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89. Yano S, Sugimoto T, Tsukamoto T, et al. Effect of parathyroidectomy on bone mineral density in hemodialysis
patients with secondary hyperparathyroidism: possible
usefulness of preoperativedetermination of parathyroid
hormone level for prediction of bone regain. Horm
Metab Res. 2003;35:259–64.
90. Chou FF, Chen JB, Lee Ch, et al. Parathyroidectomy can
improved bone mineral density in patients with symptomatic secondary hyperparathyroidism in dialysis
patients: recommendation for a change in management.
Am J Kidney Dis. 2000;35:1226–37.
91. Goldsmith DJ, Covic AA, Venning MC, et al. Blood
pressure reduction after parathyroidectomy for secondary hyperparathyroidism: further evidence implicating
calcium homeostasis in blood pressure regulation. Am J
Kidney Dis. 1996;27:819–25.
92. Zingraff J, Drueke T, Marie P, et al. Anemia and secondary hyperparathyroidism Arch Interm Med.
1978;138(11):1650–2
93. Brancaccio D, Cozzolino M, Gallieni M. Hyperparathyroidism and anemia in uremic subjects : a combined
therapeutic approach. J Am Soc Nephrol. 2004;15:S21–4
94. Ifudu O, Matthew JJ, Macey LJ, Hong JS, Sumrani N,
Sommer BG, Friedman EA. Parathyroidectomy does not
correct hypertension in patients on maintenance hemodialysis. Am J Nephrol. 1998;18:28–34.
95. Parfitt AM. Soft-tissue calcification in uremia. Arch
Intern Med. 1969;124:544–56.
96. Bleyer AJ, Burkart J, Piazza M, et al. Changes in cardiovascular calcification after parathyroidectomy in
patients with ESRD. Am J Kidney Dis. 2005;46:464–9.
97. De Francisco AM, Ellis HA, Owen JP, et al. Parathyroidectomy in chronic renal failure. Q J Med. 1985;55:
289–315.
98. Goto N, Tominaga Y, Matsuoka S, et al. Cardiovascular
complications caused advancedsecondary hyperparathyroidism in chronicdialysis patients;special focus on dilated
cardiomyopathy. Clin Exp Nephrol. 2005;9:138–41.
23
Parathyroid Carcinoma
Claudio Marcocci, Filomena Cetani, and John
P. Bilezikian
Introduction
Parathyroid carcinoma is a rare cause of primary hyperparathyroidism (PHPT) (<1%) and
is usually associated with more severe clinical
manifestations than its much more common
benign counterpart, the parathyroid adenoma
[1–3]. It usually has a rather indolent course
with the diagnosis of malignancy often made
only in retrospect when the disease recurs
locally or at distant sites. The delay in recognition is due to the fact that the histology of the
tumor tissue can be equivocal or frankly misleading [2, 4]. The prognosis of parathyroid
carcinoma is quite variable, but most patients
succumb to the effect of PTH oversecretion by
metastases and ensuing severe hypercalcemia,
not to the bulk of tumor tissue per se. A successful resection of all tumor tissue at the time of
initial surgery is a key determinant to a successful outcome. Therefore, identifying clinical features that might suggest malignancy can be
most helpful in terms of the surgical procedure.
The surgeon can also be helpful by identifying
gross characteristics of the malignant parathyroid tissue. In recent years, major advances have
been made in the understanding of the molecular pathogenesis of parathyroid carcinoma
[5–9]. This new knowledge has led to the development of diagnostic markers that show promise when the histology is ambiguous [10–13].
Moreover, there is the hope that greater
understanding of the pathogenesis of parathyroid cancer will lead to the development of new
therapeutic strategies.
Incidence
More than 290 cases of parathyroid carcinoma
were described in the English literature between
1930 and 1992 [3]. Subsequently, more than 100
cases have been reported [3]. The largest series
was collected by the National Cancer Database
that reported the majority of these cases [14]. In
most series of PHPT, parathyroid carcinoma
accounts for less than 1% of all cases [1], but an
incidence as high as 5% has been reported in two
groups [15, 16]. This higher incidence of carcinomamay be related to geographic differencesor,
more likely, to varying criteria for its diagnosis.
