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Annales d’Endocrinologie xxx (2015) xxx–xxx

Journées Klotz 2015

Parathyroid carcinoma: Challenges in diagnosis and treatment

Le carcinome parathyroïdien : défis dans le diagnostic et traitement
Daniela Betea ∗ , Iulia Potorac , Albert Beckers
Département d’endocrinologie, université de Liège, CHU Sart Tilman, 4000 Liège, Belgium

Abstract
Parathyroid carcinoma is a malignant neoplasm affecting 0.5 to 5.0% of all patients suffering from primary hyperparathyroidism. This cancer
continues to cause challenges for diagnosis and treatment because of its rarity, overlapping features with benign parathyroid disease, and lack
of distinct characteristics. The third/second generation PTH assay ratio provides valuable information to distinguish between benign parathyroid
disease and parathyroid carcinoma. An abnormal ratio (> 1) could indicate a high suspicion regarding carcinoma and metastatic disease. Early en
bloc surgical resection of the primary tumour with clear margins remains the best curative treatment. Although prolonged survival is possible with
recurrent or metastatic disease, cure is rarely achievable. The efficacy of classical adjuvant therapies, such as radiotherapy and chemotherapy, in
management of persistent, recurrent, or metastatic disease has been disappointing. In metastatic disease the goal of therapeutic support is to control
the PTH-driven hypercalcemia that represents the primary cause of mortality. Calcimimetics, which are allosteric modulators of the calcium sensing
receptor, have a sustained effect in lowering serum calcium levels. Bone anti-resorptive therapy, like intravenous bisphosphonates (pamidronate
and zolendronate), or more recently denosumab (fully human monoclonal antibody with high affinity to bind RANK ligand) might be temporarily
useful. In a small number of cases treated with anti-PTH immunotherapy, inducing anti-PTH antibodies, promising results have been seen with
clinical improvements and decrease of calcemia. In one case metastasis shrinkage has been observed.
© 2015 Elsevier Masson SAS. All rights reserved.

Keywords: Parathyroid carcinoma; Hypercalcemia; PTH ratio; Surgery; Immunotherapy

Résumé
Néoplasie endocrinien rarissime, le carcinome parathyroïdien affecte 0,5 à 5 % des patients souffrant d’hyperparathyroïdie primaire. Ce cancer
énigmatique pose une grande difficulté diagnostique et thérapeutique du fait de sa rareté, de l’absence de signes cliniques et paracliniques caractéris-
tiques, qui miment ceux de l’hyperparathyroïdie primaire bénigne. Le ratio entre les valeurs de la PTH dosées avec les kits de troisième/deuxième
génération, fournit actuellement des informations très précieuses dans le diagnostic différentiel de l’hyperparathyroïdie primaire bénigne et le
carcinome parathyroïdien. Un ratio anormal (> 1) soulève une grande suspicion de carcinome et de maladie métastatique. Le meilleur traitement,
à visée curative, demeure la chirurgie avec résection « en bloc » de la tumeur primitive avec marges de sécurité oncologique. Dans le cas de la
maladie métastatique, une survie assez prolongée est possible, aux prix des multiples interventions, la guérison n’étant que très rarement acquise.
L’efficacité des thérapies adjuvantes classiques, comme la radiothérapie ou la chimiothérapie, dans le contrôle d’une maladie évolutive, récurrente
ou métastatique, est très décevante. Dans la maladie métastatique, le but du traitement est de maîtriser l’hypercalcémie maligne PTH-induite, qui
représente la première cause de mortalité. Les calcimimétiques, modulateurs allostériques du récepteur sensible au calcium, ont un effet significatif
dans la réduction des taux de calcium sériques. La thérapie antiresorbtive, avec puissants bisphosponates en intraveineux (pamidronate et zolen-
dronate), ou plus récemment le dénosumab (anticorps monoclonal humanisé, avec grande affinité pour le RANK-ligand) peut se montrer d’une
utilité temporaire. Dans quelques cas, l’immunothérapie anti-PTH a montré des résultats encourageants, avec induction d’anticorps anti-PTH,
suivie d’amélioration clinique et réduction de la calcémie. Dans un cas, une régression des métastases a été observée.
© 2015 Elsevier Masson SAS. Tous droits réservés.

