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21
Reoperative Parathyroid Surgery
Olumuyiwa O. Olubowale and Barney J. Harrison
Every surgeon mustlearn tocome toterms withthe inadequaciesand sometimesdownright
failures of his or her actions that will be inevitable companions during a surgical life [1].
Introduction
An operation for primary hyperparathyroidism
(PHPT) will result in restoration of normocalcemia in 95–98% of patients when performed by an
experienced surgeon [2–6]. Patients to be considered candidates for reoperative parathyroid
surgery are those in whom previous operation(s)
have failed to achieve lasting cure of their hypercalcaemia. These patients have either persistent
or recurrent hyperparathyroidism (HPT).
History
In 1925, the year that Felix Mandl performed the
first successfuloperation forhyperparathyroidism
in a patient with von Recklinghausen’s disease [7],
Oscar Hirsch, a Viennese surgeonfailed to identify
a parathyroid tumor in the neck of another
patient with von Recklinghausen’s disease. In
1926, Edward Richardson in Boston, performed
two operations on Charles Martell, a sea captain
with hyperparathyroidism, but could not find
an abnormalparathyroid gland. Martell eventually
had seven operations before his parathyroid
tumour was found in the mediastinum and
removed.
Felix Mandl in July 1926 removed an abnormal parathyroid gland from the neck of Herr
Albert who had a high blood and urinary calcium with ‘apparently good outcome’. Six years
later Albert’s disease returned and at reoperation, Mandl failed to identify any abnormal
parathyroid tissue, the patient died from renal
failure [8]. In 1931, Sir James Walton reported
the first series of parathyroid operations performed in Britain; he had to reoperate on the
fourth patient to find a mediastinal adenoma
which he removed via the neck.
Definition
Persistent hyperparathyroidism is hypercalcemia that remains after neck exploration or
recurs within 6 months of initial parathyroid
surgery [9, 10]. Patients with persistent
disease may have transient postoperative
normocalcemia and a subsequent elevation,
or serum calcium levels that remain high following surgery.
J.G.H. Hubbard et al. (eds.), Endocrine Surgery, Springer Specialist Surgery Series,
DOI 10.1007/978-1-84628-881-4_21, Ó Springer-Verlag London Limited 2009
291
292
ENDOCRINE SURGERY
Recurrent HPT occurs more than 6 months
after initial successful parathyroidectomy with
postoperative normocalcemia.
The Extent of the Problem
Persistent or recurrent hyperparathyroidism for
PHPT occurs in expert hands after 2–5% of initial
procedures [11]. Persistent HPT is associated
with single- or multiglandular disease, whereas
recurrent HPT usually results from multiglandular disease [9, 12]. The incidence of recurrent
HPT is higher in patients with multiple endocrine
neoplasia (MEN) compared with sporadic HPT,
reported in 20–30% of patients with MEN I and
II after subtotal parathyroidectomy with higher
ratesobservedinpatientshavinglessthanfour
gland parathyroid resections [13–15]. In renal
HPT (RHPT), the incidence of recurrent or persistent HPT after subtotal parathyroidectomy is
reported as 2–15% [16–18]. The incidence of
recurrent HPT arising from autografted parathyroid tissue in RHPT is 3–16% [19–22].
The gold standard for the treatment of
hyperparathyroidism has been bilateral neck
exploration. Today, surgeons may perform less
than four gland exploration, i.e., scan-directed
unilateral neck exploration, a focused small
incision approach, or a minimally invasive
videoscopic parathyroidectomy [23–27]. Initial
concerns that less than four gland exploration
may render patients more vulnerable to persistent/recurrent HPT [28, 29] have not been substantiated [25, 30–35]. The results of a 5-year
follow-up of 91 patients with PHPT randomized
to unilateral or bilateral neck exploration
showed that four patients in the unilateral
group, and two patients in the bilateral group,
were found to have persistent/recurrent disease.
Half of all the patients with persistent/recurrent
disease in this study were unexpectedly found
to have germ line mutations associated with
MEN [36]. Whether a less than four gland neck
exploration/unilateral approach underestimate
the incidence of multiglandular disease, time
will tell [37].
Why Does an Initial Operation
Fail? (Table 21.1)
The serum calcium remains high after an initial
parathyroid operation because of:
1. Incorrect diagnosis, i.e., not HPT.
2. The surgeon calls an abnormal parathyroid
gland ‘normal’, i.e., misinterpretation.
