Parathyroid Carcinoma
Elizabeth Shane
Department of Medicine, Columbia University College of Physicians
and Surgeons, New York, New York 10032
Address all correspondence and requests for reprints to: Dr. Elizabeth Shane, Department of Medicine, Columbia University College of Physicians and Surgeons, 630 West 168th Street, New York, New York 10032
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Introduction
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Parathyroid carcinoma is an uncommon cause of
PTH-dependent hypercalcemia. The collective published experience with
this rare neoplasm has provided a distinctive clinical profile that
differs in a number of respects from that of benign primary
hyperparathyroidism (1, 2, 3). The distinguishing features of
parathyroid carcinoma assume even greater prominence when viewed within
the current context of primary hyperparathyroidism, which commonly
presents today as a mild asymptomatic disease (4, 5, 6, 7, 8). In
this report, the clinical features, natural history and prognosis of
parathyroid cancer are reviewed. Surgical approaches to parathyroid
cancer are outlined as well as medical therapies of the hypercalcemia
that accompanies recurrent or metastatic disease. As the ultimate
prognosis depends to a major extent upon successful resection of the
tumor at the time of the initial operation, major emphasis is placed
upon those features of parathyroid carcinoma that help to differentiate
it from primary hyperparathyroidism due to benign adenomatous or
hyperplastic disease.
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Incidence
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Approximately 290 cases of parathyroid carcinoma were reported in
the English literature between 1930 and 1992. Since 1992, more than 100
additional cases have been reported (9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25). Moreover, in
1999 the National Cancer Data Base reported 286 cases of parathyroid
carcinoma, the largest series to date (26). In most
series, this entity accounts for less than 1% of patients with primary
hyperparathyroidism (1, 2, 3, 11, 17, 27, 28, 29, 30, 31). The disease
may be somewhat more common in Japan than in Western countries,
accounting for 5% of patients with primary hyperparathyroidism
(18, 32, 33, 34). In a recent Italian study, 5.2% of patients
operated upon for primary hyperparathyroidism were eventually found to
have parathyroid carcinoma (15).
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Etiology
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The etiology of parathyroid cancer is unknown. No clear pattern of
predisposing factors has emerged in the cases described to date.
However, there are a number of clinical situations that may predispose
to the development of parathyroid carcinoma. Several cases of
parathyroid carcinoma have been reported in patients with a history of
neck irradiation (35, 36, 37). There have also been a number
of reports of carcinoma occurring within an adenoma or a hyperplastic
parathyroid gland (38, 39, 40, 41, 42, 43, 44, 45), and there is a recent report
of parathyroid carcinoma occurring in a patient with prolonged
secondary hyperparathyroidism secondary to celiac disease
(10). Despite these associations, Shantz and Castleman in
an extensive review of 70 cases (28) found no evidence for
malignant transformation of previously pathologic tissue.
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End-stage renal disease
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Parathyroid carcinoma has been described in several patients with
end-stage renal disease. A recent case report of such a patient also
reviewed 12 patients with parathyroid carcinoma published between 1982
and 1996 who were receiving maintenance hemodialysis (16).
All demonstrated hyperplasia of other parathyroid glands (16, 37, 38, 46, 47, 48, 49, 50), and one had a history of prior neck irradiation
(37). The diagnosis was made an average of 6 yr after the
start of hemodialysis. In all cases, parathyroid carcinoma was
diagnosed during or after parathyroidectomy on the basis of local
invasion (n = 5), tumor pathology (n = 4), or distant
metastases (n = 2). The average age of the patients was 49 yr.
Only 50% of these patients presented with signs of hypercalcemia; the
mean serum calcium level was 10.8 mg/dL, with a range of 8.512.6
mg/dL, considerably lower than serum calcium levels generally observed
in patients with parathyroid carcinoma (see below). PTH levels were
more than twice the upper limit of normal in all patients, not an
unusual finding in patients receiving maintenance hemodialysis.
Although the tumor recurred in one third of the patients, only one died
of hypercalcemia due to recurrent disease. The authors of the review
concluded that no preoperative features distinguished hemodialysis
patients with parathyroid carcinoma from those with parathyroid
hyperplasia and that the clinical course may be more benign because of
the tendency for renal insufficiency to lower serum calcium levels.
