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260
ENDOCRINE SURGERY
gland and a negative sestamibi scan allowing a
successful unilateral neck exploration when single gland involvement was confirmed by IPM.
Biochemical Fine-Needle Aspiration
This technique was first described by Perrier
et al. and consists of measuring PTH levels in
tissue samples obtained from fine-needle aspirations. The PTH levels in the cells differentiate
parathyroid from other tissues, such as thyroid
nodules or lymph nodes, with a specificity of
100% [42]. A 25-gauge needle attached to a syringe is used to collect the tissue sample. The
content that is aspirated, is diluted with 1cc of
saline solution, centrifuged, and the supernatant
is used for PTH measurement intraoperatively by
a rapid assay. This technique provides rapid tissue identification without frozen section, and it
can be helpful when gland identification is difficult, for example, in the case of an intrathyroidal
parathyroid gland, an indeterminate exophytic
thyroid nodule, or enlarged lymph nodes. Such
tissue identification may decrease the operative
time by preventing further dissection of suspicious, but nonparathyroid, tissue.
with BNE and excision of all enlarged glands
based on the surgeon’s judgment of size to
97% with limited parathyroidectomy guided by
parathyroid hypersecretion. Furthermore, the
operative success rate increased from 76%
with BNE to 94% with IPM guided excision in
reoperative patients [6].
Recognizes Abnormal Glands More
Accurately than Histopathology
It has been shown that IPM is more accurate in
recognizing the function of the remaining
glands left in situ than histopathology. The
assumption is that patients with diagnosis of
adenoma have single gland disease while hyperplasia was associated with multiple gland involvement. A study showed that 64% of successfully treated patients with SPHPT and single
gland involvement identified by IPM were postoperatively diagnosed as having hyperplasia
[48]. Histology would be incorrect in guiding
the extent of the resection in most cases, therefore should not be used to guide
parathyroidectomy.
Decreases in Operative Time
and Costs
After excision of the hypersecreting gland(s)
has been assured by meeting the IPM criterion,
the surgeon may complete the cervical exploration without examination and/or biopsy of the
remaining parathyroid glands. This decreases
the operative time because continued search
for normally functioning glands is unnecessary.
With biochemical confirmation predicting a
return to eucalcemia, frozen section histopathology is not necessary, thereby decreasing
the operative time. Most of the cost savings is in
the ability to perform ambulatory surgery without an overnight stay [44–47].
Improves Operative Success
IPM and the ‘‘>50% PTH drop’’ criterion have
improved the success rate of initial and reoperative parathyroidectomies in patients with
SPHPT [6, 47]. In patients having initial parathyroidectomies, operative success improved
from 94% with the previous standard approach
Limitations of Intraoperative
PTH Monitoring
IPM and ‘‘>50% PTH Drop’’ Criterion
Does not Predict the Size of the
Remaining Normally Secreting
Parathyroid Glands
Some surgeons using IPM during BNEs have
published the finding of a second enlarged
gland after successful excision of a single
hypersecreting parathyroid confirmed by an
intraoperative drop in hormone levels. Because
these enlarged, normally functioning glands
were interpreted as ‘‘second adenomas’’ and
were excised, the IPM results were reported as
false positive because eucalcemia was achieved
[28–33]. The criterion used in our studies does
not predict the size of the remaining normally
functioning glands. In our patients, these
glands were not hypersecreting either at the
time of the operation, confirmed by the return
to eucalcemia, or found to be responsible for
261
INTRAOPERATIVE PTH MONITORING
recurrent hypercalcemia during the postoperative period, which now averages 4 years. This
emphasizes that abnormal secretion is not
necessarily associated with parathyroid gland
size [49, 50]. This can also be supported by the
fact that when parathyroid excision is guided
by hormone secretion, 9–19% fewer glands are
removed with a 97% success rate, when compared with gland resection guided by surgeon’s
judgment of size [51]. Therefore, we can indirectly conclude that those enlarged glands left in
situ were not hyperfunctioning.
IPM Does Not Predict PTH Levels
in Postoperative Eucalcemic Patients
Some authors have pointed out that the use of
IPM with the ‘‘>50% PTH drop’’ criterion in
parathyroidectomy fails to predict high PTH
levels in postoperative eucalcemic patients [26].