Mots clés : Carcinome parathyroïdien ; Hypercalcémie ; PTH ratio ; Chirurgie ; Immunothérapie

∗ Corresponding author.
E-mail address: daniela.betea@chu.ulg.ac.be (D. Betea).

http://dx.doi.org/10.1016/j.ando.2015.03.003
0003-4266/© 2015 Elsevier Masson SAS. All rights reserved.

Please cite this article in press as: Betea D, et al. Parathyroid carcinoma: Challenges in diagnosis and treatment. Ann Endocrinol (Paris) (2015),
http://dx.doi.org/10.1016/j.ando.2015.03.003
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1. Introduction
A very rare malignancy, parathyroid carcinoma represents
less than 0.005% of all cancers. It is also a very rare endocrine
cancer (<1% of all cases of primary hyperparathyroidism) with a
reported incidence ranging from 0.5 to 5% with some geographic
variation (1% in Europe and USA and about 5% in Japan) [1–4].
Since the first description of a parathyroid carcinoma by De
Quervain in 1904 [5], nearly 1000 cases have been reported
around the world [1,2,4,6].
The great majority of parathyroid carcinomas are secreting
tumors, presenting as primary hyperparathyroidism (which is
the third most frequent endocrine disorder [7]). This apparently
benign presentation is responsible in part for the great diagnostic
difficulty.
More frequently, the diagnosis is retrospective, either during
surgery, or, most likely, consequent to histologic analysis. How-
ever, it is not rare to observe the relapse of hypercalcemia due
to metastatic disease years after the initial surgery.
The only curative treatment is surgery. Due to the very low
incidence of parathyroid carcinoma and the lack of specific
clinical and paraclinical signs, surgery of primary hyperparathy-
roidism is rarely performed as a specific anti-cancer intervention.
Most experts recommend en bloc resection, which is the
minimum requirement for obtaining the best survival rates.
Despite these recommendations, most retrospective studies have
shown that the commonest surgical technique is actually simple
local excision, performed in over 50% of interventions [3,8,9].
This oncologically-incomplete technique leads to a significant
increase of the recurrence and mortality risks to 60% and 35% of
cases, respectively [3,8,9]. Most likely, this important discrep-
ancy between expert recommendations and clinical practice is
due to the lack of pre-surgical factors that could raise the clinical
suspicion of a parathyroid carcinoma in regard to the numerous
cases of benign primary hyperparathyroidism.
Therefore, it becomes of paramount importance to identify
the very few patients at risk of having a parathyroid cancer
among the large group of patients suffering from primary hyper-
parathyroidism.
In this brief overview we will present, in light of the lat-
est research, the clinical, biological and imaging parameters
that may raise suspicion of malignancy in patients with primary
hyperparathyroidism prior to surgery. Also, we will focus on the
novel therapeutic possibilities in the management of metastatic
disease.
2. Epidemiology
The rarest cause of primary hyperparathyroidism (PHPT),
parathyroid carcinoma (PC) has an incidence of less than 1% of
PHPT patients reported in the USA and Europe. It accounted for
0.005% of all malignancies according to the National Cancer
Data Base from 1985–1995 and Surveillance, Epidemiology,
and End Results (SEER) Cancer Registry from 1988 through
2003 [1,3,4,6]. The incidence was 5.1% of cases of PHPT in
a national survey in Japan from 1980 to 1989, suggesting that
there may be significant regional variations [2]. Parathyroid
Please cite this article in press as: Betea D, et al. Parathyroid carcinoma: Challenges in diagnosis and treatment. Ann Endocrinol (Paris) (2015),
http://dx.doi.org/10.1016/j.ando.2015.03.003
carcinoma occurs with equal frequency in men and women.
There is a slight male predominance in some series, in contrast
with benign PHPT where females predominate. Classically, the
disease is described to occur one decade earlier than primary
benign HPT, but the largest registry studies do not seem to
confirm these data, as the mean age at diagnosis was found
between 54–56 years [3,4,10–12], similar to benign HPT.
3. Etiology and risk factors
The etiology of parathyroid cancer, like that of other malig-
nancies, is unknown. It is obvious that multiple environmental
and genetic factors interact in a very complex manner. Exposure
to radiation therapy, especially at a young age, increases the
risk of benign parathyroid disease [13,14], as well as of thyroid
and parathyroid neoplasia [15–18]. Nonetheless, whether such
exposure represents a potential etiologic factor in parathyroid
cancer is still unclear.