3. Failure to recognize the presence of multiglandular disease (PHPT, RHPT, familial disease).
4. Limitation of the surgical approach – unilateral
neck exploration with contralateral pathology
or a focused approach in which the pathology
is in the non ‘explored’ ipsilateral gland).
5. The surgeon cannot find the abnormal gland/s
(retained pathology) due to unrecognized
eutopic, ectopic, or supernumerary gland.
6. Rare pathology – incomplete resection of
parathyroid carcinoma or parathyromatosis.
Alternatively, the failure to cure at initial
operation can be summarized in relation to the
surgical approach:
A. Patient had a unilateral neck exploration for
PHPT and abnormal parathyroid tissue was
not identified.
Table 21.1. Causes of failure of initial operation for PHPT
Unrecognized pathology Incorrect diagnosis Incomplete resection
1. Eutopic abnormal gland(s)
2. Unrecognized multiglandular disease, e.g.,
adenoma, hyperplasia-sporadic or familial
(MEN or non-MEN),
renal hyperparathyroidism
3. Ectopic abnormal gland
4. Supernumerary glands
High calcium, high PTH
1. FHH
2. Ectopic PTH production
High calcium, low PTH
1. Malignancy (PTHrP)
and/or bone
metastasis
2. Other causes of
hypercalcemia
1. Incomplete excision
of multiglandular disease,
i.e., remnant size
2. Parathyroid cancer
293
REOPERATIVE PARATHYROID SURGERY
The surgeon found:
i) Two normal glands. The likely cause of
failure is one or more diseased parathyroid
glands on the contralateral side, or supernumerary glands.
ii) One normal gland. The cause of failure
is a missing abnormal gland in either
a normal anatomic location but the surgeon could not find it, or the abnormal
gland is in an ectopic location.
iii) No parathyroid glands identified. The
surgeon is either inexperienced or the
glands are in ectopic locations.
B. Focused approach uniglandular exploration.
The surgeon found:
i) No parathyroid gland. This is due to inex-
perience on the part of the surgeon, or
incorrect preoperative localization or, an
unidentified ectopic gland, e.g., intrathyroidal (Fig. 21.1).
ii) A single abnormal gland. The cause of
failure is multiglandular disease. The proportion of surgeons who routinely look for
a second gland during a focused approach
parathyroidectomy is unknown.
C. Bilateral neck exploration
Failure to cure is explained by:
i) The surgeon not identifying one or more
abnormal parathyroid glands (which may
Fig. 21.1. Intrathyroidal parathyroid. This patient’s USS, MIBI,
and CT were negative after failed initial exploration. USS had
showed a thyroid nodule (above) with follicular cytology. At
reexploration the right inferior gland was missing and a thyroid
lobectomy showed an intrathyroidal parathyroid gland cured
the patients’ persistent hyperparathyroidism. (Courtesy of Dr.
Catherine Clout, Consultant Radiologist, Northern General Hospital, Sheffield).
be eutopic, ectopic, or supernumerary
in location) or
ii) Finding four normal parathyroid glands
in which case thecause is a supernumerary
gland or
iii) The surgeon has incorrectly evaluated
identified parathyroid tissue.
Reasons for Failure
1. Eutopic abnormal gland (single gland disease):
The abnormal gland is in a normal anatomic
location but the surgeon failed to identify it. In
up to 79% of patients with recurrent/ persistent
HPT, the missed abnormal gland will be found in
a normal anatomic location. Superior parathyroid glands are more symmetrical inpositionthan
the inferior glands [38], usually found above the
inferior thyroid artery, posterior to the recurrent
laryngeal nerve (RLN). The inferior parathyroid
glands are anterior to the RLN and below the
inferior thyroid artery. For anatomical locations
of normal glands, see Chapter 15.
2. Ectopic abnormal gland: If fewer than four
normal parathyroid glands were found at an
initial bilateral operation, then failure may be
due to an abnormal gland in an ectopic location
[39, 40]. Up to 25% of abnormal parathyroid
glands are located in ectopic sites variously
positioned in the neck or superior mediastinum. Failure of descent from the third pharyngeal pouch during embryological development
can result in the inferior parathyroid gland
remaining high in the neck above the upper
thyroid pole and medial to the carotid sheath,
or low within the thymus [38]. The most common site for ectopic inferior glands is within
the body of the thymus.
