parathyroid carcinoma is a rare disorder , accounting for 0.1% to 5.0% of all cases of primary hyperparathyroidism [ 15 ] .
the disease presents at a mean age of 50  years and is equally likely to occur in males as in females [ 26 ] ( table  1 ) .
clinical and biochemical manifestations are those of severe primary hyperparathyroidism often with renal and skeletal complications [ 25 , 7 ] . a palpable neck mass can be felt in 3076% of patients [ 3 , 5 , 8 , 9 ] .
parathyroid carcinoma is associated with germline and somatic mutations in the hrpt2 gene [ 3 , 10 ] and with irradiation of the neck for other pathologies [ 3 , 11 ] . 

table  1overview of cases of parathyroid carcinoma published between 2001 and 2010authorage / sexnumber of operationsradiotherapychemotherapyembolisationradiofrequency ablationpth immunisationcalcitonincinacalcetbisphosphonatesdevelopment of local recurrence or distant metastasisoutcomefollow - up ( years)savli 47/f1noa / fod1tyler 44/m2yesyesa / fod5.5dotzenrath 43/m4yesyesdod1243/f12yesyesa / wd862/f2yesd / other9.5yamashita 43/m2yesa / wd12eurelings 45/f1yesyesyesdod4brown
51/m2noa / fod2bhansali 40/m2yesyesyesnodod0.5hundley 33/f5yesa / fod20schmidt 76/f1noa / fod1schoretsanitis 55/f1noa / fod2dionisi 35/m2yesyesdod4rufener 67/m3yesa / fod4munson 41/f1yesnoa / fod5.546/f1yesnoa / fod4.549/f1yesnoa / fod5.557/f1yesnoa / fod4.5dogan 50/f1noa / fod1.5betea 50/f2yesyesyesyesa / wd11kern 54/f2yesyesdod2.5kirkby - bott 44/m2yesyesyesdod3.570/m1yesnoa / fod736/f1yesnoa / fod566/m2yesyesdod846/m1yesyesyesa / wd125/f1noa / fod144/m1noa / fod1lin 38/m1noa / fod0.5ahmad 42/f1yesyesa / fod1chiofalo 66/m1yesnoa / fod1cheah 32/m2noa / fod0.542/f1noa / fod0.552/f2yesa / fod5.5yoshida
61/f2yesyesa / wd18.5ikeda 48/m4yesyesa / wd6pahlavan 21/m2yesnoa / fod2agarwal 22/f2yesa / fod9mezhir 64/f7yesyesyesyesa / fod8placzkowski 51/f4yesyesyesyesyesa / fod12sahasranam 53/m1noa / fod2tkaczyk 55/m2yesnoa / fod1tan 55/f1noa / fod0.5iwata 61/m1noa / fod3montenegro 50/m2yesyesyesdod5rathi 45/f1noa / fod0.5artinyan 71/m2yesyesyesyesyesa / fod0.5cetani 53/m3yesyesa / fod2temmim 63/f1noa / fod2tamura 70/m1yesa / wd0.5schoretsanitis 72/m1noa / fod478/f1noa / fod455/f1noa / fod671/m1yesdod275/m1noa / fod4kung 72/f1noa / fod2marcy 42/f1noa / fod1yuan 38/f2noa / fod4rock
60/m1yesnoa / fod0.5yong 23/m1yesyesnoa / fod2chaychi 79/f1noa / fod0.5tochio 42/m2yesyesyesa / wd8.551    2/30m:32f1.9    0.218/62 ( 29%)4/62 ( 6%)1/62 ( 2%)3/62 ( 5%)1/62 ( 2%)3/62 ( 5%)5/62 ( 8%)14/62 ( 23%)27/62 ( 44%)4.3    0.5results are expressed as mean  sedod dead of disease , d / other dead of other cause , a / wd alive with disease , a / fod alive free of disease overview of cases of parathyroid carcinoma published between 2001 and 2010 results are expressed as mean  se dod dead of disease , d / other dead of other cause , a / wd alive with disease , a / fod alive free of disease a diagnosis of parathyroid carcinoma is suggested by the presence of intra - operative features of local invasion and the diagnosis is confirmed by the world health organization histopathological criteria for parathyroid carcinoma .
these include the presence of vascular invasion , perineural space invasion , capsular penetration with growth into adjacent tissues and/or metastasis .
although parathyroid carcinoma is a slow - growing tumour , it inevitably metastasises and is invariably fatal due to the eventual inability to control hypercalcaemia .
survival is estimated to range from 50% to 86% at 5  years and 3570% at 10  years [ 16 , 13 , 14 ] .
