parathyroid carcinoma is the least common endocrine malignancy , and accounted for only 0.005% of cases reported to the national cancer database ( ncdb ) between 1985 and 1995 .
roughly half of cases are diagnosed between ages 45 and 60  years , but the tumor arises over a wide age range . in the ncdb case series , overall 5- and 10-year survival rates were 85.5 and 49.5% , respectively .
most patients ( > 90% ) present with symptoms of hyperparathyroidism , including severe hypercalcemia , an elevated serum parathyroid hormone ( pth ) level , nephrolithiasis or nephrocalcinosis , osteopenia , gastrointestinal disturbances , depression , fatigue , or memory disturbance . despite this , parathyroid carcinoma remains a rare cause of primary hyperparathyroidism , accounting for only 0.52% of cases . in comparison ,
benign parathyroid adenomas account for approximately 85% of cases , with diffuse hyperplasia comprising the remainder .
parathyroid carcinoma has been associated with hyperparathyroidism - jaw tumor ( hpt - jt ) syndrome , familial isolated primary hyperparathyroidism , and multiple endocrine neoplasia syndromes ( men-1 and men-2a ) ; patients with hpt - jt have a 15% prevalence of the tumor .
the management of parathyroid carcinoma is primarily surgical , with en bloc resection of the tumor with involved adjacent structures being the recommended primary mode of therapy .
indeed , at least one report indicates that survival is largely dependent on margin status of the primary resection .
there has been a long debate in the literature about the effectiveness of adjuvant therapy , largely fueled by the paucity of cases .
however , three recent reports suggest that adjuvant radiation therapy may reduce tumor recurrence after resection [ 35 ] .
there is no systematic data to suggest a role for adjuvant chemotherapy . despite therapy , between one - third and three - quarters of patients have recurrence or metastasis of their tumors , causing recurrent hyperparathyroidism .
re - resection is the accepted therapy for palliative control of hypercalcemia , but seems to become less effective with continued iterations .
calcimimetic agents , such as cinacalcet , have recently been used with success in the cases of primary hyperparathyroidism , and may also play a role in palliative management of inoperable parathyroid carcinoma . despite this , most patients who die of disease do so as a result of complications of hypercalcemia .
while functional parathyroid carcinoma is an uncommon tumor , non - functional parathyroid carcinoma is an exceedingly rare disease , with less than 20 reported cases in the last 80  years .
as the name implies , patients with non - functional tumors have normal serum calcium and pth levels , and do not present with symptoms of hypercalcemia .
they typically present with a neck mass , and patients who die of disease eventually succumb to systemic tumor burden . here
we report a recent case of non - functional parathyroid carcinoma from our institution necessitating extensive surgery to obtain negative margins , review the past literature on this rare entity , and discuss recent and new advances in the diagnosis of both functional and non - functional parathyroid carcinomas .
the patient is a 59-year - old white man who presented to his primary care physician in july 2008 with a chief complaint of dysphagia .
his past medical history was notable for diabetes mellitus type ii , hypertension , and obstructive sleep apnea .
he had previously undergone cervical spine surgery in 2002 , and shoulder surgery at an unknown time .
his family history was notable for a half - sister with a history of breast and gastric cancer , and an uncle with a history of an unknown head and neck cancer .
he is married and works as a mechanic , rarely used alcohol , and had previously smoked cigarettes but quit in 1975 . on review of systems , he endorsed dysphagia and hoarseness , but denied other symptoms . physical examination showed a 6-cm firm mass in the left neck .
the mass extended anteriorly to the left sternocleidomastoid and inferiorly below the clavicle . computed tomography , performed at an outside hospital in july 2008 , was interpreted as a 6-cm left thyroid mass .
the patient was subsequently referred to barnes - jewish hospital for fine - needle aspiration of the mass , and evaluation by an otolaryngologist .
under ultrasonographic guidance , a fine - needle aspiration of the presumed left thyroid lobe tumor was performed by radiology .
