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Chapter 15
Parathyroid Cancer andHypercalcemic
Crisis
NikitaN.Machado, JenniferB.Ogilvie, andCourtneyE.Gibson
Introduction
Parathyroid cancer is the least common endocrine cancer seen worldwide, as well
as the rarest cause of primary hyperparathyroidism (~1% of cases) [1]. Patients
often present with highly elevated levels of serum calcium and parathyroid hormone
(PTH). Surgical treatment with an en-bloc tumor resection is the mainstay of treatment, as these tumors show minimal response to chemotherapy or radiation. Local
recurrences are common, which makes this a challenging condition for the endocrine surgeon to treat.
Epidemiology
Parathyroid cancer tends to affect younger patients (about 50years at the time of
diagnosis), compared to the classic presentation of primary hyperparathyroidism
due to benign parathyroid disease. Unlike most endocrinopathies, male and female
patients are equally affected by parathyroid cancer [2].
N. N. Machado (*) · J. B. Ogilvie · C. E. Gibson
Section of Endocrine Surgery, Yale New Haven Hospital, New Haven, CT, USA
e-mail: nikita.machado@nghs.com; Jennifer.ogilvie@yale.edu; Courtney.gibson@yale.edu
Switzerland AG 2024
R. M. Gartland, J. A. Lee (eds.), Endocrine Surgery Clerkship, Contemporary
Surgical Clerkships, https://doi.org/10.1007/978-3-031-62091-1_15
133© The Author(s), under exclusive license to Springer Nature
134
N. N. Machado et al.
Etiology andPathogenesis
Parathyroid disease has been noted in some studies to be associated with patients
exposed to childhood radiation (especially of the head and neck) [3]. 20–30% of
patients who have a thyroid pathology are also found to have concurrent parathyroid
disease. However, it is unclear whether these associations are routinely associated
with parathyroid carcinoma.
Certain germline mutations have also been found in ~20% of patients with parathyroid carcinoma (CDC73 gene, previously known as HRPT2), as well as half of
all patients with Hyperparathyroidism-Jaw Tumor syndrome [4, 5]. Cyclin D1 gene
can undergo either translocation or overexpression, which is a driver of parathyroid
hyperplasia in general [6]. On the other hand, genetic mutations that are known to
be associated with parathyroid adenomas (MEN1, FHH, CASR, etc.) are rarely
associated with parathyroid cancer. Genetic markers are potential targets for future
immunotherapy treatments.
Clinical Presentation
Both parathyroid adenomas and carcinomas can present in a similar manner; however, certain ndings are more commonly found in cases of parathyroid carcinoma,
as shown in Table15.1 below [7–9].
Very rarely, patients with parathyroid carcinoma may present with a hypercalce-
mic crisis. This occurs with very high serum calcium concentrations (>14mg/dl
or>3.5mmol/l) and is often accompanied by multi-organ dysfunction, evidenced
by altered sensorium, acute kidney injury, and/or acute heart failure. Patients may
appear disorientated or even comatose in severe cases [10].
The management of a hypercalcemic crisis revolves around volume expansion
and reducing the serum calcium concentration. This is done through the following steps:
1. Aggressive uid resuscitation with intravenous normal saline for the initial
24–48h.
2. Once the patient is appropriately resuscitated, a loop diuretic such as furosemide
is initiated to promote urinary calcium excretion.
Table 15.1 Pertinent clinical and laboratory features in parathyroid cancer
Clinical symptoms (symptomatic
hypercalcemia) Exam ndings Laboratory values
Nausea/vomiting/abdominal pain Palpable neck
mass
Fatigue and myopathy Very high PTH concentrations (5–10
Disorientation/stupor Absolute PTH>500mg/dl
Highly elevated serum calcium levels
(>14mg/dl)
times normal)
15 Parathyroid Cancer andHypercalcemic Crisis
3. Addition of calcitonin (either intramuscular or subcutaneous), which acts by
increasing calcium excretion as well as inhibiting osteoclast function and bone
resorption. The loading dose is 4U/kg and it is administered up to every 6h. This
medication becomes less effective after 48h due to tachyphylaxis [11].
4. Administering bisphosphonates: these medications also decrease calcium
resorption from bone with minimal side effects. They are used in conjunction
with the above medications since they have a slower onset of action (usually
within 24–48h) [12].
A patient presenting in hypercalcemic crisis due to parathyroid disease requires
expedited workup and resuscitation followed by parathyroidectomy to minimize
morbidity related to these symptoms.