It is known that despite the operative approach
used, PTH levels are often elevated in eucalcemic
patients followingsuccessfulparathyroidectomy.
Many of these patients will have their PTH levels
returned to normal several months after parathyroidectomy [51–55]. Carty et al. and Bergenfelz et al. have suggested that these high PTH
levels are compensatory, with parathyroid glands
only responding to a deficit in total body calcium
[52, 55]. In addition, most of the patients who
were replaced with calcium and Vitamin D had a
return of PTH to normal range over time and the
recurrence rate remained very low.
cured and those who developed recurrent hyperparathyroidism [8].
IPM Does Not Guarantee
Operative Success
IPM predicts, but does not always prevent,
operative failure in patients whose offending
gland(s) could not be found by BNE performed
by an experienced surgeon or operative failure
due to misdiagnosis. In most operative failures,
IPM correctly predicts postoperative hypercalcemia with a specificity of 96% [24].
The Cost of Intraoperative
PTH Assays
Some of the intraoperative PTH assays are
expensive, but the costs of this adjunct have
decreased significantly over the past years. The
benefits of IPM, however, compensate for its
cost by allowing a shorter operative time, no
need for frozen section histopathology and
eliminating an overnight hospital stay in most
patients [43–46].
Isolated Familial
Hyperparathyroidism
or Non-MEN Familial
Hyperparathyroidism
IPM Does Not Assure Hypersecretion
of the First Gland Excised in MGD
IPM cannot determine the function of the first
excised parathyroid gland if the PTH level does
not drop sufficiently and an additional gland is
found and excised. IPM does not differentiate
the first gland from an enlarged normally functioning parathyroid since the hormone level
remained high after its removal.
IPM Does Not Predict
Late Recurrence
Thereisnodifferencein the operative hormone
dynamics between patients who are biochemically
TheuseofIPMtoguideresectioninpatients
with isolated familial HPT has been previously
described [22]. In the past, patients with IFHPT
(first-degree family members with primary
HPT and no other endocrinopathies) were
treated based on the principle applied to
patients with MEN with BNE and 3½ gland or
total parathyroidectomy with autotransplantation. Operative success with these extensive
excisions was achieved in most patients but
recurrent disease occurred in 19–23%, and permanent hypoparathyroidism was found in
13–41%. The report of successful parathryoidectomy with single gland excision triggered
the use of IPM in the surgical treatment of
patients with IFHPT [22]. When IPM with the
‘‘>50% PTH drop’’ criterion was used to guide
the excision in these patients, operative
ENDOCRINE SURGERY
Table 18.4. Accuracy of various intraoperative PTH criteria in predicting operative success in patients with secondary
hyperparathyroidism
Studies Number of Patients Criteria Prediction of cure (%) Overall accuracy
Ikeda [16] 18 PTH drop <45 pg/ml at 30
Weber [15] 95 (1) PTH drop > 90% 10
(2) PTH drop to NR in 10
Seehofer [21] 153 (1) PTH drop <150 at 15
(2) PTH drop >70% from T0 at 15
a
Intraoperative PTH assay used the whole intact PTH or Bio intact PTH.
b
Cure defined as normal PTH levels for 6 months.
c
Cure defined as normal calcium and normal PTH.
(3) Either <150 or >70% drop at 15
a
0
0
0
0
0
0
94% cured
(1) 97% cured
(2) 100% cured
(1) 99% cured
(2) 94% cured
(3) 99% cured
b
c
c
b
b
b
NR
NR
NR
(1) 74%
(2) 92%
(3) 94%
262
outcome was correctly predicted with a sensitivity and specificity of 100 and 80%, respectively. The success rate of this operative
approach in patients with IFHPT was 93%
with a recurrence rate of 9% over an average
follow-up of 2 years. Multiglandular disease
was present in 13% when excision was guided
by parathyroid hypersecretion alone as
opposed to the previously published incidence
of 45–75% when excision was guided by parathyroid gland size and histopathology. Falsepositive results and operative failure in these
patients was 7%.
