immediate postoperative period, serum calcium levels plummeted to 7 mg/dL consistent with hungry bone syndrome, necessitating high-dose oral calcium 2 g two times a day and vitamin D supplementation of 60K units once weekly x 8 weeks, which were continued on discharge. The patient was under regular follow-up every 6 months. She was having normal serum calcium and immunoreactive serum PTH (iPTH) for 2 years after surgery; however, serum calcium levels began to rise sharply again to 12 mg/dL, suggesting recurrence. PET-CT revealed a 2 cm recurrent lesion along the right posteriolateral aspect of the cervical trachea, with no significant uptake on sestamibi. Re-exploration revealed recurrence at the previous surgical site and hence, a wide local excision of the adjoining strap muscles and parathyroid mass was performed (figure 3). Histology confirmed recurrent PC; all 39 lymph nodes were free of tumour; no evidence of lymphovascular or perineural invasion was seen. Once again, there was immediate and significant relief of hypercalcaemia postoperatively. The following year, investigations revealed recurrent hypercalcaemia suggesting a metastatic focus or multiglandular disease. Medical management of hypercalcaemia was initiated with cinacalcet (a calcimimetic agent that indirectly blocks secretion of the PTH from the parathyroid glands via binding to calcium-sensing receptors) and the dose was titrated to 90 mg two times a day. Sestamibi scan was suggestive of a left inferior parathyroid adenoma, as there was no fluorodeoxyglucose (FDG) avid lesion on PET/CT. In (figures 4 and 5), left inferior mass can be seen. The patient was referred for parathyroidectomy with a differential diagnosis of a large adenoma versus PC. There was no evidence prior to surgery of the lesion being benign, other than there was no evidence of metastatic involvement (based on PET CT). The sestamibi was suggestive of an adenoma (which could be PC as well, until capsular involvement was ruled out histologically). However, intraoperatively only a grossly normal appearing left superior parathyroid gland was visualised, which led to the surgeon’s decision to implant half of it into the forearm, where any potential rapid growth could be more easily observed and facilitate possible future removal, after considering the risk of iatrogenic hypocalcaemia and the challenging management of lifelong hypoparathyroidism with less affordable PTH replacement or often suboptimal calcium, calcitriol and hydrochlorothiazide therapy. The surgeon’s decision, which might not be considered best practice in many countries, should be evaluated in the setting of a country with no healthcare insurance in a patient of modest means. Our patient will require lifelong postoperative follow-up and prospective surveillance for metastatic disease. Additionally, completion thyroidectomy was done since the left inferior parathyroid gland could not be localised. Postoperatively, the iPTH level remained unchanged. The last tumour resected did not have characteristics of fibrous bands or atypical parathyroid adenoma. The thyroid pathology revealed lymphocytic thyroiditis.

Figure 1.

Histopathology with the arrow showing the blood vessel, with the vascular invasion of the parathyroid cancer cells.

Figure 2.

Another slide with vascular invasion of parathyroid cells.

Figure 3.

Image showing muscular invasion of parathyroid cancer cells.

Figure 4.

PET-CT with arrow showing the parathyroid adenoma, posterior to the left lobe of the thyroid gland.

Figure 5.

PET-CT with the parathyroid adenoma, posterior to the left lobe of the thyroid gland.

No further surgical treatment was planned given that there was no evidence of resectable disease. Micrometastasis was considered responsible for the persistently elevated iPTH versus PTH secretion from the implanted fragment becoming hyperplastic. Bisphosphonate therapy with zoledronic acid 5 mg intravenously was given for underlying osteoporosis (t-scores L.spine −2.5, F.neck-2.3 and wrist-2.8), prevention of hypercalcaemia and nephrolithiasis/nephrocalcinosis due to bone resorption. Our patient remains on cinacalcet 90 mg every 12 hours with stable, normal serum calcium levels.

Germline testing of CDC73 was recommended initially, which would have helped us in anticipating the possible presence of a second primary parathyroid tumour (as opposed to recurrence or metastasis). Unfortunately, given the cost barrier for genetic testing, the patient agreed for CDC73 testing only after her third surgery.