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Familial hyperparathyroidism
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Carcinoma has been reported in association with familial
hyperparathyroidism (9, 51, 52, 53, 54, 55, 56), particularly in the
autosomal dominant form with isolated hyperparathyroidism that is not
part of the multiple endocrine neoplasia type I (MEN1) syndrome
(57). In one such family, there was no evidence of
antecedent hyperplasia in unaffected glands, and chromosomal
abnormalities commonly observed in other solid tumors were identified
(a reciprocal translocation between chromosomes 3 and 4, trisomy 7, and
a pericentric inversion in chromosome 9) (55). Analyses of
tumor DNA from one family member with parathyroid carcinoma showed no
evidence of ras gene mutations, PTH gene arrangement, or
allelic loss from chromosome 11q13, the locus of the gene for multiple
endocrine neoplasia type 1. In addition, a greatly increased risk of
parathryoid carcinoma is associated with the hereditary
hyperparathyroidism-jaw tumor syndrome (52, 56, 57),
recently localized to chromosome 1q21-q31 (58). Arnold and
colleagues have also reported, in abstract form, that inactivation of
the MEN1 gene does not appear to participate commonly in the
pathogenesis of parathyroid carcinoma (59).
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Molecular pathogenesis
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Over the past decade, evidence for the involvement of mutations of
both oncogenes and tumor suppressor genes in the development of
parathyroid tumors has accumulated. Cyclin D1 or PRAD1
(parathyroid adenoma 1) is an oncogene
located at chromosome band 11q13; its protein product is a cell cycle
regulator. A chromosomal rearrangement of the cyclin D1 gene with the
regulatory region of the PTH gene has been reported in 5% of
parathyroid adenomas (60, 61, 62). In addition, the cyclin D1
oncoprotein is overexpressed in 1840% of parathyroid adenomas
(63, 64, 65). Overexpression of cyclin D1 protein is
strikingly frequent in parathyroid carcinomas, having been identified
in 91% of such tumors in one study (65) and in two of
three in another (63). Although these data strongly
suggest that cyclin D1 overexpression is a pervasive feature of
parathyroid carcinoma, it remains to be determined whether this feature
is causative or represents an association, and whether cyclin D1 might
prove to be a therapeutic target for this disease.
Strong evidence exists for the presence of a gene on chromosome 13
whose acquired inactivation contributes to the development of
parathyroid carcinoma. In 1994, Cryns et al. studied 9
parathyroid cancers for evidence of loss of a region on chromosome 13
containing the classic tumor suppressor gene RB (retinoblastoma) and
for altered expression of RB protein. Together with cyclin D1, RB is
important in cell cycle control. The cancers were compared with 21
parathyroid adenomas (66). All 11 parathyroid cancers
lacked an RB allele, and most had complete absence of nuclear staining
for the RB protein. In contrast, only 1 parathyroid adenoma lacked the
allele, and none had abnormal staining for the RB protein. Subramaniam
et al. (67) used a mouse monoclonal antibody to
detect RB gene expression in 3 parathyroid carcinomas and 11 benign
adenomas. Evidence of RB gene inactivation was observed in 2 of the 3
cancers and only 1 of 11 adenomas (67). Pearce et
al. observed allelic deletions of the 13q1214 region involving
both the RB gene and the hereditary breast cancer susceptibility gene
(BRCA2) in 3 of 19 parathyroid adenomas, all of which had aggressive
clinical or histopathological features and 1 parathyroid cancer
(68). Yoshimoto and colleagues demonstrated allelic
deletions on chromosome 13q in parathyroid adenomas from 2 members of a
family with isolated primary hyperparathyroidism, 1 who also had
parathyroid cancer and 1 with an adenoma (9). Allelic
losses of RB or D13S71 at 13q14 in a parathyroid cancer were also
reported by Dotzenrath et al. (69). Loss of
13q, as determined by comparative genomic hybridization, has been found
frequently in parathyroid carcinomas (59, 70). These data
strongly support the presence of a tumor suppressor gene on the long
arm of chromosome 13, which is critical for the development of
parathyroid carcinoma. However, in parathyroid carcinoma the deleted
portion of chromosome 13 is large, and it remains to be determined (by
direct search for mutations in the retained alleles) whether RB, BRCA2,
or a different gene on 13q will prove to be the primary causative tumor
suppressor.