a diagnosis of positive for thyroid carcinoma was returned at the end of july 2008 , with a comment that the cytologic features raised the possibility of a poorly differentiated or insular variant of thyroid carcinoma ; the cytologic differential diagnosis at that time included follicular variant of papillary thyroid carcinoma ( fig .  1 ) . on the basis of findings ,
1fine - needle aspirate smears of non - functional parathyroid carcinoma ( 600 ) . a ethanol - fixed , papanicolaou stained preparation ; b air - dried , diff - quik stained preparation fine - needle aspirate smears of non - functional parathyroid carcinoma ( 600 ) .
a ethanol - fixed , papanicolaou stained preparation ; b air - dried , diff - quik stained preparation he was then examined by one of our head and neck surgeons , who was concerned that the physical and radiographic characteristics of the tumor seemed more aggressive than that seen in the types of thyroid carcinoma given in the cytologic differential diagnosis .
indeed , magnetic resonance imaging of the mass , performed at barnes - jewish hospital in early august 2008 , showed a large left cervical mass that displaced the trachea to the right , extended between the trachea and esophagus in the neck , and inferiorly into the superior mediastinum ( fig .  2 ) .
of note , the serum calcium was 10.1  mg / dl ( nl  =  8.610.3  mg / dl ) , and a serum thyroid function panel , including thyroid - stimulating hormone , triiodothyronine , thyroxine , thyroglobulin , anti - thyroglobulin antibody , and calcitonin , was within normal limits . in light of these incongruous findings
, the patient was scheduled for a needle biopsy of the tumor prior to further management.fig . 
2pre - operative magnetic resonance imaging of non - functional parathyroid carcinoma . a t2-weighed transverse section , with carcinoma ( arrowhead ) displacing the trachea ( single arrow ) and compressing the esophagus ( double arrow ) ; b thrive sequence frontal section , with carcinoma extending across the midline and into the superior mediastinum pre - operative magnetic resonance imaging of non - functional parathyroid carcinoma . a t2-weighed transverse section , with carcinoma ( arrowhead ) displacing the trachea ( single arrow ) and compressing the esophagus ( double arrow ) ;
b thrive sequence frontal section , with carcinoma extending across the midline and into the superior mediastinum as in the prior cytology specimen , the needle biopsy showed a poorly differentiated tumor with morphological and immunohistochemical features suggestive of neuroendocrine differentiation ( fig .  3 ; see section  pathologic summary ) .
the diagnosis was initially reported as poorly differentiated carcinoma with neuroendocrine features ; the differential diagnosis included poorly differentiated / insular thyroid carcinoma , medullary carcinoma , parathyroid carcinoma , carcinoma with thymus - like elements , and neuroendocrine carcinoma .
the common types of thyroid carcinoma ( papillary and follicular ) , as well as anaplastic carcinoma , were ruled out . a subsequent immunostain for pth showed diffuse reactivity in tumor cells , and a diagnosis of parathyroid carcinoma was rendered .
the patient had no symptoms of hyperparathyroidism , and a serum intact pth was 20  pg / ml ( nl  =  1472  pg / ml ) .
he was scheduled for en bloc resection of a non - functional parathyroid carcinoma at the beginning of september 2008.fig . 
a  c hematoxylin and eosin - stained sections at a low ( 20 ) , b intermediate ( 100 ) , and c high magnification ( 600 ) , d  f representative high - magnification images ( 600 ) of immunohistochemical stains for d cytokeratin ae1/ae3 , e cd56 , and f pth needle core biopsy of non - functional parathyroid carcinoma .
c hematoxylin and eosin - stained sections at a low ( 20 ) , b intermediate ( 100 ) , and c high magnification ( 600 ) , d  f representative high - magnification images ( 600 ) of immunohistochemical stains for d cytokeratin ae1/ae3 , e cd56 , and f pth at operation , a large left cervical tumor was found , intimately involved with the left thyroid lobe .
dissection of the anterior pretracheal tissues showed tumor adhesion to the anterior trachea ; frozen section analysis of this material was reported as  rare atypical cells ; recommend additional tissue .
 dissection of the tumor proceeded posteriorly from this point to the tracheoesophageal groove , where it appeared to invade the trachea and esophagus . at that point , it was deemed impossible to completely resect the tumor without sacrificing these structures . eventually , the tumor was resected en bloc with the left thyroid lobe and isthmus , anterior cervical soft tissue , larynx , hypopharynx , superior esophagus , and first eight tracheal rings .