the most effective treatment for parathyroid carcinoma is radical surgery with en bloc removal of the lesion together with the ipsilateral thyroid , thyroid isthmus and lymph nodes [ 2 , 3 , 5 , 13 , 15 ] .
surgery is also the treatment of choice in case of local recurrence or development of metastases [ 5 , 7 , 16 ] , although radiotherapy [ 25 , 8 , 9 ] , chemotherapy [ 3 , 5 , 9 , 17 , 18 ] , embolisation   or radio frequency ( rf ) ablation [ 1921 ] may also be attempted .
we report here the nearly two decades odyssey of a male patient with multiple metastases from parathyroid carcinoma , describing in the process the challenges and pitfalls we encountered in the management of this difficult malignancy .
we also review all original case reports and case series on parathyroid carcinoma , fulfilling the who criteria and with a follow - up of at least 6  months after initial parathyroidectomy , which were published in the english literature since the last large review on this topic in 2001 .
the literature search was conducted in pubmed using the keywords (  parathyroid neoplasms  or  parathyroid carcinoma  or 
(  case reports  or  case report  or  case  or  cases  ) .
patients with changes suggestive of carcinoma in the context of autonomous ( tertiary ) hyperparathyroidism were excluded because of the controversy in diagnosing malignancy in this case . of an initial 872 publications ,
only 45 fulfilled the who criteria for parathyroid carcinoma and follow - up as per our search criteria , and were selected for further analysis .
a 29-year - old man presented to his primary care physician with a 2-month history of severe weight loss ( 20  kg ) associated with polyuria , polydipsia , nausea , muscle weakness , difficulty in concentrating and debilitating tiredness . on physical examination , he was clinically dehydrated and had a palpable hard , fixed swelling in the left side of the neck .
laboratory investigations revealed a severe hypercalcaemia of 4.9  mmol / l ( normal range 2.152.55  mmol / l ) , a decreased creatinine clearance of 45  ml / min ( normal > 120  ml / min ) and a 10-fold increased serum intact parathyroid hormone ( pth ) concentration : 88  pmol / l ( normal
no further investigations were requested ; the patient was intensively rehydrated and referred for parathyroidectomy . at neck exploration , an enlarged parathyroid gland ( 3.5    3    3.5  cm ) invading the ipsilateral thyroid lobe was found and removed from the left side of the neck ( fig .  1 ) .
the diagnosis of parathyroid carcinoma was confirmed histologically by the finding of capsular and vascular invasion .
serum calcium and pth concentrations normalised within a few days of surgery associated with a significant improvement in renal function .
a second surgery was performed within 1  month of the first surgery to ensure complete removal of all malignant tissue and provide a negative surgical margin .
the patient was started on a course of radiotherapy , which had to be discontinued before completion because of severe pharyngitis and oesophagitis . 

1disease course of our patient spanning over 17  years disease course of our patient spanning over 17  years a recurrence of hyperparathyroidism was documented on routine laboratory control 3  years after parathyroidectomy .
mmol / l , a pth concentration of 8.4  pmol / l and a stable creatinine clearance of 75  ml / min .
tc99m - mibi - spect and ultrasonography identified a lesion in the left side of the neck , which was found to be a local recurrence of the primary tumour at extensive bilateral neck exploration .
the recurrent tumour had invaded the oesophagus , part of which was excised and reconstructed using tissue from the sternocleidomastoid muscle .
the edges of the excised specimen were tumour free and resected draining lymph nodes were clear of tumour tissue .
dna analysis of the resected recurrent tumour demonstrated a somatic hrpt2 mutation , c.165delc located on exon 2 . despite the radical nature of the surgery ,
mild hyperparathyroidism persisted post - operatively , suggesting the presence of residual probably metastatic tumour tissue .
no further localisation studies or surgery were planned principally because of the patient s reluctance to undergo further surgery but also because of the mild nature of the hyperparathyroidism .
closer clinical monitoring was arranged . over the following 4  years , serum calcium and pth concentrations and bone turnover markers slowly increased , and periods of dehydration were associated with transient worsening of renal function , which remained , however , on the whole stable despite persistent hypercalciuria and development of nephrocalcinosis .
progressive bone loss , predominantly cortical , was also documented and treatment with the non - nitrogen - containing bisphosphonate clodronate was started , resulting in normalisation of bone turnover and stabilisation of bmd measurements .
ultrasound ( us ) , selective venous sampling for pth ( svs ) and ct scan of the neck succeeded in localising a small dense lesion in the left supraclavicular region .
