Interhospital Conference Case 4
Parathyroid Carcinoma (PCA)
Parathyroid carcinoma is an uncommon cause of PTH-dependent hypercalcemia. In most series, this
entity accounts for < 1% of patients with primary hyperparathyroidism. The disease may be
somewhat more common in Japan than in Western countries, accounting for 5% of patients with
primary hyperparathyroidism (1).
Familial hyperparathyroidism
Carcinoma has been reported in association with familial hyperparathyroidism, particularly in the
autosomal dominant form with isolated hyperparathyroidism that is not part of the multiple
endocrine neoplasia type I (MEN1) In addition, a greatly increased risk of parathyroid carcinoma is
associated with the hereditary hyperparathyroidism-jaw tumor syndrome(1), recently localized to
chromosome 1q21-q31(2). Incidence increased to 15% in this group of patient. In 2002, gene encoded
parafibromin protein was identified and named HRPT2 gene. Various mutations in this gene can
cause the syndrome. Recently its name was changed to CDC73 (cell division cycle protein 73) gene.
More than half of patients with HPT-JT have germ line mutation of this gene. But somatic mutation
can also be identified in sporadic case (3).
Clinical features
The clinical features of parathyroid carcinoma 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.
The serum calcium level of most patients with parathyroid carcinoma is much higher, generally
above 14 mg/dL or 3–4mg/dL above the upper limit of normal. 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. A palpable neck mass has been reported in 30–76% 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. 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(1).
Natural history
Parathyroid carcinoma is an indolent,slow progression 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 (1).
Diagnosis
PCA is characterized by very high levels of PTH, which ultimately result in severe hypercalcemia.
In addition, high alkaline phosphatase, hypophosphatemia, and hyperchloremic metabolic acidosis
have also been observed in PCA patients (4).
Imaging of PCA
Ultrasound: A hypo-echoic soft tissue mass with irregular, poorly defined border and sign of invasion
of adjacent structures (5).
CT scan: Use to differentiate abnormal parathyroid tissues from lymph nodes and normal thyroid
tissue ,and invasion into adjacent tissue(5).
MIBI scintigraphy: (sensitive 91%) Use to assess the presence and localization of PCA but may failed
to localize mediastinal and pulmonary recurrence(5).
FDG PET/CT: Very sensitive tool to evaluate extension of disease at initial staging. Identification of
suspected tumor recurrence, evaluation of residual disease after primary treatment. Loss of
sensitivity and specificity in some conditions (i.e. small lesions and early stage)(6).
Pathology
Grossly large masses adherent to adjacent structures, capsular invasion (criteria as thyroid), growth
into adjacent tissues ,and metastases. Thick intratumoral fibrous bands is good indicator of
malignancy but not pathognomonic. Diffuse nuclear enlargement with macronucleoli suggests
malignancy (5).
Management
Surgical Surgery is the only effective and curative treatment. It should be performed as “en bloc”
tumor resection with ipsilateral thyroidectomy to avoid any capsular rupture. After an “en bloc”
removal of PCA, a drop of > 50% iPTH from baseline was predictive at least 6 months of
normocalcemia(5).
Adjuvant therapy
PCA is not a radiosensitive tumor. Radiation therapy in PCA remains controversial (5).
Chemotherapy
Attempts to control tumor burden with chemotherapy have been disappointing and data limit to
scattered case reports (1).
Management of hypercalcemia (medication)
When PCA become widely disseminated and surgical resection is no longer effective, goal at this
point is to control the hypercalcemia.
Bisphosphonates
1)Pamidronate : Transiently effective in lowering serum calcium(1)
2) Zoledronic acid: More potent than pamidronate in treating hypercalcemia of malignancy, would
also be effective for hypercalcemia due to parathyroid carcinoma (7).
Calcimimetics Drug that reduces PTH secretion by increasing the sensitivity of the calcium-sensing
receptor. Cinacalcet, Sensipar®, a longer-acting calcimimetic drug, is available for the treatment of
hypercalcemia in parathyroid cancer. In a 16-week open-label study of 29 patients with inoperable
parathyroid carcinoma, cinacalcet (dose titrated to achieve calcium ≤10 mg/dL or up to 90 mg four
times daily) successfully reduced serum calcium concentration by at least 1 mg/dL in 62% of
patients. Mean PTH levels decreased but not significantly. Adverse events (nausea, vomiting,
headache, dehydration) were common and resulted in discontinuation in five patients (8).
Anti-Parathyroid Hormone
Immunotherapy: Breaking normal immune tolerance to PTH using human and bovine PTH-like
immunogenic fragments to stimulate the production antibody that would cross-react with human
PTH,PTH immunization can improve clinical, hormonal, and biochemical measures and antitumor
effect in patients with metastatic PCA(9).
Prognosis
No one characteristic can predict the outcome of PCA. Early recognition and complete resection at
the time of the initial surgery carry best prognosis. Average time surgery to first recurrence is 3yrs
(up to 20 yr have been reported).Once 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 40–86% and 10-yr survival to be approximately 49 % (1).
Reference
1. Shane E 2001 Clinical review 122: parathyroid carcinoma. J Clin Endocrinol Metab 86:485–493
2. Szabo J, Heath B, Hill VM, et al. 1995 Hereditary hyperparathyroidism-jaw tumor syndrome: the endocrine tumor gene HRPT2 maps to
chromosome1q21–q31. Am J Hum Genet. 56:944 –950.
3. Shattuck TM, Välimäki S, Obara T, Gaz RD, Clark OH, Shoback D et al. Somatic and germ-line mutations of the HRPT2 gene in sporadic
parathyroid carcinoma. N Engl J Med. 2003;349(18):1722.
4. Abdelgadir Adam M, Untch BR, Olson JA Jr. Parathyroid Carcinoma: Current Understanding and New Insights into Gene Expression and
Intraoperative Parathyroid Hormone Kinetics Oncologist. 2010;15(1):61-72.
5. Antoine Digonnet, Adelaïde Carlier, Guy Andry. et.al Parathyroid Carcinoma: A Review with Three Illustrative Cases .Journal of Cancer
2011; 2: 532-537
6. Laura Evangelista, Nadia Sorgato, Francesca Torresan,et al. FDG-PET/CT and parathyroid carcinoma: Review of literature and illustrative
case series World J Clin Oncol 2011 October 10; 2(10): 348-354
7. P. Major, A. Lortholary, J. Hon, E. Abdi,et.al. Zoledronic Acid Is Superior to Pamidronate in the Treatment of Hypercalcemia of
Malignancy: A Pooled Analysis of Two Randomized, Controlled Clinical Trials. Journal of Clinical Oncology, Vol 19, No 2 (January 15), 2001:
pp 558-567
8. S. J. Silverberg, M. R. Rubin, C. Faiman et al. Cinacalcet Hydrochloride Reduces the Serum Calcium
Concentration in Inoperable Parathyroid Carcinoma J Clin Endocrinol Metab 2007;92(10):3803–3808.
9. D. BETEA, A. R. BRADWELL, T. C. HARVEY et al. Hormonal and Biochemical Normalization and Tumor Shrinkage Induced by AntiParathyroid Hormone Immunotherapy in a Patient with Metastatic Parathyroid Carcinoma J Clin Endocrinol Metab 2004; 89(7):3413–3420