a completion esophagectomy was performed , a gastric conduit was brought up to re - establish continuity , and a jejunostomy tube was placed for feeding .
portions of the manubrium , left clavicle , and left first rib were also excised to create access for a mediastinal tracheostomy .
post - operatively , the patient was extubated and taken to the cardiothoracic intensive care unit , where he had a relatively uncomplicated course .
he was able to transfer to an observation unit on post - operative day 2 , and eventually to the floor .
after discharge , he was seen by our department of radiation oncology , and initiated adjuvant radiation therapy in mid - october 2008 . this has been complicated by an episode of hemoptysis requiring inpatient observation about 1  month after initiating therapy . at the time of this report ,
the patient is approximately 7  months post - operative and has completed adjuvant radiotherapy .
he tolerates oral intake and exercise , and has gained 5  pounds in the last few months .
although a computed tomogram of the chest performed february 20 , 2009 showed two ill - defined  ground glass  opacities in the right and left upper lung lobes , he has no definitive evidence of tumor recurrence .
his next scheduled clinical follow - up is at 910  months post - operative .
1 ) were cellular and composed of crowded groups of tumor cells in a clean background . at high magnification
, individual tumor cells showed round to oval nuclei , granular chromatin with occasional small nucleoli , and scant cytoplasm .
the groups appeared cohesive and showed striking uniformity of size and shape . the needle biopsy material ( fig . 
3 ) showed solid nests of tumor cells separated by a dense fibrotic stroma , with tumor cells accounting for about one - quarter of the tissue examined .
as in the cytology preparation , individual tumor cells were fairly uniform , with round to oval hyperchromatic nuclei , granular chromatin with inconspicuous nucleoli , and a small amount of eosinophilic cytoplasm .
they also showed weak or focal reactivity for the neuroendocrine markers synaptophysin , chromogranin a , and cd56 .
stains for thyroglobulin , thyroid transcription factor-1 , calcitonin , carcinoembryonic antigen , cd45/leukocyte common antigen , and cd5 were uniformly non - reactive . as previously mentioned , a subsequent send - out immunostain ( gen - path ; cell marque pth antibody clone mrq-29 , prediluted ; antigen retrieval with ventana standard cc1 solution at 37c for 32  min ) showed diffuse and moderately strong staining for pth , leading to the diagnosis of parathyroid carcinoma . at operation , we received a composite en bloc resection of tumor and left thyroid lobe , larynx , superior trachea , hypopharynx , and superior esophagus ( figs .  4 and 5 ) .
the tumor and thyroid lobe was measured as 9.5    6.5    6.5  cm .
gross sections of the specimen showed extension of a tongue of tumor into the tracheoesophageal groove , as suggested by pre - operative imaging ( fig .  2 ) and operative findings .
microscopic sections of the tumor again showed large solid nests of tumor cells separated by broad bands of dense fibrosis . at high magnification
, tumor cells showed a crowded architecture , with focal areas of individual tumor cell necrosis .
nests of tumor extensively involved the thyroid gland and anterior cervical soft tissues , with extensive lymphvascular space invasion .
in addition , tumor cells extended through the membranous posterior trachea and approached the tracheal submucosal glands .
areas of the anterior trachea , near the area sampled by frozen section , also showed involvement by tumor .
although tumor approached the inked resection margins of the anterior cervical soft tissues , no tumor was seen at ink , and the sampled resection margins were free of tumor .
a biopsy of the left recurrent laryngeal nerve submitted for frozen section analysis showed rare atypical cells , suspicious for carcinoma , only on the permanent sections .
the separately received inferior esophagus and bones removed for tracheostomy access were free of tumor.fig . 