Different from benign parathyroid disease in
which females predominate over males by 3–4:1,
the incidence of parathyroid cancer is equally
divided between the sexes. The age at diagnosis is
10 years earlier than the typical age when the benign
form of PHPT surfaces (mid-40s vs mid-50s).
Etiology
The etiology of parathyroid carcinoma is
unknown. Prior neck irradiation is a risk factor
[17, 18], but the role of radiation is not clear.
J.G.H. Hubbard et al. (eds.), Endocrine Surgery, Springer Specialist Surgery Series,
DOI 10.1007/978-1-84628-881-4_23, Springer-Verlag London Limited 2009
321
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ENDOCRINE SURGERY
Parathyroid carcinoma has also been rarely
reported in patients with long-standing secondary hyperparathyroidism, namely in patients
undergoing hemodialysis for chronic renal failure
[19]. One case, however, has also been reported in
a patient with celiac disease and long-standing
secondary hyperparathyroidism [20]. However,
it is not clear in these cases whether the pathology
met criteria for a parathyroid malignancy.
Parathyroid carcinoma hasalso been reported
in association with hereditary syndromes of
hyperparathyroidism [21–25]. It occurs in as
many as 15% of patients with the hyperparathyroidism-jaw tumor (HPT-JT) syndrome [26].
HPT-JT is a rare autosomal dominant disorder
in which PHPT is due to neoplasms of one or
more parathyroid glands. Cystic changes in the
parathyroid tumors are common, thus accounting for an alternative description of this variant
as cystic parathyroid adenomatosis [27]. Ossifying fibromas of the maxilla and mandible are
found in 30% of patients; renal cysts, hamartomas, and Wilm’s tumors are seen less commonly
[5]. In another familial syndrome, namely familial isolated PHPT, parathyroid carcinoma has
been reported [28, 29]. A few recent reports
have suggested that parathyroid carcinoma, as
defined pathologically, may occur in a setting of
MEN1 syndrome and/or tumors carrying somatic
MEN1 mutations [30, 31]. However, some of these
reports should be interpreted with caution
because recurrent disease in the MEN1 may be
tenacious when it occurs at the site of previous
surgery, thus mimicking a parathyroid carcinoma.Thus,itisconceivablethatatleastsome
of these cases could be ‘‘false positives’’ on the
basis of conventional pathology, but without
the clinical expression of parathyroid carcinoma
in patients with MEN1. Only one case of parathyroid carcinoma has been reported in patients with
MEN2A syndrome [32].
Molecular Pathogenesis
In 1994 Cryns et al. [33] showed lack of expression of retinoblastoma (Rb) protein in parathyroid cancer and suggested that inactivation of the
Rb gene might be involved in the pathogenesis of
parathyroid carcinoma. Based on this finding,
loss of Rb protein was proposed as a tool for
the diagnosis of parathyroid malignancy. Since
that proposal, however, contradictory results
have been reported by other investigators [34,
35]. We further evaluated the role of the Rb
gene as a potential tool to distinguish between
benign and malignant parathyroid disease by
evaluating loss of heterozygosity (LOH) at this
locus and byRb immunohistochemistry [36]. We
showed that Rb gene alterations are not specific
for parathyroid cancer. Overall, our data do indicate that retention of Rb heterozygosity excludes
malignancy which is also suggested by the combined finding of LOH and lack of Rb protein
expression. It is worth noting that the same authors
who previously showed that Rb1 inactivation is
a key factor in the pathogenesis of parathyroid
carcinomas have recently found no microdeletion,
insertions, or point mutations in the coding or
promoter regions of the Rb gene in a small series
[37]. These results suggest that loss of Rb protein in
parathyroid carcinomas could be due to epigenetic
effects (e.g., hypermethylation) or secondary to
other genetic alterations.
Cryns et al. have found evidence for the involvement of p53, another tumor suppressor gene,
in parathyroid cancer [38]. They showed allelic
loss of p53 and abnormal p53 protein expression
in some cases of parathyroid carcinoma.
Overexpression of cyclin D1, a cell cycle regulator, is present in the majority of parathyroid
carcinomas (90%), but it is unclear whether
this is a causative feature or an epigenetic effect
[12, 39].
In addition, losses or gains in various chromosomal loci have been identified in parathyroid carcinomas, suggesting that genes located in
these chromosomes might be involved in aberrant parathyroid growth.