Ectopic superior parathyroid glands can
be found in para-esophageal locations in the
neck/posterior superior mediastinum. Other
rare sites of ectopic parathyroid tissue include
the carotid sheath, thyroid gland, vagus nerve
sheath, posterior to the innominate vein, aortopulmonary window, and the pericardium [39–41]
(Table 21.2).
3. Eutopic abnormal gland (multiple):
Abnormal parathyroid tissue may be left
behind at initial operation due to the presence
of unrecognized multiglandular disease. This
can be multiple adenoma [33] or hyperplasia
of parathyroid glands. In PHPT, 87–90%
Table 21.2. Ectopic glands identified at reoperative parathyroid surgery [38]
Intrathymic
(%)
Ectopic inferior
glands
(62%)
Ectopic
superior
glands
(38%)
Source: Data from [41].
30 22 22 17 17 – – – – –
–– 7 – – 43 2214 77
Antero superior
mediastinal (%)
Intrathyroidal
(%)
Thyro-thymic
ligament (%)
Submandibular
(%)
Tracheooesophageal
groove (%)
Retrooesophageal
(%)
Postero-superior
mediastinal. (%)
Carotid
sheath
(%)
Paraoesophageal
(%)
ENDOCRINE SURGERY
294
295
REOPERATIVE PARATHYROID SURGERY
patients have a single adenoma, 9% have multiglandular hyperplasia, and 5–10% have multiple
adenomas [42–44]. In familial HPT and RHPT,
multigland disease is more common but the
gland enlargement may be asymmetrical at the
time of initial surgery. Multiglandular disease
has been found in 90 and 83% of patients with
MEN 1 and MEN 2, respectively [45].
4. Supernumerary gland:In5%ofpatients
who undergo surgery for PHPT it is possible to
find a supernumerary gland as thecause [35–37].
In an autopsy series of 503 cases, 84% had four
glands, 3% had three glands, and supernumerary
glands were found in 13%, most frequently a
fifth gland in the thymus [38]. In patients with
end-stage renal failure who undergo surgery, the
incidence of supernumerary glands is reported
as high as 16.5–30%, over 60% of which are
located in the thymus and these are the cause of
persistent/recurrent disease when not removed
at initial exploration [39, 46, 47]. In MEN, supernumerary glands occur in 20–30%, of patients,
mostly in the thymus and should be looked for to
avoid high rates of recurrent HPT [48].
5. Incomplete resection of lesion:Ifataninitial
operation in patients with multiglandular disease,
resection of abnormal parathyroid tissue was
inadequate, i.e., less than a subtotal parathyroidectomy or too large a remnant of parathyroid
tissue was left behind in the neck, persistent HPT
will result [49, 50].
Recurrent HPT in such patients occurs
when there is regrowth of remnant parathyroid
tissue or hyperfunction of parathyroid rests in
the neck or, the autograft (after total parathyroidectomy). The stimulus that resulted in the
development of initial HPT causes hyperfunction of any remnant parathyroid tissue [51].
Incomplete excision of parathyroid carcinoma
at initial surgery due to locally advanced disease
or nodal/systemic metastasis present at the time
of surgery can result in recurrent or persistent
HPT [35–37].
Parathyromatosis is a rare condition in which
multiple nodules of hyperfunctioning parathyroid tissue are scattered through the neck and
mediastinum due to spillage of parathyroid tissue
at first time surgery, usually in renal patients. The
growth of hyperfunctioning parathyroid tissue
results in recurrent HPT [52–58].
6. Incorrect diagnosis-persistent hypercalcae-
mia not caused by PHPT: Failure to cure hypercalcemia at initial operation is inevitable if the
diagnosis of PHPT was incorrect. Patients
with hypercalcemia from causes such as
familial hypocalciuric hypercalcemia (FHH),
malignancy, and para-neoplastic syndromes
will not be cured by parathyroidectomy.
Care of the Patient
with Failed Initial Surgery
In the immediate postoperative phase the
patient should be informed of the outcome of
the initial exploration and the care pathway that
may follow. Significant hypercalcemia requires
monitoring and sometimes medical treatment
to include adequate hydration and drug treatment, e.g., biphosphonates, calcimimetics therapy [59]. There should be a follow-up plan for
regular measurement and review of the serum
calcium after discharge from hospital whilst
the patient awaits further investigations and
treatment.
Patients should be referred to an endocrine
surgical team with experience of reoperative
parathyroid surgery.