Another important cell cycle regulator and frequent participant in
human cancer, the p53 tumor suppressor gene, has been examined as a
candidate for involvement in parathryoid cancers. However, the
frequency of p53 allelic loss and abnormal p53 protein expression is
low (31), and no coding region mutations were identified
in one survey (71). Thus, it appears unlikely that p53 is
a major contributor to the pathogenesis of parathyroid carcinoma.
Recently, several new locations for potentially important oncogenes or
tumor suppressor genes were reported in 2 rather large series of
parathyroid carcinomas (59, 70) and in 1 series of 10
carcinomas (72). Comparative genomic hybridization,
validated in 1 study by molecular allelotyping of the same tumors
(59), revealed several recurrent abnormalities that seem
to be preferentially or exclusively found in carcinomas compared with
adenomas. Tumor-specific gains or losses of chromosomal material
suggested that oncogenes in locations including 1q, 5q, 9q, 16p, 19p,
and Xq and tumor suppressor genes in locations including 1p, 3q, 4q,
13q, and 21q may be involved in the pathogenesis of parathyroid
carcinoma. Moreover, as a number of the regions commonly lost in
adenomas (including 11q, home of the MEN1 gene) were never or rarely
lost in carcinomas, these results also support the hypothesis that
parathyroid carcinomas tend to arise de novo rather than
from preexisting adenomas.
Clarification of the molecular pathogenesis of parathyroid carcinoma
will aid in diagnostically difficult cases and may provide important
clues or biological targets for the development of new and more
effective therapies.
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Clinical features
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The clinical features of parathyroid carcinoma (1, 2, 3, 11, 12, 14, 15, 17, 26, 27, 28, 29, 30, 31, 34) are due primarily to the effects of
excessive secretion of PTH by the functioning tumor rather than to
infiltration of vital organs by tumor mass. Thus, signs and symptoms of
hypercalcemia often dominate the clinical picture, with contributions
from typical hyperparathyroid bone disease and features of renal
involvement, such as nephrolithiasis or nephrocalcinosis. The challenge
to the clinician rests upon differentiating between hyperparathyroidism
due to parathyroid carcinoma and that due to its much more common
benign counterpart. It is of great importance that parathyroid
carcinoma be considered in the differential diagnosis of PTH-dependent
hypercalcemia, as the morbidity and mortality associated with this
diagnosis are substantial, and optimal outcomes are associated with
complete resection of the tumor at the time of the initial operation
(1, 2, 3, 11, 12, 14, 15, 17, 26, 27, 28, 29, 30, 31, 34, 73). All too often
the diagnosis of parathyroid carcinoma is made in retrospect when
hypercalcemia recurs due to local spread of tumor or distant
metastases.
There are several presenting features of a patient with primary
hyperparathyroidism that, when present, should suggest a malignant
rather than a benign etiology. There is no association of gender with
parathyroid carcinoma. The ratio of affected women to men is 1:1 in
most series compared with primary hyperparathyroidism where there is a
marked female predominance (ratio of 34:1). Most researchers have
noted that the average age of the patient with parathyroid carcinoma is
in the fifth decade, approximately 10 yr younger than typical patients
with primary hyperparathyroidism, who most often present in their
fifties or sixties. In contrast, a recent review of the Mayo Clinic
experience (30) and that of the National Cancer Data Base
indicated that the average age of their patients was somewhat greater
(26), in the middle fifties. In any case, considerations
of gender and age are of little help in evaluating the individual
patient.
With the advent of the multichannel autoanalyzer in the late sixties,
the clinical profile of primary hyperparathyroidism due to benign
adenomatous or hyperplastic disease has changed. Today, primary
hyperparathyroidism usually presents with mild hypercalcemia (within 1
mg/dL above the upper limit of normal) that is frequently asymptomatic
and often discovered during a routine evaluation or during the
investigation of an unrelated complaint (4, 5, 6). In
contrast, the serum calcium level of most patients with parathyroid
carcinoma is much higher, generally above 14 mg/dL or 34 mg/dL above
the upper limit of normal (1, 2, 3, 11, 12, 14, 15, 17, 26, 27, 28, 29, 30, 31, 34). Moreover, this more severe hypercalcemia is almost
invariably associated with the typical signs and symptoms of
hypercalcemia. The most frequent complaints are fatigue, weakness,
weight loss, anorexia, nausea, vomiting, polyuria, and polydipsia.