Recently, major advances in the understanding of parathyroid cancer pathogenesis have
been made by the cloning of the Hyperparathyroidism 2 gene (HRPT2, CDC73), previously
known as chromosome 1 open reading frame
28 (Clorf 28) [5], as the gene responsible for
HPT-JT.
Evidence points to a strong association
between HRPT2 mutations and parathyroid carcinoma. HRPT2 is the target for germline mutation in the majority of families with the rare
HPT-JT [5, 40, 41], in which, as noted, parathyroid carcinoma occurs at higher frequency than
in sporadic PHPT series (15 vs <1%). Similar
germline mutations occur in a subset of kindreds with familial isolated hyperparathyroidism [5, 8, 42–48]. The role of the HRPT2 gene in
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PARATHYROID CARCINOMA
the pathogenesis of sporadic parathyroid carcinoma was first demonstrated by Howell and
coworkers in 2003 [6]. In their study, HRPT2
mutations were detected in the coding region of
the gene in four of four parathyroid carcinomas
and in none of 25 sporadic parathyroid adenomas. Subsequently, Shattuck et al. [7] found
HRPT2 mutations in 10 of 15 patients with
apparently sporadic parathyroid cancer. Our
group has identified HRPT2mutations in 9 of
11 parathyroid carcinomas [8, 12]; in this
study we also investigated four sporadic atypical adenomas but no HRPT2 mutations were
identified in these tumors. The majority of the
mutations were predicted to inactivate the protein, parafibromin, for which this gene codes.
Of particular interest was the demonstration
that HRPT2 mutations in parathyroid carcinomas
of six patients were germline [7, 8, 12]. This
finding suggests that a subset of patients with
apparently sporadic parathyroid carcinomas
may have the HPT-JT syndrome, a variant of
this syndrome, of some other genetic disorder
associated with this genetic abnormality. The
strong association between HRPT2 mutation
and parathyroid malignancy suggests that this
molecular event has a pathogenic role for most
sporadic parathyroid carcinomas. It is noteworthy that all the three reports of this gene in
sporadic parathyroid malignancy included
cases in which the diagnosis was clear. Indeed,
the diagnosis of parathyroid carcinoma was
defined generally by presence of either distant
metastases and/or local invasion of surrounding
organs, and/or vascular invasion, and/or recurrences after initial surgery. Combining the
results of these studies, the prevalence of
HRPT2 mutations in sporadic parathyroid carcinomas is 76.6% (Fig. 23.1). It is possible that
inactivating mutation in noncoding or regulatory regions could also be implicated in the
pathogenesis of sporadic parathyroid carcinoma and might be present in those cases in
which alterations in the coding regions of the
gene are not detected. A recent study by Haven
et al. [49] found HRPT2 inactivating mutations
in only 4 cases of 27 (15%) parathyroid carcinomas. These tumors were classified as malignant on the basis of pathological criteria alone
without the requirement for clinically malignant behavior. Moreover, in this study, the
mutational analysis was limited to exons 1, 2,
and 7, which admittedly harbor 85% of all
known mutations.
HRPT2 mutations are rarely found in sporadic parathyroid adenomas. Carpten et al. [5]
detected mutations in only 2 of 47 parathyroid
adenomas that were selected for their cystic
features, a specific characteristic of parathyroid
tumors in the HPT-JT syndrome. We found a
single mutation among 35 sporadic adenomas,
which were selected for the lack of LOH at 11q13
Fig. 23.1. Schematic representation of HRPT2 gene. Locations of known HRPT2 mutations in sporadic parathyroid carcinomas.
(Reproduced from J Bone Miner Res 2008;23:1869–1880 with permission of the American Society for Bone and Mineral Research. [3])
[8]. Two studies of unselected parathyroid adenomas (85 tumors) failed to detect any HRPT2
mutations [6, 9]. Taking all available data in
parathyroid adenomas together, the overall prevalence of HRPT2 mutations is 1.8% (3 of 167).
Krebs has suggested an even lower estimate,
0.8% (1/120) on the basis of the results of
Howell [6], our group [7] and Krebs [50].
These observations indicate that HRPT2 mutations have a very limited, if any, role in the
pathogenesis of typical sporadic parathyroid
adenomas.
Clinical and Laboratories
Features
The clinical manifestations of parathyroid carcinoma are primarily related to theeffects of markedly elevated serum PTH levels rather than to
local infiltration, distant spread, or sheer mass
of neoplastic cells. Occasionally parathyroid carcinomas may be nonfunctional [47].