Parathyroid cancer usually occurs sporadically, but it has
also been reported as part of genetic syndromes. These syn-
dromes include the rare autosomal-dominant disorder familial
hyperparathyroidism [11,19–21], as well as multiple endocrine
neoplasia types 1 (MEN1) and 2A (MEN 2A) [22–25]. The
most recent advances in the understanding of parathyroid cancer
genetics have come from clinical and genetic studies of patients
with hyperparathyroidism-jaw tumor syndrome (HPT-JT), a
rare autosomal dominant familial disorder. In this syndrome
the affected individuals develop primary hyperparathyroidism,
mandibular and maxillary fibro-osseous lesions and renal and/or
uterine tumors. Up to 15% of patients with HPT-JT develop
parathyroid cancer. The gene responsible for this syndrome is
known as HRPT2/CDC73, located at 1q13 and coding for a
nuclear protein named parafibromin [26], which acts as a reg-
ulator of transcription. Mutations in HRPT2/CDC73 gene were
found in around 25% of cases with apparently sporadic parathy-
roid carcinoma [27–30]. Genetic DNA analysis for germline
mutation in HRPT2/CDC73 gene is recommended in all patients
with parathyroid cancer, due to the potential benefit for offspring
and their surveillance.
Immunohistochemical analysis of parathyroid tumors for loss
of parafibromin expression offers new promise as a diagnostic
tool that could facilitate the histologic diagnosis of parathyroid
carcinoma, which is often far from obvious [31].
Other somatic gene mutations have been involved in the
development of parathyroid carcinoma, including aberrant
expression of retinoblastoma (RB) and p53 protein, but no clin-
ically significant conclusions have been reached [29].
4. Clinical features
When evaluating a patient with primary hyperparathy-
roidism, the most important goal is to differentiate between
benign and malignant disease prior to surgery. This can be
difficult as there are no specific clinical characteristics that
allow differentiation of parathyroid cancer from benign dis-
ease. As the majority of parathyroid cancers are functioning
tumors, many clinical symptoms are similar to those of benign
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primary hyperparathyroidism, such as fatigue, muscle weak-
ness, depression, weight loss, abdominal pain, polyuria, bone
disease, nephrolithiasis, peptic ulcer and pancreatitis [11,32,33].
The clinical symptoms usually precede local or regional invasion
of the tumour.
A positive personal or family history of primary hyper-
parathyroidism and genetic syndromes associated with parathy-
roid cancer such as HPT-JT and MEN1 should draw the
clinician’s attention.
Certain conditions are considered to be associated to
a higher risk of parathyroid carcinoma, without being
specific. Severe hypercalcemia (albumin-corrected calcium lev-
els > 3.0 mmol/L), young age, male gender, hypercalcemic
crisis, concomitant renal and bone involvement, as well as the
presence of a palpable neck mass (more than 3 cm) should raise
the suspicion of parathyroid carcinoma [1,6,8,11,34]. Patients
with this combination of symptoms have a 4.5–fold increased
risk of parathyroid cancer when compared to less symptomatic
patients. Hoarseness as a sign of recurrent laryngeal nerve palsy
due to local invasion is highly suggestive of malignancy, since
it is very uncommon in benign hyperparathyroidism.
5. Novel PTH assay
We have recently studied a new laboratory diagnostic tool
that can greatly help the clinician in differentiating benign
adenoma from malignant carcinoma. This is the ratio of PTH
measurement, obtained by dividing third-generation to second-
generation assay results [35–38].
PTH levels in parathyroid cancer are usually very high [39].
However, in most patients, high levels of PTH are secreted by
benign lesions. The first assays used to measure PTH – an 84-
amino-acid peptide hormone – were radioimmunoassays. They
recognized the full length of PTH 1-84, but also a large amount
of various C-terminal fragments (resulting from processes of
cleavage and phosphorylation).
Since 1987 various routine immunoassays of so-called intact
PTH became available [40]. These immunoassays (commonly
termed second-generation PTH immunoassay) use a pair of anti-
bodies that bind to the PTH 13-24 and PTH 39-85 regions of
the peptide. These antibodies also cross-react with a family of
large N terminal-truncated fragments, among which the most
abundant form is PTH 7-84. This latter form accumulates in
patients suffering from chronic kidney disease, leading to an
overestimation of PTH values.