CDC73 testing was performed by capillary sequencing. A previously unreported heterozygous pathogenic variant was detected, which causes deletion of exons 1–13 in the CDC73 gene.

Given the presence of germline CDC73 mutation, she was considered a new HPT-JT proband and managed accordingly. She was advised to have screening of her children at some time point, as they might have inherited the same gene defect. She was referred for genetic counselling and screening for other cancers, such as renal hamartomas, uterine tumours, and Wilms’ tumour and advised on the importance of routine gynaecological and dental care to identify any HPT-JT-associated lesions early. Her jaw, kidney and uterine imaging were all negative.

The gland in her forearm admittedly has a high risk for malignant degeneration.

Her histology revealed a Ki-67 proliferation index of 15% and did not express parafibromin.

Multidisciplinary and multimodality treatment by an endocrine, ear, nose and throat (ENT), nuclear medicine and surgical oncology team have enabled this woman to survive an aggressive PC for 5 years follow-up, postdiagnosis.

Investigations

• Serum PTH was determined by in vitro chemiluminescent microparticle immunoassay.

• Parathyroid imaging was performed by sestamibi and PET/CT scans.

• Men-1 and HPRT2/CDC73 testing was performed by capillary sequencing.

Differential diagnosis

Alternative differential diagnoses included parathyroid hyperplasia and parathyroid adenoma.

Treatment

Surgical: En bloc parathyroid resection with ipsilateral thyroid lobectomy, wide excision of local recurrence at the original surgical site, completion thyroidectomy with subsequent parathyroidectomy for apparently benign parathyroid adenoma and partial parathyroid reimplantation.

Medical: cinacalcet, bisphosphonate (zoledronic acid).

Outcome and follow-up

Eucalcaemic survival with good quality of life 5 years postdiagnosis.

Discussion

Parathyroid cancer follows a progressive course in which the tumour invades the surrounding structures and local lymph nodes and there is metastasis to the lungs, liver and skeleton. The key prognostic factor is the completeness of the initial surgical resection in preoperatively suspected PC. Survival rates at 5 years are up to 90% after complete excision and at 10 years up to 67%,^{12 13} Indicators for poor prognosis include metastases to lymph nodes or distant metastases at initial presentation and non-functioning PC.¹⁴ Men under 45 years, with higher calcium levels (>13 mg/dL) experience a more aggressive course of the disease.¹⁵ Recurrence rates are high with a general consensus of 50% of patients developing recurrence after complete surgical excision.^{16 17} Preoperative localising imaging studies are recommended to reduce morbidity. However, after onset of recurrence the chances of cure are remote and further management aims at reducing tumour burden and control of hypercalcaemia in cases of unresectable disease. Initial management of hypercalcaemia is similar to the other causes of hypercalcaemia and includes hydration and intravenous bisphosphonates. With disease progression, addition of cinacalcet is recommended and denosumab is an option for refractory hypercalcaemia. This patient’s clinical course is unique in that apparently benign HPT followed the diagnosis and treatment of PC.

Genetic testing for germline CDC73 mutation is clinically appropriate in most patients with sporadic parathyroid cancer. Approximately, 90% of patients with HPT-JT syndrome present with hypercalcaemia due to single gland disease. Thus, performing selected parathyroidectomy by removing only grossly enlarged parathyroid gland(s), guided by intraoperative PTH monitoring is suggested.^{18 19} However, HPT-JT patients have a 20% risk of developing PC, which can require a more extensive resection.

A previously unreported deletion of CDC73 involving exons 1–13 was detected in our patient.

Large genomic deletions, such as deletion of exons 1–10, exons 4–6 and exons 7–13 in the CDC73 gene, have been reported in patients affected with HPT-JT syndrome.^20–22

Patient’s perspective.