Although the accuracy of IPM in guiding
parathyroidectomy in patients with IFHPT is
lowerthaninpatientswithSPHPT,weoffer
this approach as long as they understand and
accept that in exchange for a limited neck
dissection and a decreased incidence of hypoparathyroidism, the operative failure rate and
the chance of developing recurrent HPT are
slightly higher [22].
Secondary
Hyperparathyroidism
the results of IPM guided resection in patients
with renal failure. Also the accuracy of the various criteria in predicting operative success is
difficult to compare since the expected outcomes are different among these studies. Some
investigators considered a successful parathyroidectomy when patients have a PTH level
within normal range for at least 6–12 months
while others use the PTH as high as four times
the normal range as the goal for a successful
operation [15–18]. Table 18.4 shows the accuracy of various criteria to predict complete excision in patients with secondary HPT. The use of
whole intact molecule or Bio Intact PTH seemed
to be promising in guiding parathyroidectomy
in secondary HPT, but it is currently not available in this country [16].
The usefulness of IPM and which criteria to
be used in patients with secondary HPT have
not been well established. Studies that have a
homogenous population, strict and consistent
intraoperative PTH criterion, and long-term
follow-up might eventually demonstrate the
benefit of using IPM in the treatment of
patient with secondary HPT on continuous
dialysis.
Data regarding intraoperative PTH monitoring
in patients with secondary HPT are limited and
difficult to evaluate due to the heterogenicity of
the populations studied. The operative findings
in patients with secondary and tertiary HPT are
often evaluated together and the results of
patients on dialysis are combined with the
ones that underwent renal transplantation.
This heterogenicity decreases the credibility of
Tertiary Hyperparathyroidism
The use of IPM inpatients with tertiary HPT was
previously described by Chen and Richards [14,
17]. In some of these patients, intraoperative
information on the PTH dynamics was
described only after all parathyroid glands
were excised with no blood samples collected
263
INTRAOPERATIVE PTH MONITORING
after each gland resection. It is unknown if all
the number of parathyroid glands that are
autonomously hyperfunctioning in hypercalcemic patients after kidney transplantation
is unknown. Patients with secondary HPT have
multiple metabolic imbalances resulting in
oversecretion of parathormone by all parathyroid glands. When these stimuli of chronic hypocalcemia, hyperphosphatemia, and low vitamin
D are resolved, it is unknown if all parathyroid
glands are actually autonomously hypersecreting in patients with tertiary HPT. Chen
and Richards, in two separate studies, have
answered this question when they described an
incidence of 9–33% of single gland disease
determined by the IPM in patients with tertiary
HPT [14, 17]. Conversely, Chen et al. suggested
that a BNE should be done routinely due to the
high incidence of MGD. Richards et al., on the
other hand, used IPM to guided parathyroidectomy in these patients and found that IPM with
the >50% drop was as accurate in predicting
operative success in tertiary HPT as they are in
SPHPT. The incidence of single glandular involvement is very low, but was correctly predicted
by IPM in the majority of the cases [14].
Parathyroid Cancer
The results of parathyroidectomy guided by
IPM in patients with parathyroid cancer are
rarely described. In our experience, the incidence of false-positive results are higher
in patients with cancer than in SPHPT [23].
We believe that the tumor biology causing
regrowth of the cancer before 6 months is
the reason for the false-positive results not
necessarily missed MGD. Even though IPM is
accurate in pointing out insufficient resection
during reoperations, it is not as accurate in predicting operative success during initial parathyroidectomies as it is in SPHPT. IPM sensitivity,
specificity, positive predictive value, negative predictive value, and overall accuracy in predicting
outcome in parathyroid cancer are 100, 40, 70,
100, and 75%, respectively. In patients with parathyroid cancer, intraoperative PTH values are not
as accurate in predicting complete excision, making the initial recognition of malignancy with en
bloc resection paramount for the treatment of
these patients [23].
Multiple Endocrine Neoplasia
The use of IPM to guide the excision in
patients with MEN1 was reported by Tonelli
et al. [19]. They described a 16-year experience
of surgical treatment of MEN1 patients using
total parathyroidectomy, thymectomy, and
autotransplantation. In this study, a drop in
the PTH level to <10 pg/ml at the end of the
procedure indicated total parathyroidectomy
and that autotransplantation should be done.