In 1999 a next generation of PTH immunoassays was devel-
oped (commonly termed third-generation PTH immunoassay)
[41]. These immunoassays used capture antibodies similar to
the second-generation immunoassay for the PTH 39-84 region,
but added anti N-terminal antibodies directed against the PTH 1-
4 epitope. Therefore this immunoassay can recognize the entire
PTH molecule, as well as the non-truncated amino-PTH, but
does not measure the PTH 7-84 fragment.
Amino-PTH, a recently described form of PTH, is modified
in the 15-20 amino-acid region, probably by phosphorylation
of a serine residue at position 17 [35]. Amino-PTH cross-reacts
Please cite this article in press as: Betea D, et al. Parathyroid carcinoma: Challenges in diagnosis and treatment. Ann Endocrinol (Paris) (2015),
http://dx.doi.org/10.1016/j.ando.2015.03.003
3
with these third-generation PTH kits, but not with antibodies
used in the second-generation kits.
PTH 7-84 represents 15–50% and amino-PTH less than 10%
of the total circulating PTH. Consequently, in healthy indi-
viduals the ratio between the amounts of PTH measured with
third- versus second-generation assays, will not be superior to
1. Recently it has been shown that amino-PTH is overproduced
in parathyroid carcinomas [36]. In these cases, the third- to
second-generation PTH ratio may be inverted (>1).
In our study, in a series of 24 patients with advanced parathy-
roid carcinoma – a comparatively large series, considering the
rarity of the disease –, an inverted third-generation to second-
generation PTH ratio was found in 83% of patients compared
with 0% of a series of 245 relevant controls. Our results, as
well as those from the literature, indicate than an inverted third-
generation to second-generation PTH ratio is a tumor marker
for parathyroid carcinoma, with a sensitivity of 78.5% and a
specificity of 98.9% among patients with primary hyperparathy-
roidism [35–37,42].
The overproduction of non-truncated amino-PTH in patients
with parathyroid cancer might be related to HRPT2/CDC73
inactivation [43].
6. Imaging studies
After the biological diagnosis of hyperparathyroidism,
almost all patients undergo imaging studies for tumour local-
isation. When combined, these diagnostic techniques have high
sensitivity and specificity. Neck ultrasound and technetium-
99m sestamibi scan are the most common imaging studies used
in benign disease, but they are highly informative in malig-
nant cases as well [44–48]. Computed tomography (CT-scan),
magnetic resonance imaging (MRI), 18-FDG positron emission
tomography (PET-scan) and, recently, fusion imaging of single
photon emission computed tomography (SPECT) and CT have
a better sensitivity as compared to sestamibi scan and a similar
specificity [49].
Ultrasonography (US), which is accessible, noninvasive and
inexpensive, is the most widely used technique [6]. Parathyroid
carcinoma appears as a large hypoechoic, lobulated lesion, with
irregular borders as compared to parathyroid adenomas [50,51].
In a recent retrospective ultrasonographic study, specific criteria
that predict malignancy were identified, such as infiltration and
calcifications. The absence of suspicious intra-tumoral vascu-
larisation, a thick capsule and a heterogeneous aspect has a high
negative predictive value, allowing the investigator to largely
exclude malignancy [47,52].
Fine needle aspiration (FNA) should be avoided as the
cytology obtained with this technique is largely insufficient
to differentiate between benign and malignant tumors [52,53].
Moreover, FNA risks tumor seeding on the biopsy tract [54].
Technetium-99m sestamibi scanning is used for parathyroid
tumor localization, but it does not supply information regarding
the benign or malignant nature of the tumor. The technique is
however useful in diagnosing and localizing metastatic parathy-
roid carcinoma [55–57].
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Other imaging techniques such as CT scan and MRI may be
useful for localizing recurrence or metastasis, most frequently
in the lungs, liver and bones. The combination of at least two
techniques enhances the sensitivity for detecting recurrent dis-
ease of the Tc-99m sestamibi scan, CT scan and ultrasonography
to 86, 79 and 100% in a series of 14 reintervention cases [58].
Previous results obtained in a similar series of reinterventions,
found a sensitivity for localizing parathyroid carcinoma recur-
rence using Tc-99m sestamibi scan, MRI, CT scan, ultrasound
and selective venous sampling of PTH secretion of 79, 93, 69
and 83% respectively [45].