Other common presenting symptoms characteristic of a severely
hyperparathyroid state include bone pain, fractures, and renal colic.
When reported, PTH levels have ranged from 310 times above the upper
limit of normal for the assay employed. Extremely high levels of PTH
are unusual in primary hyperparathyroidism, in which circulating
concentrations are commonly less than twice normal. Alkaline
phosphatase is also higher in patients with parathyroid carcinoma than
in those with primary hyperparathyroidism in whom levels are generally
in the vicinity of the upper limit of the normal range
(7). Patients with parathyroid carcinoma may have elevated
levels of
- and ß-subunits of hCG, whereas patients with primary
hyperparathyroidism do not (74).
A palpable neck mass has been reported in 3076% of patients
with parathyroid carcinoma. This important clinical finding constitutes
another striking difference between benign and malignant parathyroid
disease, as a palpable neck mass is distinctly unusual in primary
hyperparathyroidism (75). In addition, recurrent laryngeal
nerve palsy in a patient with primary hyperparathyroidism who has not
had previous neck surgery is also very suggestive of parathyroid
cancer.
The classical target organs of PTH, kidney and skeleton, are affected
with greater frequency and severity in parathyroid carcinoma (1, 2, 11, 12, 27, 30, 32, 33) than is commonly observed in the
modern presentation of benign primary hyperparathyroidism. Most recent
series of primary hyperparathyroidism report the prevalence of renal
involvement, including nephrolithiasis, nephrocalcinosis, and impaired
glomerular filtration, to be less than 20% (4, 7). In
contrast, renal colic is a frequent presenting complaint of parathyroid
carcinoma. The prevalence of nephrolithiasis was 56%, and the
prevalence of renal insufficiency was 84% in one recent series
(30). These figures are somewhat higher than previous
reports in which the prevalence of renal involvement generally has
ranged from 3260%. Bone pain and pathological fractures are also
common features of parathyroid cancer. Overt radiological signs of
hyperparathyroid skeletal disease, such as osteitis fibrosa cystica,
subperiosteal bone resorption, "salt and pepper" skull, and absent
lamina dura as well as less specific signs such as diffuse spinal
osteopenia are commonly seen in parathyroid carcinoma (4491%). In
contrast, patients with benign primary hyperparathyroidism rarely have
skeletal complaints, and specific radiological signs are found in less
than 5% (4, 5, 7). It is also important to note the high
incidence of concomitant bone and stone disease that occurs in
parathyroid cancer, whereas simultaneous renal and overt skeletal
involvement is distinctly unusual in primary hyperparathyroidism. In
addition to the kidneys 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 primary hyperparathyroidism.
Parathyroid carcinoma shares many clinical features with acute primary
hyperparathyroidism, sometimes called parathyroid crisis. In view of
the marked elevations of serum calcium and PTH that are common in
parathyroid crisis, the diagnosis of parathyroid cancer should be
considered. Although the distinction between these two entities is not
possible preoperatively, it is important to bear the diagnosis in mind
because the surgical approach differs.
A summary of features that might lead one to suspect parathyroid cancer
in a patient with hypercalcemia and elevated PTH levels is shown in
Table 1
. It should be noted however, that
some patients with benign primary hyperparathyroidism present with more
severe disease than is commonly seen today. In such patients, the
distinction between benign and malignant disease may be even more
difficult on clinical grounds, because profound hypercalcemia, renal
disease, and osteitis fibrosa or diffuse osteoporosis may occur, and
even concomitant kidney and bone disease may be present
(73). 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 by failing to consider
it in the differential diagnosis.
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Pathology
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Several operative findings have been described that, when present,
help to distinguish benign parathyroid adenomas from parathyroid
carcinoma. The typical parathyroid adenoma is usually of soft
consistency, round or oval in shape, and of a reddish-brown color. In
contrast, parathyroid carcinoma is frequently described as a lobulated,
firm to stony-hard mass. In about 50% of cases it is surrounded by a
dense, fibrous, grayish-white capsule that adheres tenaciously to
adjacent tissues and makes the tumor difficult to separate from
contiguous structures. If there is gross infiltration of adjacent
thyroid, nerve, muscle, or esophagus or obvious cervical node
metastases, the diagnosis of carcinoma is not difficult. However, any
one or all of these operative findings may be absent, and examination
of frozen sections is of little value in distinguishing benign from
malignant disease.