I am happy to be alive and to be able to share my case report with the doctors all over the world, and to be able to help them learn from my case. I happened to have

a healthy life with being an independent mother of two, until one day on routine investigations, it all began to unfold, the sequence of events that would be life altering for me. I was told that my serum calcium levels were alarmingly high and that my parathyroid gland was over-functioning. To further investigate the underlying cause, I had to have a picture of the glands taken, which then revealed

a growth of one of my parathyroid glands. Having consented to proceed with the surgery, I was aware that the growth could potentially be malignant. Deep inside I wished it would benign and that I would be free from further disease.

Unfortunately my Endocrinologist and my Onco-surgeon told me what I was terrified of ‘I am afraid I have to share this with you, your pathology has revealed that the parathyroid adenoma was malignant and showed invasion of the blood vessels’. I held my breath and saw my whole world collapsing after just learning that I had been diagnosed with cancer. My immediate next question was ‘what can we do to make sure that I can get cured’. I expected the worse and was afraid of how long I had to live. My girls were young and I had a lot of responsibilities. With the help of my doctors, I gained confidence that I could be monitored on periodic basis and would overcome the recurrence/spread of this disease under their guidance. Two years went by quick, I was living my life without any fear until one day on my follow up, I was told my calcium levels have risen sharply again and that I would require further investigation to look for recurrence. There I stood feeling numb as my doctor comforted me, and gave me hope. Once again began the screening process, going through PET scans and then the surgery. This time it had recurred at the previous site and I was told that part of my thyroid had to be resected as well. It looked aggressive from the pathology. I was back home and an year went by with me living a good quality of life until again to my disbelief the calcium levels were found to be elevated. After my investigations, my doctors decided to resect all the remaining parathyroid glands and have a part of it implanted in my forearm for easy access, if needed to be removed later. Once again began the tedious process of pre-op screening, the surgery and awaiting to hear about the pathology. This time to my surprise the adenoma was benign. This I was told was a rare case, haven’t been reported before of a benign adenoma following recurrent parathyroid cancer. To my relief, my calcium and parathyroid levels remain stable and are being monitored periodically. I have been told my bones are osteoporotic, for which I am receiving therapy. Over the last 5 years, I have developed a close bonding with my doctors and so has my family. They have been a great source of motivation and encouragement, all throughout my disease course. I have faith in my doctors and even though I am aware of the risk of recurrence, under their guidance, I choose to live without fear.

Learning points.

• A diagnosis of parathyroid carcinoma (PC) includes histological diagnosis on the basis of capsular, vascular or perineural invasion, or metastasis. Localising studies of PC are helpful but do not detect all tumour foci.

• While primary hyperparathyroidism (HPT) is common, parathyroid cancer rarely underlies HPT. The suspicion for malignancy should be high with hypercalcaemia greater than 14 mg/dL, extremely high serum parathyroid hormone (PTH) levels (>5 times the upper limit of normal), as well as large masses.

• In patients with CDC73 gene mutations, as in the present case, the patient typically has multiglandular disease. Both atypical adenomas and PC may underlie HPT in patients with CDC73 gene mutations, in any order. Early germline testing of CDC73 in sporadically presenting parathyroid carcinoma is recommended in all PC patients.

• CDC73 gene mutations or polymorphisms have been shown to be associated with HPT-JT syndrome, which is characterised by an increased risk for primary hyperparathyroidism and fibromas of the mandible or maxilla and, to a lesser extent, other cancers, such as renal hamartomas, uterine tumours, and Wilms’ tumour. HPT-JT syndrome due to variations in the CDC73 gene shows an autosomal dominant mode of inheritance. Family members should be screened for mutations and be offered genetic counselling.

• Adequate en bloc excision of the tumour at initial surgery offers the best chance of cure. Non-surgical therapies such as radiation and chemotherapy have yielded poor results in the treatment of PC.

• Recurrence is possible, and it is recommended that patients undergo long-term follow-up clinically and with measurements of serum calcium and PTH. Once recurrence has occurred then the chances of cure are remote and treatment is generally focused on surgical intervention to decrease tumour burden for symptomatic control and medical control of hypercalcaemia.