The typical clinical picture is characterized
by signs and symptoms of severe hypercalcemia, with renal involvement (nephrocalcinosis,
nephrolithiasis, impaired renal function) in up
to 80% of patients as well as bone involvement
(osteitis fibrosa cystica, subperiosteal resorption, ‘‘salt and pepper’’ skull, diffuse osteopenia)
in up to 90% [1, 3]. The combination of both renal
and bone manifestations at the time of presentation suggests the possibility of parathyroid malignancy because in benign PHPT, overt bone and
stone disease is uncommon. Despite these clinical
features which may suggesta malignant tumor, the
challenge to the clinician rests upon identifying
the patient with malignant disease, particularly
since the benign counterpart is so much more
common. A few helpful clinical clues would favor
a malignancy [1, 3]:
male gender. There is no sex preference,
whereas the female:male ratio in benign
PHPT is 3–4:1.This is not particularly help-
ful, however, in an individual case.
relatively young age. The average decade of
malignant parathyroid disease is 40–50,
about 10 years younger than the usual
patient with adenoma. However, the Mayo
Clinic experience [51] and that of National
Cancer Database [14] indicate that the aver-
age age may be higher, in the 50–60 decade.
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ENDOCRINE SURGERY
markedly elevated serum calcium and PTH.
Most patients with typical parathyroid adenomas have serum calcium levels within
1 mg/dl above the upper normal limit and
are asymptomatic. In parathyroid cancer, the
serum calcium levels are usually in excess of
14–15 mg/dl. These patients are typically
symptomatic with weakness, fatigue, depression, nausea, polydypsia, and polyuria. Bone
pain and renal colic may be present. As
might be expected, PTH levels are markedly
elevated (typically 10 times normal) in
patients with parathyroid carcinoma in contrast to benign disease in which PTH levels
are typically only 1.5- to 2-fold above normal.
size of the parathyroid lesion at initial surgery. A parathyroid carcinoma size is usually
large, over 3 cm in diameter, and strongly
adherent to adjacent structures. The gross
appearance is often a major clue to the histological diagnosis.
A summary of the typical features differentiating parathyroid carcinoma from adenoma is
reported in Table 23.1.
It is important that parathyroid carcinoma is
considered in the differential diagnosis of PTHdependent hypercalcemia when clues are present,
because the morbidity and mortality associated
with this diagnosis are substantial. Better outcomes are associated with complete resection of
the tumor at the time of initial operation [1–3].
Unfortunately, in the majority of cases the diagnosis of parathyroid carcinoma is made in
Table 23.1. Clinical features suggestive of parathyroid
carcinomas vs benign PHPT*
Parathyroid
carcinoma Benign PHPT
Average age (year) 48 55
Female:male ratio 1:1 3–4:1
Serum calcium (mg/dl) >14 11.2
PTH Markedly
elevated
Palpable cervical mass Common Rare
Renal involvement (%) 30–80 4–18
Skeletal disease (%) 35–91 <5
Concomitant renal and
skeletal disease
Modified from Shane et al. [1]
Common Rare
Mildly
elevated
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PARATHYROID CARCINOMA
retrospect when hypercalcemia recurs due to
parathyroid hormone secretion by local tumor
or distant metastases.
Recent data by us have demonstrated that in
some patients with parathyroid cancer, a new
PTH moiety is overproduced, i.e., an N-terminal
PTH molecule (N-PTH), distinct from the intact
human 1-84 PTH, which is recognized in a
third-generation assay of ‘‘whole’’ PTH (wPTH;
the 1-2 epitope) [52]. The clinical implications
of this finding in parathyroid carcinoma await
additional studies in a large series of patients
with an emphasis on N-PTH’s biological activity. Serum alkaline phosphatase activity is also
substantially higher in patients with parathyroid carcinoma than in those with parathyroid
adenoma, in whom serum levels are generally at
or only slightly above the upper limit of the
normal range. and subunits of hCG may
be elevated in patients with parathyroid cancer
but not in those with benign tumors [53]. On
physical examination, up to 75% of patients
with parathyroid carcinoma have a palpable
neck mass [54]. Since a palpable parathyroid
gland is rare in the benign disease, this finding
should automatically raise the suspicion of cancer. Parathyroid cancer should also be suspected in a hypercalcemic patient, who presents
with recurrent laryngeal nerve palsy, without a
history of prior neck surgery.