ct scan of the thorax also revealed a small solitary lesion of 1-cm radius in the inferior lobe of the right lung ( fig . 
the patient refused to undergo a thoracotomy , but did agree to a fourth neck exploration at which a lymph node metastasis was excised from the left supraclavicular region ( fig .  1 ) . although less severe , hyperparathyroidism persisted post - operatively , as expected due to the unresected lung metastasis .
in contrast , radiofrequency ablation ( rfa ) of the lesion , although complicated by an episode of severe pleuritis , was very successful in achieving biochemical remission , with serum pth concentrations decreasing from 265  pmol / l to < 1  pmol / l ( fig .  2 ) , suggesting that the metastasis targeted with rfa was the only source of pth secretion . however , remission was not permanent and pth levels started to rise within 9  months of rfa .
3 ) , which was complicated by multiple small cerebral infarcts resulting in right haemianopia , dysphasia , acalculia and transient epilepsy .
disappointedly , there was also only partial improvement in serum calcium and pth concentrations , which continued to increase within 2  months of lobectomy ( fig .  3 ) . 

2radiological ( a pre - rf ablation , b after rf ablation ) and biochemical changes after rf ablation of the lung metastasis , demonstrating a severe drop in serum pth concentrations , which persisted for almost a yearfig . 
3radiological and biochemical changes following lobectomy of the lung metastasis , which resulted in only partial improvement in serum calcium and pth concentrations radiological ( a pre - rf ablation , b after rf ablation ) and biochemical changes after rf ablation of the lung metastasis , demonstrating a severe drop in serum pth concentrations , which persisted for almost a year radiological and biochemical changes following lobectomy of the lung metastasis , which resulted in only partial improvement in serum calcium and pth concentrations further localisation studies , in the form of tc99m - mibi - spect and a ct scan of the neck and thorax , were unable to localise any residual pathological parathyroid tissue suggesting the presence of ( micro)metastasis .
the now available calcimimetic cinacalcet was prescribed eventually at a maximum dose of 90  mg twice daily , which decreased pth concentrations from 120  pmol / l to 85  pmol / l , stabilised calcium concentrations to about 2.80 
in the course of the following year , serum calcium and pth concentrations further increased , however , despite maximal doses of cinacalcet and intermittent intravenous bisphosphonates .
repeat tc99m - mibi - spect and ct scan of the thorax , now demonstrated a new large ( 4    3    2  cm ) subcarinal mediastinal metastasis , which was successfully excised using a transpericardial approach ( fig . 
the elimination of the source of pth secretion was associated with a very severe hungry bone syndrome for which the patient needed intensive care for over 2  months , requiring very large doses of iv administered calcium ( up to 14  g / day ) and maximal doses of active vitamin d metabolites .
remission lasted for more than 1  year , after which pth levels started to rise again and a new metastatic lesion was localised pretracheally in the upper mediastinum on ct scan of the thorax .
there was also suggestion of a second subcarinal lesion at the site of the previously excised metastasis . 

4ct scan of the thorax demonstrating a large ( 4  3    2  cm ) subcarinal mediastinal lymph node metastasis ( white arrow ) ( a , b ) , which was successfully excised using a transpericardial approach ( c ) ct scan of the thorax demonstrating a large ( 4  3    2  cm ) subcarinal mediastinal lymph node metastasis ( white arrow ) ( a , b ) , which was successfully excised using a transpericardial approach ( c ) in view of the complications associated with his previous surgeries , the patient was at that stage again reluctant to undergo any further surgery . within the next few months ,
pth steadily increased associated with uncontrollable hypercalcaemia and deteriorating renal function eventually requiring haemodialysis using a very - low - dialysate calcium concentration .
the pretracheal lesion was accessible from the neck and was radically removed by a cervical approach ( fig .  1 ) .
there were no post - operative complications and serum pth concentration decreased from 590  pmol / l to 155  pmol / l , as expected due to the remaining subcarinal mediastinal metastasis .
surgical removal of this metastasis would have required a third thoracotomy , which would be associated with too high an operative risk , especially in view of the patient s poor clinical condition .
excision of the metastasis by mediastinoscopy was also not considered to be an option because of multiple scarring due to previous surgeries .
the patient remains on haemodialysis and is still treated with cinacalcet , with intermittent courses of intravenous bisphosphonates .
the patient was not considered to be a candidate for pth immunisation [ 23 , 24 ] because of surgical clearance of cervical and mediastinal lymph nodes , poor general immune status and recurring infections .
