Journal of Cancer 2011, 2
Jo ou ur rn na al l o of f CCa an nc ce er r
2011; 2: 532-537
Parathyroid Carcinoma: A Review with Three Illustrative Cases
Antoine Digonnet1, Adelaïde Carlier1, Esther Willemse1, Marie Quiriny1, Cécile Dekeyser1, Nicolas de Saint
Aubain3, Marc Lemort2, Guy Andry1
1. Department of Head and Neck Surgery, Free University of Brussels. Jules Bordet institute, 1000 Brussels, Belgium.
2. Department of Radiology, Free University of Brussels. Jules Bordet institute, 1000 Brussels, Belgium.
3. Department of Pathology, Free University of Brussels. Jules Bordet institute, 1000 Brussels, Belgium.
Corresponding author: Antoine Digonnet, Jules Bordet institute, rue Heger Bordet, 1, 1000, Brussels, Belgium. Tel: +322
541 33 19 Fax: +322 541 31 41 email@example.com
© Ivyspring International Publisher. This is an open-access article distributed under the terms of the Creative Commons License (http://creativecommons.org/
licenses/by-nc-nd/3.0/). Reproduction is permitted for personal, noncommercial use, provided that the article is in whole, unmodified, and properly cited.
Received: 2011.08.21; Accepted: 2011.10.20; Published: 2011.10.27
Parathyroid carcinoma is a rare disease, which accounts for less than 1% of all case of primary
hyperparathyroidism and is usually not detected until the time of surgery or thereafter. For
most patients preoperative staging is not available. A radical excision remains the standard
management; the place of adjuvant radiotherapy is not well established yet. Local recurrence
and/or the metastases are unfortunately frequent. The present paper presents an up to date
review of the literature illustrated by three clinical cases.
Key words: parathyroid carcinoma, hypercalcemia, hyperparathyroidism, prognosis, surgery,
methylene blue, radiotherapy
Parathyroid carcinoma, a rare endocrine malig-
nancy, accounts for less than 1% of cases of sporadic
primary hyperparathyroidism. Clinical manifesta-
tions are generally more severe than in common be-
nign diseases such as parathyroid adenoma or hy-
When diagnosed, this neoplasm is a solitary le-
sion but anecdotal cases of multiple lesions have been
described 1, extremely rarely were bilateral parathy-
roid carcinomas reported 2.
Usually the disease has an indolent but slowly
progressive course. Most of the patients will die due
to complications of hypercalcemia, rather than direct
tumor invasion or metastases. The management of PC
is difficult in terms of diagnosis, treatment and fol-
The distinction between malignant and benign
lesions of the parathyroid is difficult, even with a
histopathological examination. For most patients
preoperative staging is not available. Intraoperative
findings are important: the surgeon has to distinguish
between an adenomatous disease and a carcinoma 3.
A radical excision remains the standard management;
the place of adjuvant radiotherapy is not well estab-
Local recurrence and/or metastases are unfor-
We present here a review focused on the most
recent advances in parathyroid carcinoma illustrated
by three patients treated at our institution.
Parathyroid carcinomas, a rare entity, accounts
for less than 1 % 4,5 of all cases of primary hyperpara-
thyroidism. A higher incidence has been reported in
Japan and Italy where it rises up to 5-5,2%. 6,7
It is habitually a sporadic disease, but familial
cases have been described.
Journal of Cancer 2011, 2
Parathyroid carcinoma occurs equally in men
and women, while benign parathyroid disease pre-
dominates in women by a ratio of 3-4:1.
The average age of diagnosis is the fourth decade
of life whereas for benign adenomas the average age
is thirty 8. The 3 patients treated at our institution
were respectively 35, 58, 76 years old, 2 women and 1
Paratyhyroid carcinomas have been described in
15% of hyperparathyroidism-jaw tumor (HPT-JT)
syndrome, a rare autosomal disorder. In HPT-JT, os-
sifying fibromas of the maxilla and mandible are seen
in 30 % of cases9. Less commonly, kidney lesions in-
cluding cysts, polycytic disease, harmartomas or
Wilm’s tumor can be present.