During surgery, in the absence of massive local invasion or
regional metastasis, the diagnosis of carcinoma is very diffi-
cult. In a large retrospective study in 1999, for 86% of patients
the diagnosis of parathyroid carcinoma could not be estab-
lished during surgery, although it was performed by experienced
parathyroid surgeons [1]. Frozen section analysis is of little
value, since the histopathological features of carcinoma may
overlap those of benign adenoma [59].
Before referring patients with suspected parathyroid can-
cer to the surgeon, the most reliable parameters that indicate
an increased cancer risk are blood calcium levels corrected
for albumin, PTH assay ratio and tumour size. The values of
these parameters will orient the surgeon towards an oncological
approach.
7. Histopathological diagnosis
Confirmation of parathyroid cancer is histopathological. The
cardinal features for the diagnosis of any cancer rely on local
invasion and metastasis. However, these features are not com-
monly found at the first presentation in parathyroid carcinoma
[60].
Many pathological criteria have been proposed to help dis-
tinguish between benign and malignant lesions, as no single
histopathological feature is pathognomonic for parathyroid car-
cinoma. Early reports in the 1970s [61] describe a combination
of criteria highly suggestive of malignancy: fibrous trabeculae,
mitotic figures, capsular and vascular invasion. None of these
criteria are sensitive or specific enough to confirm or recuse
the diagnosis, as mitotic activity and trabecular pattern are also
found in benign lesions [62,63].
More recently, the histopathological diagnosis of parathy-
roid cancer, according to the WHO criteria [64], is defined as
the presence of minor criteria such as capsular and soft tissue
invasion as a sign of infiltrative growth or a major criterion as
histological proof of vascular invasion, with or without invasion
of vital organs, or presence of local or distant metastasis [64,65].
In practice, capsular invasion is only found in some of the spec-
imens, whereas vascular invasion is rarely present [32,66]. It is
hence of great importance to consider the overall clinical picture,
rather than any single histopathological feature [2,52,60].
Because of these difficulties, considerable efforts have been
directed towards developing other methods such as immunohis-
tochemistry and DNA analysis [67,68]. Immunohistochemical
staining for parafibromin can help to avoid diagnostic errors;
the absence of parafibromin is a powerful tool to diagnose
Please cite this article in press as: Betea D, et al. Parathyroid carcinoma: Challenges in diagnosis and treatment. Ann Endocrinol (Paris) (2015),
http://dx.doi.org/10.1016/j.ando.2015.03.003
parathyroid cancer, as it is rarely observed in sporadic benign
cases. Recent reports suggest using a combination of different
markers including loss of parafibromin together with Rb
expression and overexpression of galectin-3 and Ki-67 labelling
index. This combination was found to be highly relevant in
differentiating parathyroid carcinoma from atypical adenoma
and other non-malignant lesions [68,69].
Moreover, a more recent study explored the value of
parafibromin staining as a prognostic marker in parathyroid
carcinoma. The authors found that negative staining for parafi-
bromin was associated to a higher risk of recurrence, decreased
5-year survival rates of 59% and significantly decreased 10-year
survival rates of 23% [70].
Finally, all patients with parathyroid carcinoma should be
considered for germline testing for HRPT2/CDC73 because
more than 20% of them have unrecognised HPT-JT syndrome
even in the absence of family history [27,29,71].
8. Management/therapeutical support
8.1. Staging
Because of the rarity of the disease, there is no universally
agreed-upon staging system.
Several research groups have proposed possible staging sys-
tems for parathyroid cancer [8,72].
Shaha and Shah proposed a staging system based on the size
of the tumour, extent of local invasion, presence of regional
lymph node extension and distant metastases [72].
The other classification system proposed by Talat and Schulte
focuses more on the extent and type of tumor invasion rather than
tumor size [8]. They also divide parathyroid carcinoma cases into
low and high risk. Low-risk disease is defined as invasion limited
to the capsule and soft tissue. High-risk disease is defined as any
of the following: vascular invasion, lymph node metastasis or
invasion of vital organs (trachea, oesophagus or major cervical
vessels). The same research group recently published an analysis
of a new classification system that further subgrouped high-
risk cancer. In this classification low-risk cancer corresponded
to class I. The high-risk cancers were subdivided into vascu-
lar invasion alone (class II), lymph node metastasis or organ
invasion (class III) and distant metastasis (class IV). A statisti-
cally significant overall survival difference was found between
these different classes (98.6, 72, 71.4, 40% respectively), thereby
confirming the validity of this classification system [8,73].