As is the case with many endocrine neoplasms, the histopathological
distinction between benign and malignant parathyroid tumors is
difficult. In 1973 Shantz and Castleman, based upon an analysis of 70
cases of parathyroid carcinoma, established a set of criteria for the
pathological diagnosis of this malignancy (28). These
histological features are 1) uniform sheets of (usually chief) cells
arranged in a lobular pattern separated by dense fibrous trabeculae, 2)
capsular or vascular invasion, and 3) mitotic figures within tumor
parenchymal cells that must be distinguished from endothelial cell
mitoses. Unfortunately, none of these features is pathognomonic of
parathyroid carcinoma. Several features, namely, dense fibrous
trabeculae, trabecular growth pattern, mitoses, and capsular invasion,
have been found in parathyroid adenomas (75). Capsular and
vascular invasion appear to correlate best with subsequent tumor
recurrence.
Several other histological techniques have been investigated to improve
further the accuracy of diagnosing parathyroid carcinoma. Electron
microscopy of parathyroid cancer tissue reveals nuclear and
mitochondrial alterations and evidence of increased secretory activity,
but does not appear to be of value in distinguishing benign from
malignant tumors (76, 77, 78). Nuclear diameter appears to be
greater in parathyroid carcinomas than in adenomas (28, 76, 77, 78, 79, 80), but this index is not very useful in the individual
case. Measurement of nuclear DNA content by flow cytometry may be of
some value both in establishing the diagnosis of parathyroid carcinoma
and in predicting the invasive potential of the tumor. Mean nuclear DNA
content is greater, and an aneuploid DNA pattern is more common in
parathyroid carcinoma than in adenomas; when present, aneuploidy
appears to be associated with a poorer prognosis (33, 73, 81). Unfortunately, however, aneuploidy occurs too frequently in
parathyroid adenomas to be of great use in differentiating benign from
malignant parathyroid lesions (34, 81, 82).
Some experts believe that the overall histological pattern is more
useful than any single feature in the differentiation of parathyroid
carcinoma from benign disease, and the presence of more than one in a
lesion should raise the index of suspicion (32, 34).
Bondeson and colleagues consider that cellular atypia, including
nuclear pleomorphism and enlargement and macronucleoli, are associated
with a greater likelihood of malignancy (83).
Immunohistochemical staining of RB protein may also prove useful in
distinguishing benign from malignant parathyroid tumors. Cryn and
colleagues were the first to report that staining for RB protein with
polyclonal antibodies was commonly absent in parathyroid carcinomas and
was almost always present in parathyroid adenomas (66).
Other investigators have corroborated their results (67).
In contrast, Farnebo et al., who used monoclonal antibodies
directed against the RB protein, did not find immunostaining of RB
protein to be useful in distinguishing between benign and malignant
parathyroid tumors (84). However, these investigators did
observe a trend for more intense immunostaining in parathyroid cancers
of the cell cycle-associated antigen Ki-67, a marker for proliferative
activity. In their hands, the technique was not useful for
distinguishing carcinomas from adenomas (84), although
Abbona et al. did find significant differences in Ki-67
staining between benign and malignant parathyroid disease
(85). Further studies are necessary to assess the value of
immunohistochemical stains for the differential diagnosis of
parathyroid lesions.
Invasive growth of various neoplasms may be facilitated by tumoral
secretion of proteolytic enzymes. One such enzyme is gelatinase A.
Farnebo et al. recently reported that gelatinase A messenger
ribonucleic acid was detected in 14 of 18 unequivocal and 4 of 13
equivocal parathyroid cancers (86). The strongest signal
was detected in the fibroblasts and macrophages at the tumor border,
rather than in the tumor cells themselves. This new technique may
provide additional support for the diagnosis of malignancy.
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Natural history
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Parathyroid carcinoma is an indolent, albeit tenacious, tumor with
rather low malignant potential. It tends to recur locally at the
operative site and spread to contiguous structures in the neck.