IPM was also helpful in the excision of hyperfunctioning grafts causing recurrence and the
drop of 50% in the PTH level 10 minutes after
the excision of the hyperplastic tissue predicted successful resection.
Summary
IPM has changed the management of patients
with SPHPT. The use of this surgical adjunct has
become a standard of care in the treatment of
SPHPT by most endocrine surgeons.
IPM can be used with several intraoperative
criteria and blood sampling times, but in our
experience, the ‘‘>50% PTH drop’’ criterion
that includes a >50% peripheral PTH drop,
from the highest either preincision or preexcision level, 10 minutes after the excision of a
suspicious gland predicts the operative outcome with an overall accuracy of 98%. We
recommend using the preincision and preexcision levels in all operations in an attempt to
increase the accuracy of the IPM and criteria
by decreasing FN results. If the surgeon wants
to use stricter criteria to decrease falsepositive results therefore preventing missed
MGD, the drop of PTH to normal range will
achieve this goal; on the other hand, it will lead
to a significant increase in the incidence of FN
results with excision of normally secreting
glands.
The use of IPM has proved to be accurate in
patients with SPHPT and isolated familial HPT,
but its accuracy is questionable in patients with
secondary, tertiary HPT, parathyroid cancer,
and MEN syndrome. Further studies are needed
to prove the usefulness of this surgical adjunct
in these patients.
Despite the recognized limitations, IPM
using the ‘‘>50% PTH drop’’ criterion is very
264
ENDOCRINE SURGERY
helpful to the surgeon intraoperatively and has
become a valuable tool in the treatment of
hyperparathyroidism.
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19
Focused Parathyroidectomy
Johan Westerdahl and Anders Bergenfelz
Background
The parathyroid glands were first described in
1880 by the Swedish anatomist and medical student Ivar Sandstr¨om. He named them ‘‘glandula
parathyroideae.’’ In 1908 the association between
serum calcium and the parathyroid glands was
established by MacCallum and Voegtlin [1].
The first successful parathyroidectomy was performed in 1925 by Felix Mandel in Vienna on a
patient with severe osteitis fibrosa cystica [2]. During theearly daysof parathyroidsurgery removalof
one large gland was usually successful. However,
the concept ofchief cell hyperplasiawas established
in 1958 by Cope [3], and with the recognition of
primary parathyroid hyperplasia as a distinct histopathologic entity, it became obvious that in a
proportion of patients with primary hyperparathyroidism (pHPT) more parathyroid tissue had
to be removed [4]. Since it was not possible to
distinguish between uniglandular and multiglandular disease without identifying all parathyroid
glands, bilateral exploration was advocated.
Evolution of Surgery for pHPT
Bilateral neck exploration, with identification of at
least four parathyroid glands and removal of all
enlarged glands yields excellent results [5, 6] and
has over the years evolved as the gold standard
for the surgical treatment of pHPT. With the introduction of autoanalyzers in clinical chemistry
during the 1970sthe diagnosis ofpHPT has become
more frequent. The symptoms of pHPT patients
today bear little resemblance with the severe disorder of the bones and the kidneys described by Albright in the 1930s [7]. Contemporary patients
are typically elderly women, with mild aberrations
in serum calcium and associated cardiovascular
comorbidityiscommon[8].Inresponsetothe
more frequent diagnosis of pHPT surgery has over
the past 20 years evolved rapidly worldwide [9].
It is knownthat upto 90% ofpatients with pHPT
have a solitary adenoma [10, 11]. In these patients
only one gland requires excision for cure. A bilateral surgical approach is associated withpostoperative hypocalcemia in up to 15% [12]. To simplify
thesurgicalprocedureandreducetheriskofpostoperative hypocalcemia the concept of limited
parathyroid exploration was first suggested by
Wang in the 1970s [13]. He used intraoperative oil
red O staining and the saline float test to help
determine whether a parathyroid gland was normal. Later the unilateral approach was refined by
Tibblin [14], who thereby started the new era of
parathyroid surgery.