Although parathyroid carcinomas are not a fea-
ture of multiple endocrine neoplasia type 1 (MEN 1),
recently 10-11 parathyroid carcinomas have been de-
scribed in MEN 1. According to our Knowledge, only
one case of parathyroid carcinoma has been reported
in MEN 2 a syndrome 12.
More than 90% of parathyroid carcinomas (PCA)
are functional, and as such, the clinical features are
due primarily to the effects of markedly elevated se-
rum PTH and calcium levels. The most frequent
complaints are weakness, fatigue, anorexia, nausea,
vomiting, loss of weight, dyspepsia, constipation,
headaches, polydipsia and polyuria. Bone, joint,
muscular pain, pathological fractures, and renal
stones are frequent when hyperparathyroid state is
severe. Recurrent severe pancreatitis, anemia and
peptic ulcer disease can also occur. Among our 3 pa-
tients, 2 were symptomatic. One patient experienced
fatigue, ankle and knee pain and the other fatigue,
polyuria and polydipsia.
All those clinical signs are unspecific and often
lead to a delayed diagnosis; furthermore even with a
hypercalcaemia biologically proven, diagnosis may be
missed. This was the case for all our patients before
referral; all of them have been treated in the setting of
a longstanding disease with a tumor size ranging
from 4.5 cm to 7 cm.
A palpable mass in the neck is found in 30-76%
of patients with parathyroid carcinoma 13. This clinical
finding can help to differentiate between a benign and
a malignant parathyroid disease; indeed fewer than
5% of patients with benign disease have a palpable
neck mass 14. The American national cancer data base
15 confirmed in a report of 286 PCA a median size of
3.3 cm. Despite this size, we would like to underline
the fact that, due to intrathoracic localization, a pal-
pable mass was not found in 1 of our patients.
Higher serum PTH and calcium levels than in
parathyroid benign disease may be useful in the di-
agnosis of PCA. PTH levels higher than 300 pg/ml are
indicator of potential malignant disease. In our pop-
ulation PTH level ranged from 642 to 1192pg/ml (N
15-80pg/ml). Iacobone et al 16 reminded that these
high values should be considered as risk factors in
individual patients. Owen et al 17 state that the pres-
ence of vocal cord palsy should alert the examiner of
the possibility of cancer in a patient with hyperpara-
thyroidism. Thus, until proven otherwise, the patient
should be considered to have a thyroid or parathyroid
Ultrasound and tomography allow defining the
extent of a neck mass. The ultrasound appearance of
PCA is a hypo echoic soft tissue mass with irregular,
poorly defined border and sign of invasion of adjacent
structures 18. Ultrasonography (US) revealed neck
mass in 2 patients, no signs of invasion was found.
One PCA was located under the thyroid capsule and
appeared like and enlarged thyroid lobe, the other
presented like a cystic mass at the inferior aspect of
thyroid lobe. The latter located in the thorax was not
detected on ultrasound.
Tomography Density measurements can assist
in differentiating abnormal parathyroid tissues from
lymph nodes and normal thyroid tissue 19.
However, the only feature that may permit the
preoperative diagnosis of parathyroid cancer is clear
evidence of invasion into adjacent tissue. Tomogra-
phy was performed in one patient and demonstrated
a cystic mass at the inferior aspect of the thyroid lobe
Differential diagnosis includes thyroid carcino-
ma and benign parathyroid disease 19.
With a sensitivity of 91% MIBI scintigraphy may
be a valid tool to assess the presence and localization
of PCA. However, in a study dealing with 19 PCA 16,
scintigraphy failed to localize mediastinal recurrences
and pulmonary metastases.
The patient with negative US underwent MIBI
scintigraphy (Fig 3) which allowed us to localize an
intra thoracic parathyroid carcinoma.
Given the lack of reliable factors to diagnose
PCA, it is preferable to suspect it than fail to diagnose
it because inadequate surgery leads to recurrences.