Metastases occur late in the course of the disease with spread via both
lymphatic and hematogenous routes. Cervical nodes (30%) and lung
(40%) are involved most commonly, followed by liver (10%). Occasional
involvement of bone, pleura, pericardium, and pancreas has been
reported.
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Management
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Surgery. The single most effective therapy for parathyroid
carcinoma is complete resection of the primary lesion at the time of
the initial operation when extensive local invasion and distant
metastases are less likely (1, 18, 27, 29, 34, 75). For
this reason both preoperative suspicion and intraoperative recognition
are of paramount importance. Patients whose clinical presentation is
suggestive of parathyroid carcinoma warrant thorough exploration of all
four parathyroid glands, as parathyroid carcinoma has been reported to
coexist with benign adenomas or hyperplasia (10, 87). When
the gross pathological findings suggest malignancy, the following steps
should be taken: en bloc removal of the lesion together with
the ipsilateral thyroid lobe and isthmus, and skeletonization of the
trachea and removal of any contiguous tissues to which the tumor
adheres. Great care must be exercised to avoid rupture of the capsule
of the gland, which increases the likelihood of local seeding of the
tumor. If the recurrent laryngeal nerve is involved with tumor, it must
be resected. 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 anterior cervical
nodes.
The situation becomes more complex when the diagnosis is made in the
early postoperative period on the basis of pathology. This is
particularly so in view of the controversy that exists regarding the
histopathological diagnosis of parathyroid carcinoma. If the gross
characteristics of the lesion were typical of a parathyroid cancer and
if the subsequent pathology appears to be aggressive with extensive
vascular or capsular invasion or if the patient remains hypercalcemic,
reexploration of the neck is indicated. The structures adjacent to the
tumor site should be resected in the manner described above. If none of
these features is present, but the diagnosis is made on the basis of
the microscopic characteristics, immediate reoperation may not be
necessary, as a simple complete resection of the tumor is often
curative. Such a patient must be observed carefully with frequent
measurements of PTH and serum calcium levels.
The postoperative management of a patient with parathyroid cancer must
include careful attention to the serum calcium level. As calcium and
phosphorus are deposited into the skeleton, symptomatic hypocalcemia
(hungry bone syndrome) may ensue and should be regarded as a sign that
the surgery has been successful. The hypocalcemia may be severe and
protracted, requiring large doses of iv calcium. Sufficient
supplemental calcium and calcitriol should be prescribed to maintain
serum calcium at the low end of the normal range. As the bones heal and
the remaining parathyroid glands recover, the requirement for calcium
will decrease, permitting gradual reduction of the doses of calcium and
calcitriol. After this point serum calcium and PTH levels should be
monitored every 3 months.
The management of recurrent or metastatic parathyroid carcinoma
reflects the rather indolent biology of this cancer and, in contrast to
many other tumors, is primarily surgical (1, 11, 15, 18, 19, 26, 29, 30, 33, 88). As even very small tumor deposits may produce
sufficient PTH to cause severe hypercalcemia, significant palliation
may result from resection of lesions in the neck, lymph nodes, lungs,
or liver (18). Many situations have been described in
which resection of such lesions has resulted in periods of
normocalcemia that range from months to years. Even though surgery is
only palliative, amelioration of the hypercalcemia may also result
making its control more amenable to medical therapies.
In patients with recurrent hypercalcemia, localization studies should
be performed before reoperation. Careful palpation of the neck should
be performed, as recurrence occurs earliest and most often at the
original site, and such tumors are frequently palpable. Thallium
201-technetium 99m scanning is useful in locating tumors in the neck
and upper mediastinum (89, 90, 91). Technetium 99m-sestamibi
used concurrently with a hand-held,
-detecting probe may also prove
to be useful for the intraoperative localization of abnormal
parathyroid tissue (22). Thallium 201 is also helpful for
situations in which the thyroid has been partially or completely
resected or when pulmonary metastases are suspected. Computerized
tomography and magnetic resonance imaging are useful adjuncts to
ultrasonography in evaluation of the neck and are superior for
detection of distant metastases in the chest or abdomen. If noninvasive
testing does not yield results, arteriography or selective venous
catheterization may be useful. Fine needle aspiration biopsy in
conjunction with ultrasonic localization and immunoperoxidase
confirmation may be useful in localizing parathyroid tissue in patients
with recurrent hyperparathyroidism (92). However, biopsy
must be used with caution, if at all, in parathyroid carcinoma to avoid
seeding the needle track with deposits of malignant tissue. Recurrent
carcinoma in the neck should be treated with wide excision of the
involved area, including the regional lymph nodes and other involved
structures. Accessible distant metastases should also be resected when
possible.