The classical target organs of PTH, the kidney, and the skeleton, as noted before, are
affected with greater frequency and severity in
patients with parathyroid carcinoma [1, 3]
than in patients with benign PHPT. Indeed, in
benign parathyroid disease, the prevalence of
renal involvement, including nephrolithiasis,
nephrocalcinosis, and impaired glomerular filtration, is less than 20%. Renal colic, on the
other hand, can be the presenting complaint in
the patient with parathyroid carcinoma. Bone
pain and pathological fractures are also common features of parathyroid malignancy. In
addition to the kidney and the skeleton, other
organs are frequently affected. Recurrent severe
pancreatitis, peptic ulcer disease, and anemia
occur with greater frequency in patients with
malignant disease than in those with benign
PHPT. Parathyroid carcinoma shares many
clinical features with acute PHPT, sometimes
called ‘‘parathyroid crisis’’ (marked elevations
of serum calcium and PTH) and the diagnosis
of parathyroid cancer should thus always be
considered in these patients [55]. Although the
distinction between the two entities is not possible preoperatively, it is important to bear in
mind the diagnosis of malignancy because the
surgical approach differs.
In patients with severe PHPT, but not in parathyroid crisis, the distinction between benign or
malignant disease may be even more difficult on
clinical grounds, because severe hypercalcemia,
renal, and bone involvement may occur, and the
latter manifestations may present at the same
time. However, it is preferable to have a high
index of suspicion for parathyroid carcinoma
when these features are present than to miss the
opportunity for surgical cure (more extended
surgery) by failing to consider it in the differential diagnosis.
Pathologic Features
Carcinomas are mostly irregular and hard,
adherent to the surrounding soft tissues of the
neck or the thyroid gland. They are usually over
3 cm in diameter and weight between 2 and 10 g
[2, 4, 56]. On cross-section, carcinomas are
gray-white and areas of necrosis may be present
as yellow foci.
In 1973 Shanz and Castleman recognized a
set of features of parathyroid carcinoma [57].
These features include uniform sheets of cells
(usually chief) arranged in a lobular pattern and
separated by dense trabeculae, capsular or vascular invasion, and mitotic figures within the
parenchymal cells, which must be differentiated
from endothelial cell mitoses. Unfortunately,
none of these features is pathognomonic of
parathyroid malignancy, since they can also be
found in a subset of parathyroid adenomas,
which are referred as ‘‘atypical adenomas’’ [2].
Thus, as mentioned before, the distinction
between benign and malignant parathyroid
tumors cannot be definitively established by
histology, unless there is evidence of invasion
of extratumoral vessels, perineural spaces, or
surrounding tissues (thyroid gland and other
adjacent structures). However, it is noteworthy
that capsular and vascular invasion are present
in approximately 60 and 10–15% of cases,
respectively [2]. Thus, a substantial proportion
of unequivocal carcinoma lacks those features
which are pathognomonic of malignancy. On
the other hand, the diagnosis of parathyroid
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ENDOCRINE SURGERY
cancer is definitely established by the presence
of local or distant metastases [1, 3], features
which identify a late stage of the disease with a
poor prognosis and low cure rate.
To further improve the accuracy of the diagnosis of parathyroid carcinoma several other
histological techniques have been investigated.
Electron microscopy of parathyroid cancer
tissue reveals nuclear and mitochondrial alterations, nuclear diameter and DNA content
greater than in adenoma, and evidence of
increased secretory activity, but none of these
features clearly distinguish benign from malignant tumors [58–61].
In addition, immunohistochemistry has been
widely used in an attempt to further improve the
differential diagnosis between benign and
malignant parathyroid tumors. One approach
has involved the use of proliferation markers.
Increased labeling of cell cycle-associated antigens (Ki-67, cyclin D1) has been shown in parathyroid carcinoma as compared to adenoma
[62–66], but the overlap among these tumor
types has limited the utility of this approach,
particularly in equivocal cases. Decreased
expression of p27, an inhibitor of cyclin-dependent kinase, has been demonstrated in carcinomas and the association between low p27 and
high Ki-67 labeling has been suggested to
increase the likelihood of malignancy [67].