sixty - two new cases have been reported in the literature since the last published review in 2001 , and data of these cases are summarised in table  1 .
the median age of the reported patients was 50  years ( 2179 ) and there was an equal number of men and women reported .
data on initial presentation were available in 43 of the 62 patients ( 69% ) , 37 of which were symptomatic ( 86% ) .
polyuria and polydipsia were reported in nine patients ( 21% ) , constipation in seven ( 16% ) , tiredness in 13 ( 30% ) , bone and joint pain in 17 ( 40% ) , muscle weakness in seven ( 16% ) , nausea and vomiting in 10 ( 23% ) and weight loss in seven patients ( 16% ) .
seventeen patients ( 40% ) had renal stones and six patients ( 14% ) had sustained a documented fracture .
a palpable neck mass was reported in 22 of 27 patients in whom this was checked ( 81% ) .
similar to the review of 2001 , surgery is still the most frequently chosen therapy for the initial treatment of parathyroid carcinoma but also for the treatment of recurrent or metastatic parathyroid carcinoma ( table  1 ) .
it is of note that the use of both chemotherapy and radiotherapy has decreased over the last 10  years , likely due to several reports and reviews which showed disappointing results [ 25 ] .
the last case report on the use of chemotherapy and radiotherapy dates from 2005 and 2008 , respectively ( table  1 ) .
in contrast to the review of 2001 , reports on the use of the newer techniques embolisation ( n  =  1 ) , radiofrequency ablation ( n  =  3 ) and
pth immunisation ( n  =  1 ) have been recently published , although the number of cases reported is still very limited .
use of the calcimimetic , cinacalcet , has increased over the last few years after the first report in 2007 , while the use of bisphosphonates has remained stable .
the median follow - up reported in the 62 cases is relatively short at 3  years ( range 0.520  years ) , considering that the average time to a first recurrence is also approximately 3  years [ 1 , 3 ] .
this could explain why only 27 of the 62 patients ( 44% ) developed a local recurrence and/or distant metastasis and nine patients ( 15% ) died as a result of parathyroid carcinoma during the reported follow - up period .
to our knowledge , we report here one of the longest survival and follow - up in one centre of a patient with recurrent metastatic parathyroid carcinoma .
although parathyroid carcinoma is a slow - growing tumour , it is associated with a relatively high incidence of local recurrence ( 4082% within 5  years ) [ 13 , 5 , 6 , 13 ] .
metastases tend to occur later in the course of the disease with spread to cervical nodes ( 30% ) , lung ( 40% ) and liver ( 10% ) , via both lymphatic and haematogenous routes .
survival is estimated to range from 35% to 70% at 10  years [ 16 , 13 , 14 ] , with an average survival of 6  years after local recurrence , and of 4.5  years after the development of distant metastases . in patients with parathyroid carcinoma ,
determinants of survival include delay in diagnosis , the presence of locally invasive features , distant metastasis at diagnosis and the radical nature of initial surgery [ 3 , 6 , 13 , 14 ] . a further important determinant of survival and disease - free survival is the due care taken at initial surgery to avoid rupturing the capsule of the gland to prevent local seeding of tumour tissue .
initial surgery has been reported not to be radical in up to 48% of patients because of failure to establish the diagnosis of parathyroid carcinoma pre- or intra - operatively [ 6 , 14 ] .
this was also the case in our patient at initial surgery , despite very suggestive clinical features of parathyroid carcinoma , in the form of severe hyperparathyroidism in a young male patient , palpable neck swelling and intra - operative features of local invasion .
a second surgery had to be performed within 1  month of the first to ensure complete removal of all malignant tissue and to provide a negative surgical margin .
the main determinant of survival in all patients remains , however , the eventual inability to control hypercalcaemia [ 2 , 5 ] and its association with fatal renal and cardiovascular complications [ 1 , 2 , 5 , 7 ] .
end - stage renal failure has been reported in up to 84% of patients due the deleterious effects of severe persistent hypercalcaemia on kidney function [ 2 , 5 , 7 ] .
a persistently elevated circulating pth level is also associated with increased bone turnover and bone loss predominantly at cortical sites and with increased risk of fractures . in parathyroid carcinoma ,
the main goal of treatment is control of hyperparathyroidism by eradicating the source of pth secretion [ 7 , 16 ] .
although the morbidity associated with re - exploration of the neck is estimated to be 617% , that of re - exploration of the mediastinum or lungs is clearly much higher . in our patient ,
the recurrent laryngeal nerve had to be unavoidably sacrificed during the second surgical intervention due to invasive growth of remnants of the primary tumour , resulting in transient loss of voice and permanent hoarseness .