Open Unilateral Neck
Exploration (Original approach)
The unilateral approach has no place in the
management of patients with multiple endocrine neoplasia (MEN1 and MEN2) and familial
J.G.H. Hubbard et al. (eds.), Endocrine Surgery, Springer Specialist Surgery Series,
DOI 10.1007/978-1-84628-881-4_19, Ó Springer-Verlag London Limited 2009
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hyperparathyroidism since these conditions by
definition have a multiglandular involvement.
Previous parathyroid or thyroid surgery is generally a contraindication.
The technique was introduced in our department in 1977 by Tibblin. The main principle of
the unilateral technique is to restrict the operation to the side on which the solitary adenoma is
located. Originally no preoperative localization
study was used. Surgery was performed through
a short (<5 cm) standard Kocher incision, with
the strap muscles separated in the midline and
not divided. If an adenoma was found on the
first side, then both the adenoma and the normal appearing gland were removed and the
procedure was terminated. If the adenoma was
not found, the two normal parathyroid glands
were left in situ and the contralateral side
explored, removing both the adenoma and the
normal gland on the second side. The diagnosis
was confirmed with the help of intraoperative
frozen section. Oil red O staining of parathyroid
tissue, introduced by Roth and Gallagher [15]
and later modified by Ljungberg and Tibblin
[16] was used to distinguish between normal
and abnormal parathyroid tissue as well as
between adenoma and hyperplasia. Typically,
suppressed chief cells are stained whereas adenomatous cells do not stain. The distinction
between a solitary adenoma and a hyperplastic
gland remains controversial for some pathologists since they believe it is not possible to
differentiate between an adenoma and a hyperplastic gland without a histological comparison
with a normal gland. The presence of a suppressed rim of normal parathyroid tissue aids
the diagnosis of an adenoma. Since this tissue
usually is located where the vessels enter the
gland, the surgeon can help the pathologist by
marking the vascular pedicle.
From the beginning, the unilateral approach
has yielded good results with a reduced risk of
hypocalcemia [17–20]and vocal cord injury [19].
A systemic review, undertaken a few years ago,
comparing unilateral with bilateral neck exploration indicated a tendency to favor the unilateral
approach [21]
The unilateral technique has been modified
with the advent of improved preoperative localization and measurement of intraoperative
parathyroid hormone (ioPTH). Thus, the modern method for unilateral exploration is as follows: If an adenoma is found on the first side
explored, it is excised. If the adenoma is not
found or the result of ioPTH measurement is
inconclusive (see below), comprehensive bilateral exploration is performed. The exploration
always starts on the side indicated by the preoperative localization. When preoperative localization is negative, the exploration always starts
on the same side, e.g., the left side. No attempt is
made per se to visualize normal glands. Frozen
section is not used.
This modified unilateral approach has recently
been compared with conventional bilateral neck
exploration in a prospective randomized trial
[22]. Unilateral neck exploration demonstrated a
lower incidence of biochemical and severe symptomatic hypocalcemia, most marked in patients
with a solitary adenoma. Cost and long-term cure
did not differ between techniques [22, 23].
Preoperative Localization
As solitary adenomas are equally distributed in
the neck, about 50% of patients would undergo a
unilateral neck exploration without the use of preoperative localization, provided this was always
startedonthesameside[17].However,fora
higher success rate in focused parathyroid surgery, preoperative localization studies with a
high accuracy are required. When comparing the
accuracy between different modalities and studies
it isimportant toconsider thecharacteristics of the
patients under study, particularly adenoma size,
PTH values, and concomitant thyroid disease. We
advocate the use of preoperative localization studies in patients with previous thyroid or parathyroid surgery and in patients planned for focused
parathyroid surgical techniques.
Sestamibi-technetium scintigraphy has emerged as the noninvasive localization procedure
of choice [24–27]. Previous studies have
reported sensitivity of up to 90% [28–30]. However, a recent meta-analysis has shown wide
differences in reported sensitivity [31]. Furthermore, an audit from the Scandinavian quality
register for parathyroid surgery reported a
modest sensitivity of only 64.4% [32]. A further
concern is the inability of the technique to predict multiglandular disease [28, 33, 34]. The
sensitivity of sestamibi scintigraphy may be
improved by the addition of delayed imaging
based on differential washout kinetics [35], single photon emission computed tomography
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FOCUSED PARATHYROIDECTOMY
(SPECT) [36], or oblique views with higher dose
[37]. This remains to be proven in prospective
trials.