a anterior view of inked and sectioned gross specimen , with tumor in relation to contiguous structures ; b low - magnification image of tumor ( 20 ) ; c low - magnification image of tumor invading left thyroid lobe ( 20 ) ; d high - magnification image of tumor ( 600)fig .  5en bloc resection of non - functional parathyroid carcinoma . a transverse section of gross specimen , with tumor invading tracheoesophageal groove ; b low - magnification image of tumor ( arrow ) invading membranous posterior trachea ( 20 ) ; c low - magnification image of tumor ( double arrow ) invading lymphvascular space of anterior trachea ( 20 ) ; d high - magnification image of tumor deposit from previous panel ( 400 ) en bloc resection of non - functional parathyroid carcinoma . a anterior view of inked and sectioned gross specimen , with tumor in relation to contiguous structures ; b low - magnification image of tumor ( 20 ) ; c low - magnification image of tumor invading left thyroid lobe ( 20 ) ; d high - magnification image of tumor ( 600 ) en bloc resection of non - functional parathyroid carcinoma . a transverse section of gross specimen , with tumor invading tracheoesophageal groove ; b low - magnification image of tumor ( arrow ) invading membranous posterior trachea ( 20 ) ; c low - magnification image of tumor ( double arrow ) invading lymphvascular space of anterior trachea ( 20 ) ; d high - magnification image of tumor deposit from previous panel ( 400 )
table  1 lists the 19 cases of non - functional parathyroid carcinoma reported in the literature since 1929 , including the present case [ 826 ] .
one case previously considered a non - functional carcinoma is in fact a non - functional recurrence of a primary functional parathyroid carcinoma   and so is not considered here . to summarize , most patients presented in the sixth or seventh decade with a neck mass , with an age range of 27 to 71  years .
all patients were considered normocalcemic at the time of diagnosis , and had normal serum levels of pth in cases where this was measured .
tumor size was variable , but almost half of the cases had tumors between 5 and 11  cm in size ; in comparison , the ncdb case series reported a median tumor size of 3.3  cm .
the primary spread of tumor was locoregional invasion into the thyroid gland , cervical soft tissues , or superior mediastinum .
slightly over half of patients had recurrence of their tumors by the time of case report .
sixteen of 19 patients were alive at the time of case report , although most cases reported a relatively short follow - up period ; only three of the cases have data beyond 5  years from the date of initial therapy.table  1reported cases of non - functional parathyroid carcinomareferenceage / sexclinical presentationpre - operative dxserum ca ( mg / dl)serum pth ( nl)tumor size ( cm)ln involvementcurrent study 59/mdysphagia , hoarseness , neck massyes ( ihc)10.1 ( nl 8.6 - 10.3)20 pg / ml ( 14 - 72)9.5x6.5 x6.5nofernandez - ranvier et al .
67/fmultinodular goiterno ( mng)9.119 ng / dl ( 12 - 65)4.5x2 xo.8nokirkby - bott et al .
39/mneck mass , hoarseness , nephrolithiasisyes ( parathyroid scan)9.20.4 ng / nl ( 0.3 - 2.9)7.5x5.5 x5?collins et al .
59/mneck mass , vcp , dysphagia , axillary lnno ( adenoma w / high ml)normalnormal8x6x4yesyamashita et al .
[ 1618]27/mneck massno ( cystic thyroid mass)9.2 - 9.8?5.5?49/mneck massno????59/mneck massno ( follicular thyroid ca)9.5?2.5yeschahinian et al .
69/fneck mass , pleural effusionnonormalnormal2x2 , 14?dhom and hohbach   38/mneck massno ( thyroid nodule)normal?2.5x1.5?altenahr and saeger 50/mneck massno ( thyroid tumor)normal??yespachter and lattes 50/fchest painnonormal?diffuseyessieracki and horn 43/fneck mass , pain , dysphagk vcpno9.1?5x4?mcquillan 53/fneck massnonormal?golf ball?armstrong 71/fneck massno ( hodgkin lymphoma)11.9?11x11 x4?guy 29/fneck mass , dysphagia , painno ( thyroid adenoma)8?8x6x4yesreferencevascular invasionclear marginslocal invasionlocal recurrencedistant metastasistreatment ( initial s)survivalcurrent studyyesyesyes ( thyroid , trachea , hypopharynx)nonos + r ( en bloc resection)alive at 7 monthsfernandez - ranvier et al . yes?yes ( thyroid)yes ( neck , mediastinum)yes ( lung)s + r ( total thyroidectomy)alive at 2 years and 7 monthskirkby - bott et al . ? ?