135
Diagnosis
All patients with suspected parathyroid carcinoma should have the following
evaluation:
1. Thorough history and physical examination.
2. Laboratory tests: serum calcium, parathyroid hormone (PTH) levels, Vitamin D
levels as well as a serum TSH since 20–30% of patients have co-existing thyroid
and parathyroid disease.
3. Neck ultrasound for localization of the affected gland and better visualization of
the rest of the thyroid gland.
4. Cross-sectional imaging with CT/MRI to evaluate lymph nodes and adjacent
structures.
5. Laryngoscopy if any recurrent laryngeal nerve involvement is suspected (new
voice weakness).
While the presence of severe symptomatic hypercalcemia and a larger adenoma
size can raise the suspicion for a parathyroid carcinoma, the true diagnosis is a clinical one, made intra-operatively.
A pre-operative ne needle aspiration (FNA) is not recommended since it is not
possible to differentiate between a parathyroid adenoma and parathyroid carcinoma
based on histology alone. An FNA also increases the risk for tumor seeding along
the biopsy tract [13].
Management
The management of parathyroid carcinoma depends on when the disease is diagnosed and its extent.
136
N. N. Machado et al.
Surgical Management
Pre-Operatively Suspected Parathyroid Carcinoma
The goal for the primary operation in a patient with suspected parathyroid carcinoma is complete surgical excision without any violation of the parathyroid capsule, to prevent tumor seeding and future recurrence. This is achieved by following
the surgical principles outlined below in Fig.15.1. Intraoperatively, the diagnosis is
conrmed when there is an absent plane between the parathyroid gland and thyroid
lobe, or when there is invasion of the parathyroid tumor into other surrounding
structures (Figs.15.2 and 15.3) [14].
In this case, the safest way to accomplish removal of the tumor is with an en-bloc
resection of the parathyroid gland with the ipsilateral adjacent thyroid lobe. If the
tumor is invading surrounding strap muscles or other structures, they must also be
appropriately excised to obtain negative margins. The recurrent laryngeal nerve is
rarely involved in parathyroid carcinoma, however it may be sacriced if necessary
to avoid the possibility of future local recurrence. There is insufcient data to support routine prophylactic central lymph node dissection for parathyroid cancer.
Post-Operatively Diagnosed Parathyroid Carcinoma
When parathyroid carcinoma is diagnosed on surgical pathology, additional surgery
may be indicated for removal of the ipsilateral thyroid lobe (especially in the setting
of positive margins). Of note, extent of initial surgery has not been necessarily
related to recurrence rates [15]. Surveillance is very important in these patients due
to the potential for tumor spillage/seeding during the original operation. Patients are
usually followed with regular labs (serum calcium and PTH) as well as neck ultrasounds. Surveillance is a helpful adjunct due to the slow-growing nature of
these tumors.
PRINICIPLES OF EN-BLOC RESECTION FOR
PARATHYROID CARCINOMA
- Bloodless field and meticulous dissection
- Thorough exploration of ipsilateral side, looking for invasion
of the thyroid lobe, strap muscles and surrounding tissues
- Minimal tumor manipulation to avoid spillage and tumor
seeding
- Preservation of RLN if possible, however it can be
resected if necessary
Fig. 15.1 Surgical principles of en-bloc resection for parathyroid carcinoma
15 Parathyroid Cancer andHypercalcemic Crisis
Fig. 15.2 Uncut gross
specimen of a right
superior parathyroid
carcinoma, resected
en-bloc with the ipsilateral
thyroid lobe (390mg,
1.4×1×0.3cm)
137
Fig. 15.3 The parathyroid is serially sectioned to reveal tan-pink, homogenous cut surfaces with
prominent vessels. Histology demonstrated inltration into surrounding broadipose tissue, suspicious vascular invasion, brosis, nuclear atypia, and pleomorphism with two mitoses per high
powered eld. Courtesy of Courtney Gibson MD, Section of Endocrine Surgery, Yale New Haven
Hospital
Recurrent Disease
Since the primary mainstay of treatment for parathyroid carcinoma is surgical,
patients with recurrent disease are best served by re-operation to remove any residual foci of tumor. Surgery is guided by pre-operative imaging such as ultrasound
and cross-sectional imaging such as CT and/or MRI for anatomic localization and
characterization [16]. Newer studies have evaluated the utility of nuclear medicine
as a second-line modality for parathyroid imaging, especially 11C-MET PET
(methionine), and more recently 18F-FCH PET(choline) [17]. Some patients require
138
multiple surgeries, which is associated with increased morbidity, often related to
potential injury to the recurrent laryngeal nerve. It is important to approach these
cases in a multidisciplinary fashion with input from laryngologists regarding preoperative vocal cord function. Intra-operative PTH levels are followed in the operating room after excision (the expectation is >50% decrease in PTH levels from
baseline, as well as PTH within normal range) [18]. This can be complicated in
patients with widespread disease who present for tumor debulking.