Over the last years the development and path-
ophysiology of parathyroid carcinoma has become
clearer. Oncogenes and tumor suppressor genes haves
been linked to parathyroid carcinomas. There is no
Journal of Cancer 2011, 2
definitive evidence of a primary role but altered ex-
pressions of these genes may play a part in the process
of malignant transformation. Five genes with a po-
tential role in malignancy have been identified and
studied: p53, breast
(BRCA2), cyclin D1/parathyroid adenomatosis gene 1
(PRAD1), retinoblastoma tumor suppressor gene (RB)
and hyperparathyroidism 2 tumor suppressor gene
The HRPT2 gene has provided the best evi-
dence. This gene is also responsible for the hy-
(HPT-JT). PCA occurs with higher frequency in
HPT-JT patient than in sporadic PHHT (15% versus<
1%) 20. HRPT2 may also play a role in the pathogene-
sis of sporadic PCA. Shattuck et al21 found HPRT2
mutation in 10 of 15 patients with sporadic PCA.
The prevalence of HPRT2 mutation in sporadic
PCA may be as high as 76.6%. Most mutations are
nonsense forms leading to a lack or reduction of the
encoded protein expression. HPRT2 encodes a protein
called parafibromin (parathyroid disease and fi-
bro-osseous lesions) which is a tumor suppressor
protein. Parafibromin is involved in the cell cycle
regulation by inhibiting cell proliferation by blocking
cyclin D1 expression.
Cyclin D1 is highly expressed in parathyroid
carcinomas, in a study by Vassef et al 22 91% (10/11) of
PCA specimens were positive for cyclin D1 over ex-
pression compared with 39% (11/28) of the adenoma
specimens. Cyclin D1 over expression may be a result
of loos of parafibromin expression.
Even by experienced surgeons, up to 86% of
PCA have been missed initially. The result is enuclea-
tion or piece meal resection, with the risk of tumor
seeding in the operative field 15. Surgery is the only
effective and curative treatment of PC; it should be
performed as “en bloc” tumor resection with ipsilat-
eral thyroidectomy to avoid any capsular rupture. In
the present report surgery had been undertaken un-
der IV methylene blue perfusion, thus obtaining a
better localization of the PC and allowing us a com-
plete resection. Kuriloff 23 et al demonstrate that
methylene blue facilitates the identification of ab-
normal parathyroid tissue in 97 % and a dark blue
purple staining was observed in 89 %. Methylene blue
helped to localize PC in our patients except the one
located beneath the thyroid capsula. This condition
allowed us to perform in each case an “en bloc“ re-
moval of the tumor.
Intra operative (io) monitoring of intact PTH has
proven its utility in predicting cure rate in benign
hyperparathyroidy 24. Few studies address the issues
of ioPTH monitoring in PCA. Solorzano et al 25
demonstrated, that after an “en bloc” removal of PCA,
a drop of > 50% from baseline was predictive at least 6
months of normocalcemia. Abdelgadir et al 26 reached
the same results and conclude that ioPTH monitoring
is accurate in predicting normocalcemia after initial
“en bloc” resection.
Furthermore we believe that a significant drop
(>50%) of ioPTH could be the reflection of an optimal
surgery with “en bloc” resection of the lesion. PTH
assay was undertaken just after surgery and strongly
decreased in all patients ranging from 8 to 70 pg/ml.
The management of recurrent or metastatic PC is
primarily surgical 13. Recurrences in the neck should
be treated with wide resection including the regional
lymph nodes. Recent data demonstrated that omis-
sion of lymph node resection carried a 1.5-2-fold
higher risk for recurrence and death at 5 days 27.
All our patients underwent a central lymph node
dissection; none of them had invaded lymph nodes.
Distant metastasis should be excised if possible.
Although resection of distant metastases or other foci
of malignant tissue is rarely curative; their removal
may result in a long period of normocalcemia, ranging
from months to years 13.
The differential diagnosis between parathyroid
carcinoma and adenoma is difficult for the
pathologist. Grossly, parathyroid carcinomas can be
indistinguishable from adenomas. They are usually
present as larger masses that are adherent to adjacent
structures, but these adherences are not diagnosed as
periglandular fibrosis occasionally occurs in adeno-
mas following haemorrhage 28, 29.