8.2. Surgery
The treatment of choice is undoubtedly complete surgi-
cal resection, the only technique that is potentially curative
[1,3,6,32,45]. The goal is to remove the entire tumour, prevent
local recurrence and eliminate the risk of distant metastasis origi-
nating from regionally persistent disease [9]. The most important
factors determining patient outcome are tumour characteristics
and surgical approach.
Surgery is indicated in two distinct clinical scenarios: at the
time of diagnosis of hyperparathyroidism, when it could be
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curative and in case of recurrent or metastatic disease, when
multiple interventions are usually necessary.
Complete en bloc resection with ipsilateral hemithyroidec-
tomy and centrocervical lymphadenectomy should represent the
minimum oncological approach in all patients with suspected
parathyroid carcinoma. When performed by dedicated endocrine
oncologic surgeons, this procedure has moderate risks [65]. It
is of great importance that clear gross margins are obtained and
rupture of the capsule is avoided, preventing tumour seeding
and local recurrence [74,75]. If the recurrent laryngeal nerve is
involved, it can be sacrificed [45].
At presentation, 15–30% of PC patients have cervical node
involvement. The therapeutic ipsilateral cervical compartment
lymph node dissection is indicated if preoperative or intraoper-
ative findings indicate lymph node involvement. Prophylactic
neck dissection in patients without evidence of local inva-
sion is not indicated, because it does not improve survival,
but does increase morbidity [76]. More extensive surgical
resection advocated by certain investigators is usually not rec-
ommended because of increased morbidity and unimproved
survival [77].
The evolution of the disease is directly influenced by the sur-
gical approach, hence the importance of the en bloc resection.
Patients who were diagnosed before or during surgery and ben-
efited from an en bloc resection had a recurrence rate of 33%,
whereas patients who were diagnosed after the initial surgery
had a recurrence rate of over 50%, as only local excision was
performed [1,3,76]. The use of rapid intraoperative PTH assay,
when available, can be useful in the management of parathy-
roid carcinoma. Normalization of PTH levels postoperatively is
reassuring that the tumour was most likely completely resected
[37,52,78]. If PTH levels do not decrease into the normal range
and the patient remains hypercalcemic, incomplete resection
should be suspected and additional localisation studies and re-
intervention is warranted. In these cases, adequate pre-operative
imaging techniques are of capital importance to help localise the
disease and guide the surgeon toward the adequate intervention.
Parathyroid carcinoma usually recurs two to five years after
the initial surgery [74,76]. Local recurrence rates vary between
33% and 82% at five years [6,32,61,76] and are most likely due
to incomplete resection.
Metastases occur through lymphatic and hematogenous dis-
semination. The most common sites of distant metastasis are the
lung, liver and bones [6,61,75].
Patients with recurrent disease or distant metastasis present
with gradually increasing serum calcium along with high PTH
values. At this point, management of hypercalcemia and per-
forming appropriate imaging studies to localise the site of
recurrence are essential. Combining techniques, from less to
more invasive, such as selective venous sampling with PTH mea-
surement, should be undertaken in case of inconclusive results
[45].
Repeat surgery with metastasis resection has shown to
decrease PTH and calcium levels, providing symptomatic relief
and temporary biochemical normalisation, which is why it is
always recommended when feasible. Resection of distant metas-
tasis has been shown to improve patient survival, as the mortality
Please cite this article in press as: Betea D, et al. Parathyroid carcinoma: Challenges in diagnosis and treatment. Ann Endocrinol (Paris) (2015),
http://dx.doi.org/10.1016/j.ando.2015.03.003
5
in advanced parathyroid carcinoma is mostly related to severe
hypercalcemia rather than the tumour mass [44].
The goal of metastasis resection is to remove all lesions
located in the neck, mediastinum, as well as in distant sites and to
obtain clear margins. In patients who have repeated recurrences,
a combined treatment modality could be employed complemen-
tary to surgery: embolization, radio-frequency ablation [79].
8.3. Chemotherapy
There is no evidence supporting the efficacy of chemother-
apy in parathyroid carcinoma. Due to the rarity of the disease,
experience is limited to case reports [11,32,74,80]. These scat-
tered case reports showed some benefits with regimens including
dacarbazine alone or in combination with other agents in patients
with advanced metastatic disease, but a survival benefit was not
demonstrated [11,80].