Recently abnormal Galectine-3 expression has
been reported in parathyroid carcinoma [68].
Loss/altered expression of the calcium-sensing
receptor (CASR) is present in a subset of parathyroid carcinoma [69].
Following the demonstration that the HRPT2
gene is involved in the pathogenesis of sporadic
parathyroid carcinoma, several studies have
Fig. 23.2. Pathology (left panels) and parafibromin immunohistochemistry (right panels) of parathyroid tumors and lung metastasis.
Upper pan els: Parathyroid carcinoma. (A) Oncocytic cells arranged in trabeculae, fibrous bands, (hematoxylin and eosin, 100); (B)the
neoplastic cells were completely negative for parafibromin (200). Middle panels: Lung metastasis of a patient with parathyroid
carcinoma. (C) A solid trabecular neoplastic lesion and adjacent normal lung parenchyma (hematoxylin and eosin, 100); (D)The
tumor cells showed a diffuse loss of parafibromin staining (200). Lower panels: Atypical parathyroid adenoma. (E) Trabecular pattern
with fibrous vascular pseudo invasion (hematoxylin and eosin, 100); (F) Diffuse nuclear immunoreactivity of parathyroid cells
(200).
327
PARATHYROID CARCINOMA
Table 23.2. Diagnostic value (%) of HRPT2 gene abnormalities for differentiating parathyroid carcinomas from adenomas
(including atypical adenomas)
Loss of
parafibromin
immunostaining HRPT2 mutation LOH
Sensitivity (95% CI) 100 (68–100) 82 (48–97) 64 (32–88)
Specificity (95% CI) 88 (69–97) 96 (78–100) 96 (78–100)
Positive predictive value at 0.5% prevalence (95% CI) 4 (0–11) 10 (1–19) 8 (0–16)
Negative predictive value at 0.5% prevalence (95% CI) 100 (100–100) 100 (99–100) 100 (98–100)
Modified from Cetani et al. [12]
been performed to evaluate whether immunostaining of the parafibromin, the gene product, might have some diagnostic utility. A
loss (total or focal) of staining has been
reported in the large majority of parathyroid
carcinomas and very rarely in adenomas
[10–13] (Fig. 23.2), but limited data are currently available in equivocal cases, where this
would have a major diagnostic value. In this
regard, our data indicate that negative parafibromin staining combined with HRPT2 mutations is strongly associated with parathyroid
cancer. Therefore, in our opinion, all suspected
parathyroid tumors should be evaluated for
abnormalities of HRPT2/parafibromin.
ThehighrateofHRPT2 abnormalities in
carcinomas suggests the potential diagnostic
utility of HRPT2 mutation status and/or parafibromin staining, particularly in cases with
equivocal initial histology (see below). The
diagnostic potential of such a test hinges on
the high frequency of abnormalities in carcinomas as opposed to the low frequency in
adenomas. The clinical utility of a diagnostic
test depends on the prevalence of the disease
in a given population (Table 23.2). The prevalence of PHPT ranges between 1 and 5% in the
general population, but may be as high as 2%
in postmenopausalwomen [1,70]. Itis dueto a
benign, single adenoma in 80% of cases and
very rarely to parathyroid carcinoma (<1%).
Thus, even a low detection rate of HRPT2
abnormalities in parathyroid adenomas could
adversely impact the diagnostic specificity and
to a greater extent the positive predictive value
of HRPT2 abnormalities in the differential
diagnosis between parathyroid adenomas and
carcinomas.
Natural History
Parathyroid carcinoma typically runs an indolent, albeit progressive, course because the
tumor has a rather low malignant potential. At
initial presentation, very few patients have the
involvement of regional lymph nodes (<5%) or
distant sites (<2%) [1, 3].
It recurs locally and spreads to contiguous
structures in the neck. Metastases occur late in
the course of the disease with spread to cervical
nodes (30%) and lung (40%), and, less frequently, to liver (10%). Rarely distant metastases
occur in bone, pleura, pericardium, and pancreas. Many patients with the diagnosis of parathyroid cancer are alive 10 years afterwards.