Ultrasonography (US) has become one of
the preferred preoperative localization techniques. US is operator and equipment dependent,
and accordingly the reported sensitivity varies
widely in the literature [38–40]. The importance
of the combination of skill, experience, and
interest, was shown in a study comparing surgeon-performed with radiology-performed US
[41]. Surgeon-performed US had the best accuracy, and it has been suggested that surgeonperformed US, which has the advantage of being
a cheap, noninvasive, and comparatively sensitive investigation, should be the initial localizing test [42]. With the addition of fine-needle
aspiration and PTH sampling the precision of
US may approach 100% [43].
Computed tomography and magnetic resonance imaging are superior to US in identifying
ectopic parathyroid glands but normally has no
role in the management of pHPT patients prior
to initial surgery.
Both [18F]-Fluoro-2-deoxy[44] and [11C]-methionine [45] positron emission tomography (PET) have been used to localizing parathyroid glands. However, PET is not
routinely available at most institutions and the
cost is high, it is considered an option only
when other localization modalities have failed
in reoperative situations. Selective venous sampling and PTH measurement can be used for
preoperative [46] localization in reoperative
surgery, or intraoperative [47] localization as
an aid to the surgeon.
D-glucose (FDG)
Intraoperative Measurement
of PTH
In recent years, the intraoperative measurement
of PTH (ioPTH) has become an adjunct to parathyroid surgery for pHPT. This means a shift
from a gross morphological definition to a biochemical definition of a hyperfunctional parathyroid gland. A method for intraoperative
measurement of intact PTH was developed in
the late 1980s by Nussbaum [48]. To shorten the
time for intraoperative analysis, the assay was
modified, enabling the incubation time to be
shortened to about 15 min. Subsequently other
groups have adopted the idea and developed
techniques for ioPTH measurement [49–52].
Today the turnaround time has become even
shorter since the analysis is performed in the
operating room by laboratory personnel [53].
The basic concept of ioPTH measurement is
straightforward. It is based on the fact that PTH
in plasma has a short half-life of about 3–5 min.
Therefore, it is possible to detect a significant
drop in plasma PTH following the excision of a
parathyroid adenoma. When an enlarged parathyroid gland is excised and there is no significant decrease of ioPTH, multiglandular disease
must be suspected and a comprehensive bilateral exploration undertaken.
We have used ioPTH since the early 1990s.
We obtain our samples from a peripheral vein
according to a strict protocol [51]. Since parathyroid manipulation may affect the PTH value,
it is important that meticulous dissection is
performed without pressure on the parathyroid,
before the vessels are ligated or clipped. The
baseline, preexcision sample should be obtained
when the enlarged gland is first visualized. In
our opinion it is important that samples are
obtained from a peripheral vein and not the
jugular veins because the latter will be more
affected by the manipulation of the enlarged
gland. Furthermore, a parathyroid adenoma,
whether up- or downstream from the sample
site will influence the PTH level differently.
Second and third samples are collected 5 and
15 min after excision, respectively. In our hands
the efficacy of the method relies on a decline of
ioPTH at 15 min of >60% of baseline [51]. If this
criterion is fulfilled ioPTH reliably predicts a
solitary adenoma with an excellent early as well
as a late operative success [54]. The Miami group
and others successfully use a decrease in ioPTH
of >50% at 10 min as a criterion to terminate
neck exploration [55–58]. This criterion has
become the most widely used to predict cure in
patients with sporadic pHPT (but is not suitable
for patients with other causes of HPT). However,
it is important to realize thatmodifications of the
technical aspects of ioPTH and the applied criterion have a significant impact on the overall
accuracy of the test [59]. It is interesting to note
that the reported proportion of patients with
multiglandular disease is considerably lower in
series using focused approaches combined with
ioPTH measurement, i.e., a biochemical definition of a hyperfunctional gland, compared to