Radiation therapy. Parathyroid carcinoma is not a
radiosensitive tumor. The use of radiation therapy to control tumor
growth and decrease hormone production has been ineffective in the
majority of cases in which it has been attempted (3, 28).
In the occasional situation, radiation to the neck after surgery for
recurrence may be helpful in preventing tumor regrowth (23, 75). An apparent cure (10 yr) of locally invasive parathyroid
carcinoma by radiation therapy was reported by Wynne and colleagues
(30). In addition, six patients who received adjuvant
radiation therapy for microscopic residual disease have been followed
for 12156 months without recurrence (23).
Chemotherapy. Because of the rarity of parathyroid carcinoma,
few investigators have sufficient numbers of patients to permit large
scale clinical research trials. Thus complete investigations of the
utility of a given therapy do not exist, and experience is usually
limited to scattered case reports. It is with these unavoidable
limitations in mind that the following comments should be
interpreted.
Attempts to control tumor burden with chemotherapy have been
disappointing. Several regimens (nitrogen mustard; vincristine,
cyclophosphamide and actinomycin D; adriamycin, cyclophosphamide, and
5-fluorouracil; and adriamycin alone) have been ineffective (87, 93, 94). Two patients have been treated with synthetic estrogens
with some success (95, 96). A single patient with
pulmonary metastases responded to treatment with dacarbazine,
5-fluorouracil, and cyclophosphamide with a decrease in PTH and
normalization of serum calcium for 13 months (97). Another
patient responded to dacarbazine alone with a brief, but significant,
decline in her serum calcium level (98). An 18-month
remission with regression of a mediastinal mass and pleural effusion
was induced in a patient with a nonfunctioning parathyroid carcinoma by
a regimen consisting of methotrexate, doxorubicin, cyclophosphamide,
and lomustine (99). Such approaches warrant further
investigation.
Management of hypercalcemia. When parathyroid carcinoma has
become widely disseminated and surgical resection is no longer
effective, the prognosis is poor. However, even at this juncture
relatively prolonged survival is possible. The therapeutic goal at this
point is to control the hypercalcemia, which because of the extremely
elevated PTH levels and the intensity of the associated bone
resorption, may be a difficult and frustrating task.
The acute hypercalcemia of parathyroid carcinoma is treated in the same
way as hypercalcemia due to any other cause (100, 101).
Management includes infusion of saline to restore fluid volume and
enhance urinary calcium excretion, and loop diuretics to further
increase calciuresis. Such measures rarely suffice, however, and
addition of agents that interfere with osteoclast-mediated bone
resorption is always necessary.
Bisphosphonates: The bisphosphonates are a group of drugs
that inhibit osteoclast-mediated bone resorption. Several of these
drugs have shown some promise in the therapy of parathyroid carcinoma.
Clodronate (Cl2MDP) lowers serum calcium in
parathyroid carcinoma when administered iv (102, 103, 104). It
is widely available in Europe and the United Kingdom, but it is not
available in the United States. Etidronate has also been shown to
lower serum calcium transiently in parathyroid cancer patients
(105). It is administered iv over a 2-h period at a dose
of 7.5 mg/kg and may be repeated daily or until the serum calcium falls
to normal for a maximum of 7 days. Although the drug is available in an
oral form, it is not effective in patients with parathyroid carcinoma,
and even the iv preparation may not normalize the serum calcium.
A more potent bisphosphonate, pamidronate, is now widely available for
iv use. When infused for periods ranging from 224 h and in doses
ranging from 4590 mg/day, pamidronate has been at least transiently
effective in lowering serum calcium levels in several patients with
parathyroid cancer (18, 20, 21, 106, 107, 108). New and more
potent bisphosphonates (ibandronate and zoledronate) are being
investigated actively in the United States and soon may become
available for the treatment of hypercalcemia of malignancy, including
that due to parathyroid cancer.