8.4. Radiotherapy
Parathyroid carcinoma is not considered to be radiosensitive
and there is no evidence for the efficacy of radiation treatment
as primary therapy in local or metastatic disease. There is some
evidence, however, suggesting the benefit of postoperative radio-
therapy, in several case reports [11,32,81,82]. In these cases,
radiotherapy reduced local recurrence and increased disease free
interval. In one study, the investigators recommended adjuvant
post-surgery radiation with 40-50 Gy in patients at high risk of
local recurrence [82], while in another study the dosage admin-
istered was 70 Gy [81]. These results should be interpreted with
great caution, as the studies were retrospective and each included
a very small number of patients.
8.5. Metastatic disease
For most patients with metastatic dissemination, parathyroid
carcinoma becomes a chronic disease. The severe hypercalcemia
is the most frequent cause of morbidity and mortality. Prolonged
survival is still possible at this stage, as long as hypercalcemia
is controlled.
Medical intervention is required in patients with disseminated
or unresectable local disease, in case of hypercalcemic crisis and
also in patients selected for surgical reintervention.
In such patients, severe dehydration arises because of the
calcium-induced nephrogenic diabetes insipidus and the associ-
ated nausea and vomiting. Aggressive volume expansion with
saline infusion and use of loop diuretics to enhance renal excre-
tion of calcium are required on an urgent basis [56].
The use of agents interfering with osteoclast bone resorption
is almost always necessary.
8.5.1. Bisphosphonates
Bisphosphonates, which are potent inhibitors of osteoclast-
mediated bone resorption, have been shown to reduce
serum calcium in patients with parathyroid cancer [6,56,83].
Potent agents such as pamidronate and zolendronate can be
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administered intravenously, but their control of hypercalcemia
is only temporary, ranging from days to several months at best.
8.5.2. Denosumab
Denosumab, an humanized monoclonal antibody that binds
to the “receptor activator of nuclear factor kB ligand (RANKL)”
was recently reported to be effective in the management of severe
hypercalcemia in patients with metastatic disease [84,85]. It is
effective for several months.
Use of other agents such as mithramycine [6], plicamicyn
and gallium nitrate is limited due to their toxicity, particularly
renal. Moreover, their efficacy is only transient [86].
Calcitonin and octreotide as well as corticosteroids can also
be administered, but with only temporary benefit [6,87].
8.5.3. Calcimimetics
Calcimimetics represent another class of drugs, which are
allosteric modulators of the calcium sensing receptor. These
drugs bind to the calcium-sensing receptor on the surface of
parathyroid cells, increasing the receptor’s sensitivity to extra-
cellular calcium. This results in a reduction of PTH secretion by
parathyroid cells [83].
After encouraging results with a first-generation cal-
cimimetic (R-568), a second-generation product, cinacalcet,
proved its efficacy by decreasing serum calcium in patients
with metastatic parathyroid carcinoma enrolled in a multicen-
tric study. In this study 18 out of 29 patients responded to
treatment with an average reduction in serum calcium from
15 mg/dL to 11 mg/dL. Patients with the highest calcium levels
at the beginning of the study had the most significant responses.
Patients tolerated total daily doses up to 360 mg, nausea and
vomiting being the most common side effects. Interestingly,
decreased serum calcium levels were achieved without a sig-
nificant decrease in PTH levels [88,89].
8.6. Radiofrequency ablation of metastasis
In metastatic disease with unresectable disseminated lesions,
alternative methods such as radiofrequency ablation were report-
edly used in the management of lung metastasis [90,91]. A
combination of radiofrequency ablation and transcatheter arte-
rial embolization has been used to treat multiple metastatic
lesions in the liver [92]. In these reports, improvement of serum
calcium and PTH levels were obtained following treatment.
8.7. Immunotherapy
The early years of immunotherapy in the treatment of solid,
aggressive cancers have seen inconclusive results. Progressively
the mechanisms of antigen presentation, immune tolerance and
autoimmunity became more clearly understood. This raised
interest in developing a variety of methods used to induce and
enhance targeting of antigens expressed by cancer cells.