yesyes ( neck)yes ( bone , lung)s + r ( neck exploration , incomplete exc)dead at 8 years and 2 monthsyamashita et al .   no?yes ( thyroid)nonos + r ( mass + thyroid lobe)alive at 10 monthsklink et al .
yesnoyes ( mediastinum)yes ( incomplete resection)nos + r + c ( incomplete resection)alive at 11 monthsmerlano et al . ? ?
yes ( mediastinum)yes ( mediastinum)yes ( axillary ln , liver , supraclavicular ln)pre - operative r + s + r   ( biopsies)alive at 4 yearsyamashita et al . ? ?
yes ( thyroid)nonos + r ( completion l thyroid lobectomy)alive at 20 monthshickey et al .
[ 1618]??yesyesyes ( axillary ln , lung , brain)s + r + c ( simple excision)dead at 2 years and 4 months??yes ( neck , mediastinum)yes ( mediastinum)yes ( lung , bone)calive at 9 months??yesyes ( mediastinum)yes ( lung , bone , ln)s + c ( total thyroidectomy , l radical neck dissection)dead at 1 years and 8 monthschahinian et al . ? ? yes ( neck ,
mediastinum)yes ( neck , mediastinum)yes ( lung)s + calive at 8 yearsdhom and hohbach yes?yes ( thyroid)??s ( radical thyroidectomy)?altenhr and saeger ? ? yes ( thyroid)yes ( neck)yes ( cervical ln)s + r ( l thyroid lobectomy)alive at 7 yearspachter and lattes no?yes (
mediastinum)yes ( incomplete resection)yes ( ln , skin)s ( partial excision)alive at 5 yearssieracki and horn yes?yes ( neck , thyroid)suspicious ( pericardium)suspicious ( paratracheal ln)s + r ( subtotal resection)alive at 3 yearsmcquillan ? ? yes ( thyroid)yes ( neck)nos + r ( r thyroid lobectomy)alive at 2 years and 4 monthsarmstrong ? ?
yes ( neck , mediastinum)nonos ( en bloc resection)alive at 2 monthsguy ? ? yes ( neck)yes ( neck)yes ( lung)s + r ( simple excision)alive at 2 years and 4 monthsan entry of ? indicates that the information was not provided in the original case reportihc immunohistochemistry , mng multinodular goiter , vcp vocal cord paralysis , mi mitotic index , ca carcinoma , s surgery , r radiation therapy , c chemotherapy reported cases of non - functional parathyroid carcinoma an entry of
? indicates that the information was not provided in the original case report ihc immunohistochemistry , mng multinodular goiter , vcp vocal cord paralysis , mi mitotic index , ca carcinoma , s surgery , r radiation therapy , c chemotherapy more striking than the data presented in the above cases , however , is the data not reported . as noted in the section 
introduction ,  the recommended mode of therapy for parathyroid carcinoma ( both functional and non - functional ) is en bloc resection of tumor with involved adjacent structures , and that overall survival directly correlates with the margin status of the initial resection . indeed , our present case report is the first non - functional parathyroid carcinoma to report negative margins after en bloc resection .
although most case reports do not comment on final margin status , we believe it is likely that many of these cases may have had tumor at or closely approaching the resection margins .
this assumption is based on the fact that only 4 of the 19 patients received an en bloc or radical procedure as initial therapy .
however , as listed in table  1 , only 2 of the 19 patients had a pre - operative diagnosis of parathyroid carcinoma ; many more carried diagnoses that would not have indicated an extensive resection .
if not definitely the case , it is likely that this diagnostic uncertainty also contributed to the surgical management of these patients . to summarize , non
- functional parathyroid carcinoma is a rare endocrine malignancy that presents with mass symptoms . due to the paucity of cases and
often limited clinical follow - up , it is difficult to compare survival to patients with functional parathyroid carcinoma .
non - functional parathyroid carcinoma is larger at presentation , appears to be best managed surgically , is often incompletely excised , and shows frequent locoregional recurrence and metastasis .
it is likely that improvements in the accuracy of diagnosis will improve the management and outcomes for patients with both functional and non - functional carcinomas .
clinically , a patient with primary hyperparathyroidism is most likely to have a parathyroid adenoma .