Metastatic Disease
Given the rarity of parathyroid cancer, there are no large-scale trials that demonstrate the optimal treatment in patients with distant metastatic disease. Up to a third
of patients with parathyroid carcinoma present with metastatic disease at the time of
diagnosis [19]. The mortality rate in parathyroid carcinoma is usually related to
complications of hypercalcemia, rather than cancer progression. Small case series
have described surgical resection of metastatic deposits to improve the burden of
hypercalcemia and prolong patient life [20].
N. N. Machado et al.
Adjuvant Radiation
Parathyroid carcinoma is largely considered to be a radio-resistant malignancy.
Smaller observational studies have shown mixed results with adjuvant external
beam radiotherapy (EBRT); however, the overall consensus is that EBRT does not
prolong overall survival in these patients [21]. Like other locations in the body,
radiation increases tissue brosis, scarring, and may make subsequent procedures
more technically challenging.
Adjuvant Chemotherapy
In the absence of randomized controlled trials, chemotherapy has been used sporadically for parathyroid carcinoma in small case series with variable effect. Some
examples of chemotherapeutic agents include dacarbazine, 5-uorouracil, and
cyclophosphamide, either alone or in combination with one another [22, 23].
15 Parathyroid Cancer andHypercalcemic Crisis
139
Targeted Therapy
Certain therapeutic agents that target parathyroid cell proliferation (telomerase
inhibitors such as azidothimadine/AZT) and genetic targets (parabromin, which
blocks cyclin D1 expression) have recently been the subject of interest for novel
approaches to treat parathyroid cancer [24, 25]. Further studies are clearly indicated
but this represents an exciting new frontier for treatment of this challenging
condition.
Management ofHypercalcemia
While not related to treatment of the primary tumor, hypercalcemia management is
a cornerstone of parathyroid carcinoma treatment. Hypercalcemia is a signicant
contributor to both morbidity and mortality in this condition. The initial management of severe hypercalcemia has been described earlier in this chapter. Long-term
hypercalcemia is managed with oral agents such as bisphosphonates, cinacalcet
(Sensipar), and denosumab (a potent inhibitor of bone resorption used in patients
with hypercalcemia refractory to the above agents) [26].
Prognosis andLong-Term Disease Progression
Parathyroid carcinoma progresses in an indolent fashion, often marked by local
recurrence and symptomatic hypercalcemia. Aggressive disease progression is less
common but can be seen in up to a third of patients. Despite advances in medical
and surgical treatment, data from the US National Cancer Database showed a 5-year
survival of 82% and a 10-year survival of 66% [27]. Ongoing clinical trials are
evaluating targeted therapies to improve long-term survival and outcomes.
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141
Chapter 16
Parathyroidectomy: Techniques, Adjuncts,
andPotential Complications
ReeseW.Randle
Introduction
Parathyroidectomy offers the only chance of cure for patients diagnosed with primary hyperparathyroidism. Primary hyperparathyroidism is a biochemical diagnosis, and once solidied, indications for surgery include symptomatic disease,
objective evidence of end-organ effects, young age, or patient desire [1, 2]. Operative
indications for secondary and tertiary hyperparathyroidism differ but parathyroidectomy plays an important role in these processes as well. See Chaps. 13 and 14 for
workup and management of primary, secondary, and tertiary hyperparathyroidism.
Although imaging cannot conrm or rule out disease, it can be helpful in aiding the
operative approach. In general, parathyroidectomy is safe and cure rates are high
regardless of the indication. Numerous approaches and techniques aid the surgeon
in customizing the approach to the specic patient and disease process and adjuncts
to maximize the chances of a successful operation. While complications are rare,
they remain an important consideration for patients undergoing
parathyroidectomy.
R. W. Randle (*)
General Surgery, Atrium Health Wake Forest Baptist, Winston Salem, NC, USA
e-mail: rrandle@wakehealth.edu
Switzerland AG 2024
R. M. Gartland, J. A. Lee (eds.), Endocrine Surgery Clerkship, Contemporary
Surgical Clerkships, https://doi.org/10.1007/978-3-031-62091-1_16
143© The Author(s), under exclusive license to Springer Nature