Management and Prognosis
Surgery
Surgery is the only effective treatment for parathyroid carcinoma and consists of complete
resection of the primary lesion at the time of
initial operation when extensive local invasion
and distant metastases are less likely [1, 3, 54,
71–73]. For this reason, both preoperative suspicion and intraoperative recognition of a
potential malignant lesion are of great importance. Patients with a clinical presentation suggestive of parathyroid carcinoma warrant thorough exploration of all four parathyroid glands,
as parathyroid carcinoma has been report to
coexist with benign adenomas or hyperplasia
[20]. The most effective therapy is en bloc resection [74]. The standard en bloc resection consists of the removal of the parathyroid tumor
328
ENDOCRINE SURGERY
along with the ipsilateral thyroid lobe. Holmes
et al. [75] suggested a more aggressive approach
including ipsilateral thyroidectomy and isthmusectomy, skeletonization of the trachea, excision
of the neighboring muscles, and removal of the
recurrent laryngeal nerve, if involved. Care
should be taken during dissection to avoid rupture of the capsule, as cell spillage is associated
with multifocal recurrences and persistent
hypercalcemia. Tracheoesophageal, paratracheal, and upper mediastinal lymph nodes
should be excised, but an extensive lateral neck
dissection is indicated only when there is spread
to the lateral cervical nodes.
When the diagnosis is made in the early postoperative period on the basis of pathology, as
most usually happens, the management plan
becomes more complex. A further element of
complexity relates to the fact that some malignant lesions lack those features which are virtually diagnostic of malignancy. If the macroscopic characteristics of the tumor were typical
of a parathyroid carcinoma and the pathology
showed extensive vascular or capsular invasion
or if hypercalcemia persists, reexploration of the
neck is indicated. The structuressurrounding the
tumor should be excised as described above.
When the telling histological features are absent,
the patient is normocalcemicand the diagnosis is
only based on the pathology, immediate reoperation is not indicated, as a simple complete resection of the tumors may be curative. Such patients
should be monitored closely with serum calcium
and PTH level measurements.
Following parathyroidectomy patients may
experience the hungry bone syndrome, which
results in symptomatic hypocalcemia due to the
rapid deposition of calcium and phosphorus in
the bones [1, 3]. Hypocalcemia may be severe and
require administration of intravenous calcium.
Supplements of calcium and calcitriol should be
given in order to maintain normal levels of the
serum calcium. When recovery of the normal
parathyroid glands occurs, generally after several
weeks,the vigorous replenishment of calcium can
be stopped. Thereafter, serum calcium and PTH
levels should be monitored every 3 months.
Despite a potentially curative resection, parathyroid carcinoma has a recurrence rate of more
than 50%. Most recurrences occur 2–3 years
after the initial operation, but this period is variable and a prolonged disease-free interval of as
long as 23 years has been reported [1, 3, 73].
Parathyroid carcinoma metastasizes through
both lymphatic and hematogenous routes. The
regional lymph nodes are common sites of
metastases (30%), and distant metastases most
frequently involve lungs and bones, followed by
the liver and other visceral organs [1–3, 13].
When a recurrence of parathyroid carcinoma
is suspected, a thorough physical examination
of the patients should be performed, with particular attention to the neck, since recurrences
most often occur at the original site, and may
be appreciated by simple palpation. Imaging
studies should be performed in all patients
before reoperation. Neck ultrasonography is fast
and can detect cervical recurrences. Technetium
99m-sestamibi can visualize local recurrences
and distant metastases [76]. It can be also used
for the intraoperative localization of abnormal
parathyroid tissues [77]. Octreotide scanning
has also been used [unpublished data]. Computerized tomography and magnetic resonance
imaging are useful adjuncts to ultrasonography
in the evaluation of the neck and are superior
for detection of metastases in the chest or abdomen. If noninvasive examinations are negative,
arteriography and selective venous sampling
for PTH measurement may be useful. Fineneedle aspiration and measurement of PTH in
the eluate [78] should be used with caution, if
at all, to avoid seeding the needle track with
deposit of malignant cells [79].
The management of recurrent or metastatic
parathyroid carcinoma is primarily surgical [1,
3, 54, 71–75]. Recurrences in the neck should be
treated with wide resections, including the regional lymph nodes and other involved structures.
Distant metastases should also be excised, if
possible. Even a small tumor may produce sufficient amount of PTH to cause hypercalcemia.
Although resection of single metastasis or other
foci of malignant tissue is rarely curative, its
removal may result in periods of normocalcemia ranging from months to years [3]. Decreasing tumor mass may also render the patient’s
hypercalcemiamoreamenabletomedical
treatment.