the increasing morbidity attached to repeated surgical interventions has led to the search for other treatment options , such as radiotherapy , chemotherapy , rf ablation , embolisation , use of the calcimimetic cinacalcet and pth immunisation .
although parathyroid tumours are relatively resistant to radiotherapy [ 25 ] , this management approach showed some promise as adjuvant treatment for microscopic residual disease [ 8 , 9 ] . in our patient , the prescribed course of radiotherapy could not be completed due to the development of severe side effects in the form of pharyngitis and oesophagitis .
embolisation of localised and/or ectopic parathyroid adenomas has been reported to have only limited success [ 19 , 2527 ] , and in metastatic parathyroid carcinoma , embolisation has only been described in combination with rf ablation in one patient . in our patient ,
the outcome of twice attempted embolisation of a lung metastasis was disappointing , largely because it was not technically possible to selectively embolise the arterial branch that fed the lung metastasis .
the outcome of combined embolisation and rf ablation in a patient with liver metastasis due to parathyroid carcinoma , and the effectiveness of rf ablation in various types of cancer   has led us to consider rf ablation in our patient .
this approach was indeed very successful in eradicating pth production by the metastasis , as has also been subsequently reported in two patients with parathyroid carcinoma and lung metastases [ 20 , 21 ] .
the beneficial effect was unfortunately transient , lasting only 9  months after the procedure , when pth production was documented to resume from the same site .
in parathyroid carcinoma , attempts at reducing tumour load are not always successful , in which case control of serum calcium by other means becomes central to prevent the deleterious effects of hypercalcaemia on various organ systems .
intensive rehydration , use of medications such as bisphosphonates and calcimimetics and use of dialysis represent diverse means to control hypercalcaemia and are often used in combination .
bisphosphonates decrease the skeletal efflux of calcium from bone by suppressing osteoclast - mediated bone resorption and overall bone turnover .
these agents , however , have no effect on renal tubular reabsorption of calcium so that they improve hypercalcaemia but do not normalise serum calcium [ 3 , 29 ] .
cinacalcet is a calcimimetic , which reduces parathyroid hormone secretion by binding to the calcium - sensing receptor on parathyroid cells , increasing the sensitivity of these cells to extracellular calcium concentrations [ 15 , 30 , 31 ] .
these agents are widely used in the management of secondary and tertiary hyperparathyroidism in renal failure and have been also recently registered for the management of primary hyperparathyroidism , including that due to parathyroid carcinoma . in our patient , combined treatment with bisphosphonates and cinacalcet resulted in reasonable control of the hypercalcaemia initially , but eventually failed to do so , even when used at maximal doses .
dialysing against low - dialysate calcium became necessary in order to better control the hypercalcaemia .
the very high operative risks associated with a third thoracotomy , the patient s poor lung function and current metabolic status despite regular dialysis , preclude the option of further surgery to remove the identified source of pth secretion .
pth immunisation is being explored as a potential non - invasive option , although experience with this approach is still limited and the patient s general condition may not permit its use [ 23 , 24 , 32 ] .
although we are rapidly running out of options in the management of our patient , we believe that we have nonetheless managed to secure for him a longer albeit not disease - free survival .
this clinical case with a follow - up spanning over 17  years illustrates that the long - term management of patients with metastatic parathyroid carcinoma remains indeed a daunting task , despite all recent imaging , surgical and medical advances .
 a 29-year - old man presented to his primary care physician with nausea , severe weight loss and muscle weakness . 
 he had a hard , fixed neck swelling . 
 he was severely hypercalcaemic with 10-fold increased parathyroid hormone ( pth ) concentrations . 
 a diagnosis of primary hyperparathyroidism was established and the patient was referred for parathyroidectomy . at neck exploration , 
 an enlarged parathyroid gland with invasive growth into the thyroid gland was found and removed , lymph nodes were cleared and hemithyroidectomy was performed . 
 a suspected diagnosis of parathyroid carcinoma was confirmed histologically . 
 serum calcium and pth levels normalised post - operatively , but hyperparathyroidism recurred within 3  years of surgery . over the following 17  years , 
 control of hypercalcaemia represented the most difficult challenge despite variable success achieved with repeated surgical interventions , embolisations , radiofrequency ablation of metastases and treatment with calcimimetics , bisphosphonates and haemodialysis using low - dialysate calcium . in this paper , we report the challenges and pitfalls we encountered in the management of our patient over nearly two decades of follow - up and review recent literature on the topic . 
Introduction
Case Report
Review of the Literature 20012010
Discussion