clues that the patient may have parathyroid carcinoma include a markedly elevated serum calcium ( > 14  mg / dl ) or pth ( > 5 the upper limit of normal ) , a palpable neck mass , or hoarseness ( indicating involvement of the recurrent laryngeal nerve ) .
intraoperatively , a firm grey - white gland with adherence to , or invasion of , adjacent structures is suggestive of malignancy .
much like other endocrine malignancies , the gold standard for diagnosis of carcinoma is distant metastasis .
the histological criteria for the diagnosis of parathyroid carcinoma were published by schantz and castleman   in 1973 , and are still valid today .
they include : sheets or lobules of tumor cells separated by dense fibrous bands , mitotic figures , necrosis , capsular invasion , or vascular invasion .
all of these features are seen in the present case . however , over 80% of parathyroid carcinomas
are well - differentiated tumors , and some of these histologic features can be seen in atypical parathyroid adenomas . are there any other criteria to distinguish benign adenomas from their malignant counterparts ?
recent data have suggested that molecular testing may be useful in the cases of parathyroid tumors with equivocal histologic features .
the first step in this process was the identification of hrpt2 , located on chromosome 1q , as the gene mutated in hpt - jt .
germline mutations were found in patients with hpt - jt , and sporadic mutations were also discovered in non - hpt - jt - associated parathyroid carcinomas .
additional studies also showed hrpt2 mutations in hpt - jt parathyroid adenomas and carcinomas , and sporadic carcinomas , suggesting that the gene may act as a tumor suppressor , and that its loss may be an initiating event in carcinogenesis [ 32 , 33 ] .
expression of the gene product , termed parafibromin , has also been investigated in parathyroid neoplasia .
two studies suggest that sporadic adenomas show expression of parafibromin by immunohistochemistry , whereas most sporadic carcinomas and all hpt - jt - associated parathyroid tumors display loss of expression , in parallel with the gene mutation studies [ 34 , 35 ] .
the exact mechanism of carcinogenesis induced by the loss of parafibromin remains to be elucidated .
recent data suggest that the protein associates with rna polymerase , regulates genes involved in cell growth and survival , acts as a cell cycle regulator , and plays a role in transducing transcriptional output from the wnt pathway [ 3640 ] .
in addition to hrpt2 , data also show that parathyroid carcinomas lose a greater proportion of tumor suppressor alleles as compared to benign causes of primary hyperparathyroidism , indicating genomic instability . testing for loss of these markers may supplement hrpt2/parafibromin analysis for diagnosis of borderline parathyroid neoplasms . the status of hrpt2/parafibromin in non - functional parathyroid carcinomas has not been investigated .
parathyroid carcinoma is a rare cause of primary hyperparathyroidism , and < 20 cases of it have been reported in the literature . in this study , we have reported the first case of non - functional parathyroid carcinoma with negative surgical margins after en bloc resection .
diagnosis of parathyroid carcinoma , whether functional or non - functional , is based on a number of clinical and histological criteria but can be challenging to differentiate from benign adenoma in many cases .
in addition to traditional criteria , new advances in molecular diagnosis , including evaluation of hrpt2/parafibromin , may aid in improving diagnostic accuracy .
 parathyroid carcinoma is a rare malignancy , and only accounts for 0.52% of cases of primary hyperparathyroidism . 
 less than 10% of parathyroid carcinomas are non - functional , and as such , they have been rarely reported in the literature . 
 importantly , margin status at resection is related to prognosis , and only a handful of case reports of non - functional carcinoma note this important parameter . here 
 we report the first case of non - functional parathyroid carcinoma with negative margins , and review the literature on this rare entity . 
 whether functional or non - functional , parathyroid carcinoma can often be difficult to differentiate from benign parathyroid adenoma . 
 while diagnosis has been based on clinical and histological criteria , recent data concerning the molecular underpinnings of parathyroid carcinoma may allow for improved accuracy in distinguishing benign and malignant parathyroid tumors . 
Clinical Features of Parathyroid Carcinoma
Case Summary
Pathologic Summary
Non-Functional Parathyroid Carcinoma
Diagnosis of Parathyroid Carcinoma
Summary