Chemotherapy
The rarity of parathyroid cancer precludes any
prospective study to examine the effects of chemotherapy, and thus, most knowledge on this
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PARATHYROID CARCINOMA
matter comes from case reports. It is with these
limitations in mind that the following comments should be interpreted. Several regimens
have been attempted, using nitrogen mustard,
vincristine, cyclophosphamide, actinomycin D,
and adriamycin alone or in combination with
cyclophosphamide and 5-fluorouracil, but
none of them proved to be effective [51, 80].
Currently, there is no role for chemotherapy in
the management of patients with parathyroid
carcinoma.
Radiotherapy
With the exception of Wynne et al. [51], who
reported an apparent cure (10 year) in a patient
with tumor invasion of trachea, radiation therapy has little, if any, effect in the management of
invasive parathyroid cancer [73]. Recent reports
have suggested the use of irradiation as adjuvant
therapy. The Mayo Clinic has reported a diseasefree survival at a median follow-up period of 60
months in four patients who received postoperative radiotherapy[81]. The MD Anderson Cancer
Center experience suggests a lower local recurrence rate if adjuvant radiation was given after
surgery, independent of the type of operation
and the disease stage [82, 83].
Management of Hypercalcemia
When parathyroid carcinoma has become widely
metastatic and surgical options are exhausted,
clinical management turns to controlling the
hypercalcemia.
Hypercalcemia of parathyroid carcinoma is
treated in the same way as hypercalcemia due
to any other cause is treated [84]. Saline infusion and loop diuretics are often used, but, in
the majority of cases drugs that inhibit bone
resorption are needed. Potent intravenous
bisphosphonates (pamidronate and zoledronate) may transiently control hypercalcemia,
but patients frequently become refractory to
them. Plicamycin, another inhibitor of bone
resorption, is effective, but the response is
transient, and repeated courses may be associated with toxicity. Gallium nitrate inhibits
bone resorption by preventing dissolution of
hydroxyapatite crystals. It is an effective hypocalcemic drug, but its use is limited by nephrotoxicity. Calcitonin also reduces transiently
serum calcium in patients with parathyroid
carcinoma. WR-2721 is a hypocalcemic agent
that acts by inhibiting PTH secretion and bone
resorption [85]. Severe toxicity limits its use.
Octreotide, the long-acting somatostatin analogue, has also been reported to inhibit PTH
secretion in two cases of metastatic parathyroid carcinoma [86, 87].
Another approach is to target the parathyroid CASR. Calcimimetics, allosteric modulators of the CASR, directly reduce parathyroid
cell hormone secretion by binding to sites that
increase the receptors affinity for calcium.
Thus, sensitivity to extracellular calcium is
enhanced [88]. A first-generation calcimimetic, R-568, was used for 2 years in a patient
with metastatic parathyroid cancer with controlled hypercalcemia [89]. R-568 has been
replaced by cinacalcet, a more potent secondgeneration agent with a longer half-life. In
benign PHPT, cinacalcet normalized serum
calcium and reduced PTH concentrations for
up to 3 years [90]. Recently, we published the
results of a multicentric investigation of cinacalcet in 29 patients with inoperable parathyroid carcinoma [91].The primary endpoint of
the study was the proportion of patients
experiencing a 1 mg/dl reduction in serum
calcium frombaseline at the end of the titration
phase. Secondary endpoints included changes
from baseline in serum calcium, plasma PTH,
bone turnover markers, and health-related
quality of life variables. Duration of treatment
ranged from 1 to 1051 days (mean 328 –306
days). Cinacalcet effectively reduced hypercalcemia in about two thirds of patients with
inoperable parathyroid carcinoma. This drug,
may, therefore, represent an important new
treatment option for these patients.
Another novel and promising approach is
anti-PTH immunotherapy [92]. A positive
response has been observed in a patient with
metastatic parathyroid carcinoma immunized
with a mixture of human and bovine PTH peptides [93]. This treatment was followed by a
rapid control of hypercalcemia and improvement in clinical condition, decrease of the size
of lung metastases, without relevant adverse
effects. Recently, a monoclonal antibody to
PTH has been used for the treatment of parathyroid carcinoma [94]. Dendritic cell immunotherapy may also be applicable to induce a
T-cell immune response [95].