At the referral center, clinical management is
based on the outcome of the following enquiries
(Fig. 21.2):
1. Symptoms and severity of hypercalcaemia:
History of symptoms and complications of
hypercalcemia should be noted, e.g., frac-
tures, nephrolithiasis, and calciphylaxis.
2. Family history of HPT: A detailed history
should be taken to identify affected family
members with hypercalcaemia and other
associated conditions which may suggest
familial disease (MEN1/2 or non MEN famil-
ial HPT).
3. Confirmation of the biochemical diagnosis of
HPT: The results of investigations including
adjusted calcium, parathyroid hormone
(PTH), urea and electrolytes, creatinine, 24
hour urinary calcium, and vitamin D should
be reviewed. Patients with vitamin D deficiency
and FHH as a cause of hypercalcemia should
be excluded prior to further investigations.
4. Localization studies/operation findings and
pathology: The results of localization studies
performed prior to the initial exploration
should be reviewed and correlated with
operative and pathology findings.
296
ENDOCRINE SURGERY
Fig. 21.2. Flow chart.
The key to success in reoperative parathyroid
surgery is a clear understanding of the findings and procedure carried out at the initial
operation. What the surgeon found and
which parathyroid glands were identified
and removed should be clarified, in addition
to the areas which were and were not
explored. It is important to know if transcervical thymectomy was performed and if
any parathyroid tissue was found within it.
All this information serves as a road map for
reoperation.
297
REOPERATIVE PARATHYROID SURGERY
An experienced pathologist should review
specimens from the initial exploration to confirm the presence (or absence) of parathyroid
tissue and the pathological features which might
suggest single or multiglandular disease.
5. An assessment of HPT-related comorbidity:If
available, the results of prior bone mineral
density (DEXA) scans (T scores) should be
reviewed to identify patients with significant
osteoporosis in whom reoperation may be
beneficial. Ultrasound (USS) of the kidneys
may identify calculus disease.
6. Assessment of vocal cord mobility: All
patients considered for reoperation should
undergo laryngoscopy. The need for reopera-
tion in a patient with unilateral RLN palsy
should be carefully considered; the potential
risk of injury to the contralateral nerve in a
patient with a damaged nerve from the initial
operation should be weighed against the
benefits of exploration of that side.
7. Are there indications for reoperation?
The indications for reoperation include one or
more of the following:
Symptomatic hypercalcemia.
Severe hypercalcemia (>3.0 mmol/l).
Hypercalcemia with complications such as
renal stones, calciphylaxis, pancreatitis,
osteoporosis, fractures, etc.
In renal patients, high PTH, calcium phosphate
product, high alkaline phosphatase, and/or
symptoms/complications, e.g., calciphylaxis.
Young patients with mild to moderate
hypercalcemia.
Parathyroid Gland
Localization in Recurrent/
Persistent HPT
When there is a clear indication/s for reoperation, parathyroid localization studies should be
requested. A repeat of investigations carried out
prior to the initial operation may be necessary, as
well as additional tests to confirm the location/s
of abnormal parathyroid gland/s. Remember
that localization studies are less reliable when
there is multiglandular involvement as they
may fail to identify all enlarged glands.
Preoperative
1. Ultrasound: USS in recurrent/persistent
HPT requires a radiologist with interest and
experience in parathyroid imaging to whom
information about the operative findings and
areas in the neck which have been explored at
initial surgery are important guides. Neck USS
immediately after a failed initial exploration
may not be comfortable for the patient but can
usually be performed after the first week [60].
Postoperative tissue reaction may obscure
normal tissue planes and vascularity which are
essential for the identification of abnormal
parathyroid glands. The sensitivity of USS in
persistent/recurrent HPT is 50–87%, with a
positive predictive value of up to 84%, and a
false-negative rate close to 11% [61–67].
USS-guided fine-needle aspiration and measurement of PTH from suspected parathyroid
lesions has been found to have 100% specificity
and allows a directed surgical resection avoiding further invasive work up when the aspirate
is positive [67–75].
2. MIBI scan: The sensitivity of MIBI in per-
sistent/recurrent HPT is 50–82% [62, 63, 76–79].
The combination of ultrasonography and
sestamibi scan gives sensitivity rates ranging
between 64–90% and a true-positive rate of
over 90% with few false positives. Reoperation
can proceed if these results are positive and
concordant [60, 80, 81] (Fig. 21.3).