In 1999, Bradwell and Harvey showed that it was possible
to reduce hypercalcemia in a patient with terminal metastatic
parathyroid carcinoma, by immunologically blocking the effects
Please cite this article in press as: Betea D, et al. Parathyroid carcinoma: Challenges in diagnosis and treatment. Ann Endocrinol (Paris) (2015),
http://dx.doi.org/10.1016/j.ando.2015.03.003
of high PTH concentrations. This was achieved by immunisa-
tion and induction of neutralizing autoantibodies against human
PTH. This procedure involved breaking normal immune toler-
ance to PTH by using human and bovine PTH-like immunogenic
fragments in order to stimulate the production of antibodies that
would cross-react with human PTH [93].
We immunised our first patient in 2001 following the same
protocol [94]. We chose a combination of human, modified
human and bovine peptides for the immunotherapy. The human
modified peptides contained single amino-acid substitution at
position 2 of each fragment, remaining more similar to human
molecule than to the bovine one. These minimal structural dif-
ferences are required to favour cross-recognitions of human
proteins, assuring a satisfactory major histocompatibility com-
plex presentation of antigens from B cells to T cells. Antigenicity
was enhanced by synthesizing each of the PTH fragments as
multi-antigenic peptides (octamers) on lysine webs connected to
a lysine core. These immunogenic peptides were further mixed
with whole human PTH and with Freund adjuvant and were fur-
ther administrated as intradermal injections targeting cervical,
axillary and inguinal lymph nodes.
After the fourth immunisation, we observed a decrease and
even normalisation of calcium concentrations followed by the
same trend in PTH levels. Both calcemia and PTH levels were
normalised at the time of the fifth immunisation and remained
stable for more than 72 months [94].
Semi-quantitative dot-blot analysis was used to demonstrate
the presence of antibodies against all the human and bovine PTH
fragments. These were identified as early as three weeks after
the first immunisation [94].
Regular surveillance of pulmonary metastases found a
progressive decrease from the baseline (before starting
immunotherapy) to the time of the eight immunisation of
39.2–71.4% in their size [94]. The patient remains alive and
well but has required intermittent but irregular immunisations
due to increases in serum calcium,
Few other patients with metastatic parathyroid carcinoma
were immunised by following the same protocol. A significant
reduction in calcium levels was obtained and it lasted for over
six months, with no change of PTH levels or metastases volume
[95,96].
Almost at the same time, another immunisation method has
been attempted. Dendritic cells, pulsed with patient’s tumour
extract in vitro have been used in parathyroid carcinoma, as
well as in medullary thyroid carcinoma, but with poor clinical
results [97,98], possibly related to antigen processing.
In our opinion, immunotherapy represents a promising tech-
nique. It provides significant clinical benefits in term of survival
and quality of live and has fewer side effects when used as
adjuvant therapy. Nevertheless, this treatment requires further
validation in clinical trials, which are difficult to conceive due
to the rarity of the disease.
In the past decade, significant advances in the understanding
of mechanisms underlying tumour immunology were achieved.
Immunotherapy has become an important therapeutic strategy,
with advanced phase III clinical studies demonstrating sur-
vival advantages in the treatment of melanoma, lung or prostate
+Model
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cancer. Various immunotherapy techniques have been devel-
oped recently with a wide field of application. These focus
on stimulating an immune response against tumour antigen
or on reducing immune tolerance to cancer cells by block-
ing inhibitory immune checkpoint molecules, as in the case of
advanced melanoma [99].
9. Conclusion
Parathyroid carcinoma is a rare disease, usually presenting
with clinical signs of severe hypercalcemia, but often disguising
as apparently benign primary hyperparathyroidism. As for many
other cancers, its cause is unknown, although recently mutations
in the HRPT2/CDC73 gene were found to play a fundamental
role in pathogenesis.
Clinical suspicion prior to surgery is crucial, since specific
surgical procedure is the only potentially curative therapy. The
combination of high levels of serum calcium, tumour size and
an inverted (>1) PTH ratio are efficient in orienting towards an
oncological surgical approach.
In the case of metastatic disease and when surgery is no longer
indicated, combined techniques, such as powerful bisphospho-
nates, new antiresorbtive agents, calcimimetics, radiofrequency
ablation and immunotherapy, are useful tools in controlling the
complications of severe hypercalcemia.
Disclosure of interest
The authors declare that they have no conflicts of interest
concerning this article.
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