Histologically, a definitive diagnosis of malig-
nancy should be restricted to tumors displaying evi-
dence of vascular invasion, capsular invasion with
growth into adjacent tissues, or metastases. As criteria
for malignancy are mostly architectural and require
adequate sampling, frozen sections are of little value.
Criteria for vascular and capsular invasion are similar
to those used in thyroid pathology: vascular invasion
should be observed in the capsule or in the sur-
rounding soft tissues rather than inside the tumor.
The presence of thick intratumoral fibrous bands is
often regarded as a good indicator of malignancy but
it is inconstant and not pathognomonic. Diffuse nu-
clear enlargement with macronucleoli suggests ma-
lignancy. However, these atypia are only observed in
2/3 of carcinomas and focal pleomorphism is com-
mon in adenomas 29, 17.
Journal of Cancer 2011, 2
Figure 1: Enhanced neck computed tomography showing a
cystic mass (arrow) at the inferior aspect of the right thy-
roid lobe with a tracheal compression.
Figure 2: Cystic mass (arrow) (5,5 x 3,5 x 3,5 cm) against
the right thyroid lobe
Figure 3: Preoperative MIBI isotopic scan disclosing a left
anterior mediastinal captation
Two patients underwent radiotherapy (60-65gy)
after surgery for capsular and vascular invasion.
During irradiation time PTH level decreased from 119
pg/ml to 75 pg/ml and from 71 to 41 pg/ml sug-
gesting a cytototoxic effect on residual tumor cells.
The efficiency of radiation therapy in parathyroid
carcinoma remains controversial 30, 31, and radiother-
Journal of Cancer 2011, 2
apy have been reported to be ineffective. The contro-
versy stems from 2 points. Firstly, the first studies
performed with subjects with bulky neck disease who
had not undergone surgery, have failed to demon-
strate either a reduction in the mass of malignant tis-
sue or the attainment of normocalcemia. The common
belief is that radiation therapy does not result in a
meaningful antitumor response 32, 33. Secondly, all the
studies dealing with radiotherapy as adjuvant thera-
py include a small number of patients without any
comparison, thus no strong conclusion can be drawn.
The M.D. Anderson group treated 6 of 18 patients
suffering from invasive parathyroid cancer with ad-
juvant radiotherapy in doses of 50 to 63 gy. Five of 6
did not recur locally suggesting that radiation therapy
could be effective in prevention of recurrence. A series
from the mayo clinic reviewed 61 patients with PCA,
57 underwent en bloc surgery alone and 4 surgery
with adjuvant radiotherapy. The 4 patients who re-
ceived adjuvant radiotherapy were alive with no re-
currences at 60 months whereas 25 patients (44%) had
locoregional recurrence at a median time of 27 months
Both data suggest that radiotherapy could be
helpful as adjuvant therapy in preventing tumor re-
growth after surgery 35, 36. There is no consensus in the
literature regarding the doses to be administered but
these studies report doses ranging from 50 to 66 Gy. In
the present report, no recurrence occurred 2 and 4
years after surgery.
However, Prognosis is not predictable, because
when malignancy is confirmed, recurrences occur in
most case. The average time of recurrence is approx-
imately 3 years, although longer intervals up to 20
years have been reported 14.
PC is a very rare disease and probably an un-
der-diagnosed pathology. This condition leads to a
delayed diagnosis when the tumor is already palpa-
Patients with persistent unexplained hyper-
calcemia should undergo a complete focusing in-
cluding neck imaging (US/CT/MRI) and MIBI iso-
topic scan. In the setting of a suspected PC, neck ex-
ploration must be performed with an “en bloc” resec-
tion of the lesion with ipsi lateral thyroid lobectomy to
avoid capsular rupture. A systematic central lymph
node resection may improve outcomes in PC.
Adjuvant radiotherapy appears to limit tumor
regrowth after surgery.
Since recurrences up to 20 years have been de-
scribed, patients should undergo a life time follow up.
Conflict of Interest
The authors have declared that no conflict of in-
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