Plicamycin: Plicamycin (mithramycin), another specific
inhibitor of bone resorption, lowers serum calcium levels in
parathyroid carcinoma (109). It is administered iv at a
dose of 25 µg/kg over 48 h and may be repeated at daily intervals
for up to 7 days until the serum calcium falls into an acceptable range
(100, 101). Unfortunately, complete normalization of the
serum calcium is often not achieved, and the effectiveness of the drug
is not only transient but diminishes with repeated courses. Conversely,
the toxic effects of plicamycin on the liver, kidney, and bone marrow
increase with the number of exposures. Plicamycin therapy should be
reserved for therapy of life-threatening hypercalcemia, unresponsive to
iv bisphosphonates, while surgically accessible metastases are sought
or for those patients whose hypercalcemia can be controlled in no other
way.
Calcitonin: This agent both inhibits osteoclast-mediated
bone resorption and increases urinary calcium excretion. However, it
lowers serum calcium transiently, if at all, in most patients with
parathyroid carcinoma (1, 97, 102, 110, 111, 112). It has been
effective in a single patient when used in doses of 200600 Medical
Research Council units/day in combination with glucocorticoids
(300 mg hydrocortisone) (113) and in occasional patients
when used alone (114).
Gallium: Gallium nitrate appears to inhibit bone
resorption by preventing dissolution of hydroxyapatite crystals
(115). Gallium nitrate lowered serum calcium in two
patients with parathyroid carcinoma (115) and was later
reported to be effective in four of five patients (19). It
is administered as a continuous 5-day infusion at a dose of 200
mg/m2·day. Significant toxicities include
elevation of the serum creatinine that is potentiated by volume
depletion and the concomitant use of potentially nephrotoxic drugs. It
remains unclear whether gallium nitrate will prove useful in the
management of chronic hypercalcemia due to parathyroid cancer.
Calcimimetics: Under normal circumstances, PTH secretion is
mediated by a cell surface calcium-sensing receptor, and this
regulatory response is generally retained in benign parathyroid tumors.
Recently, an allosteric modulator of the calcium receptor with
calcimimetic properties has been shown to lower serum PTH and calcium
concentrations in patients with primary hyperparathyroidism
(116). This same agent was used to treat a patient with
parathyroid carcinoma. Serum calcium was controlled for 2 yr without
adverse effects (24). Such agents show promise in the
management of parathyroid cancer.
WR-2721: WR-2721
[5-,2-(3-aminopropyl)amino]ethylphosphorothoric acid, is a
hypocalcemic agent that acts by inhibiting PTH secretion and bone
resorption. It has been shown to lower PTH levels and serum calcium
levels in parathyroid carcinoma (117). Severe toxicities
limit its use.
Octreotide: The long-acting somatostatin analog, octreotide,
has also been reported to inhibit PTH secretion in a woman with
parathyroid carcinoma metastatic to bone (118).
Immunization: Finally, a novel approach to therapy of
hypercalcemia due to parathyroid cancer has recently been published in
case report form (25). A patient with parathyroid
carcinoma metastatic to lungs and pleura had severe hypercalcemia that
was resistant to oral clodronate, iv pamidronate, octreotide,
5-fluorouracil, and streptozotocin. She was immunized with human and
bovine PTH peptides, followed by booster doses at 4 and 11 weeks.
Antibodies against PTH were detected at 4 weeks. Before therapy, serum
calcium varied between 3.5 and 4.2 mmol/L. Serum calcium levels
remained significantly lower (2.53.0 mmol/L) throughout the 6 months
of observation. There was rapid improvement in her clinical condition,
and no significant adverse effects were observed. If confirmed, this
would seem to be a novel and relatively simple approach to the control
of hypercalcemia in patients resistant to other measures.
 |
Prognosis
|
---|
The prognosis of parathyroid carcinoma is quite variable. No one
characteristic correlates predictably with outcome. Early recognition
and complete resection at the time of the initial surgery carry the
best prognosis. The average time between surgery and the first
recurrence is approximately 3 yr, although intervals of up to 20 yr
have been reported. Once the tumor has recurred, complete cure is
unlikely, although prolonged survival is still common under these
circumstances with palliative surgery. Five-year survival rates vary
from 4086%. The National Cancer Database survey recently reported
10-yr survival to be approximately 49% (26).
Received April 12, 2000.
Revised October 9, 2000.
Accepted October 18, 2000.
 |
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