3. Computerized tomography (CT) scanning
and fusion imaging: The sensitivity of CT in
persistent/recurrent disease is 67–86% but the
false-positive result rate is high at 14% [63, 82,
83]. CT with contrast after neck operations may
be difficult to interpret because of scar tissue
and artifacts and should be reserved for patients
in whom a mediastinal gland is suspected, especially when USS and MIBI scans are negative
[83, 84].
SPECTcan be combined with MIBI to produce
fusion images, and this increases the sensitivity of
the procedure to 91% and provides better anatomical location which is helpful for the surgeon
[85–87] (Fig. 21.4).
4. Magnetic resonance imaging (MRI):
Enlarged parathyroid glands have increased
intensity on T2-weighted images on MRI. The
sensitivity of MRI in reoperative parathyroid
surgery is 64–88% with a positive predictive
298
ENDOCRINE SURGERY
Fig. 21.3. A mediastinal abnormal parathyroid gland identified on MIBI in a patient with four normal cervical glands. This
supernumerary gland was removed at reoperation from the anterior mediastinum.
value of 89% [88, 89], 10% better than for CT, in
addition to lower false-positive rates/higher
true-positive rates. MRI however cannot be
performed in claustrophobic patients, or those
with metallic heart implants. It cannot be used
to guide FNA of suspected parathyroid lesions
for PTH assay.
5. Positron emission tomography (PET):
A positron emitting analogue of ((d))-glucose, 2(fluorine-18-fluoro-2-deoxy-((d))-glucose (FDG),
allows glucose metabolism to be measured and
evaluated using PET. There is differential concentration of FDG in abnormal parathyroid tissue
compared with normal glands and the sensitivity
in recurrent and persistent HPT is up to 79–90%
[67, 90, 91]. FDG may also be taken up by thyroid
tissue in thyroiditis, thyroid adenoma, and carcinoma,aswellasothermalignanttissuesinthe
neck or superior mediastinum. It may be useful
if parathyroid localization using the abovementioned modalities is negative (Fig. 21.5), but
the initial reports of promising results with PET
have not translated into major impact on clinical
practice.
6. Selective venous sampling (SVS) and angio-
graphy: SVS for PTH is indicated when noninvasive tests are negative, equivocal, or inconclusive.
A catheter is inserted into the femoral vein and
guided to cervical or mediastinal veins and
their branches under X-ray control to obtain
blood samples for PTH. Values of PTH in the
cervical or mediastinal vein samples are compared with those in peripheral venous blood
to provide a combined anatomical/biochemical
gradient of PTH concentrations. A greater than
1.5- to 2-fold increase in PTH levels is viewed as a
positive result, which in practical terms allows
regionalization of the missing gland into right
Fig. 21.4. MIBI/CT fusion image of a parathyroid adenoma medial to the left thyroid lobe.
299
REOPERATIVE PARATHYROID SURGERY
Fig. 21.5. PET/CT fusion image of right superior parathyroid.
cervical, left cervical, or thymic/mediastinal
region [84]. SVS is useful in identification of
mediastinal and cervical pathology. The technique can be highly sensitive (up to 94%) [64, 65]
but without concomitant angiography has a
false-positive rate of 6–18% [67, 92, 93].
Selective angiography should be considered
at the time of SVS to examine branches of
the external carotids, the internal mammary
arteries, and the thyrocervical trunks in order
to identify the characteristic contrast ‘vascular
blush’ (Fig. 21.6). Sensitivity of the technique
approaches 60%, when combined with SVS this
increases to 91–95% [94]. In our center, from
1999 to 2007, we performed SVS for recurrent/
persistent PHPT in 13 patients. SVS correctly
identified the abnormal parathyroid gland in
12 cases (sensitivity of 92%). Simultaneous
selective angiography was performed in six
cases but revealed an abnormality concordant
with venous sampling in only two cases.
7. Casanova test: This test is used to distinguish
neck recurrence (supernumerary gland) from
hyperfunctioning forearm parathyroid autograft
after total parathyroidectomy with parathyroid
autotransplantation. Patients with a hyperfunctioning forearm autograft will demonstrate a
significant reduction in PTH following induced
Fig. 21.6. Internal mammary angiogram showing a hypervas-
cular lesion in the right side of the mediastinum near the right
atrium (vascular blush of parathyroid adenoma) – a parathyroid
adenoma. Other localization tests prior to reoperation including
SVS did not localize this lesion. (Courtesy of Professor Peter
Gaines, Consultant Radiologist, Northern General Hospital,
Sheffield).