Interhospital Conference Case 4
Parathyroid Carcinoma
Parathyroid carcinoma is a very rare cause of primary hyperparathyroidism with
an overall incidence of less than 1% and also one of the rarest malignancies (1). It
typically presents between 45–59 years of age and occurs equally in men and women (2).
The pathogenesis of parathyroid cancer is unknown. It may occur sporadically or
as a part of a genetic syndrome include hyperparathyroidism- jaw tumor syndrome (HPTJT), MEN1, MEN2A, and isolated familial hyperparathyroidism (3).
Table 1: Familial disorders characterized by primary hyperparathyroidism
From Journal of Internal Medicine 2003; 253: 634–642
Presentations
Patients may develop non-specific symptoms of hypercalcemia. It can be difficult
to diagnose but should be promptly suspected in primary hyperparathyroidism case with a
palpable neck mass, hoarseness, severe hypercalcemia (serum calcium level ≥ 14.0
mg/dl) and overt bone or kidney disease (4). PTH level is markedly elevated 3 to 10
times the upper limit of normal (2, 3, 5). Other abnormally elevated biochemical serum
markers include alkaline phosphatase and α- and β- subunits of hCG (2). Many
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parathyroid carcinoma patients initially present with hypercalcemic crisis, also known as
parathyrotoxicosis (6).
Pathology
Fine-needle aspiration (FNA) prior to initial operation is not recommended due to
technical difficulty in differentiating benign and malignant disease on cytology
specimens (7). Its cytomorphologic similarities with Hurthle cell thyroid neoplasm
especially intrathyroidal oncocytic parathyroid adenoma. Misinterpreted lesions were due
to monotonous proliferation of oncocytic cells. Cytopathologists have some features that
can help to distinguish between these two cell types. Hurthle cell lesion tends to have
larger nuclei with prominent nucleoli and the cells are more dyscohesive. In contrast,
many naked nuclei in the background can be more often observed in parathyroid lesions
(8). Immunocytochemical panel such as, PTH, TTF-1 and thyroglobulin may be useful to
the diagnosis. However, the most important things to obtain a right diagnosis are clinical,
radiologic and laboratory information (9).
Genetic testing
Parathyroid carcinoma is more common in patients with HPT-JT syndrome.
Incidence is increased to 15% in this group of patients (10). Genetic locus associated with
HPT-JT was first described in 1995, located on the long-arm of chromosome 1 (1q21q31)(11). 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 germline mutation of this gene. But somatic mutation can also be identified
in sporadic case (12).
Treatment
Surgical removal is a primary treatment of parathyroid carcinoma. En bloc
resection is a procedure of choice to remove tumor and adjacent involved tissue (6, 13)
Complete resection of the tumor offers a chance of cure. Hungry bone syndrome is an
important postoperative complication, which may require hospitalization. Close
monitoring of postoperative serum calcium should be done regularly (2). Other surgical
complications such as recurrent laryngeal nerve injury, esophageal injury, tracheal injury,
neck hematoma, and wound infection have been reported, depending on the extent of
tumors and surgical procedures. Recurrent rate of parathyroid carcinoma is high
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especially those who already had lymph node and/ or distant metastasis (14). The 5-yearsurvival of the patients is 85.5% (13).
Hyperparathyroidism- Jaw Tumor Syndrome (HPT-JT)
HPT-JT syndrome was first described in 1990 by Jackson et al (15). This
syndrome can represent either sporadic or inherited transmission. The inherited
transmission is in an autosomal dominant pattern. Its most common manifestation is
parathyroid tumors with primary hyperparathyroidism in late adolescents and early adults
(16) with high tendency to be malignant in nature.
Thirty percent of patients from report series developed fibro-osseous lesions
(ossifying fibroma) in maxilla or mandible. The term ‘jaw tumor’ is a misnomer because
tumor can be found not only in the jaw (mandible) but also develop in maxilla (16).
Unlike brown tumors in primary hyperparathyroidism, these lesions will not resolve after
treatment of primary hyperparathyroidism and can manifest without hyperparathyroidism
(17). Other tumors those can be found are renal tumors and uterine tumors. Kidney may
develop polycystic kidney disease. Tumors consist of solid and cystic part, are quite large
and can be found in both cortical and medullary layer of kidneys. Other kidney tumor
reported in this syndrome is Wilm’s tumor, which is less common but has been found in
3 patients with this syndrome. Renal harmatoma and renal cell carcinoma can rarely be
reported (16, 18, 19). In women, uterine tumor either benign or malignant can be affected
in 75% of patients (10, 20).
Clinical and Genetic Screening
CDC73 direct sequencing of the gene can be performed on patients suspected of
HPT- JT. If the families are tested negative but have sufficient number of affected and
unaffected cases for testing, linkage analysis using microsatellite polymorphic markers
encompassing the gene can be carried out.
For hyperparathyroidism, annual blood tests measuring ionized calcium and intact
parathyroid hormone (iPTH) levels should begin by 15 years of age. Surgical intervention
should be performed when hyperparathyroidism is established. For lesions in the maxilla
and mandible, orthopentography of the face should be performed, perhaps once in every
3 years. For abdominal lesions kidney and uterine tumors, annual abdominal ultrasound
or computed tomography scan with and without contrast is advisable (16).
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References:
1.
Marcocci C, Cetani F, Rubin MR, Silverberg SJ, Pinchera A, Bilezikian JP. Parathyroid
carcinoma. Journal of bone and mineral research : the official journal of the American Society for Bone and
Mineral Research. 2008;23(12):1869-80.
2.
Shane E. Clinical review 122: Parathyroid carcinoma. The Journal of clinical endocrinology and
metabolism. 2001;86(2):485-93.
3.
Kebebew E. Parathyroid carcinoma. Current treatment options in oncology. 2001;2(4):347-54.
4.
Chang YJ, Mittal V, Remine S, Manyam H, Sabir M, Richardson T, et al. Correlation between
clinical and histological findings in parathyroid tumors suspicious for carcinoma. The American surgeon.
2006;72(5):419-26.
5.
Dudney WC, Bodenner D, Stack BC, Jr. Parathyroid carcinoma. Otolaryngologic clinics of North
America. 2010;43(2):441-53, xi.
6.
Kebebew E, Clark OH. Parathyroid adenoma, hyperplasia, and carcinoma: localization, technical
details of primary neck exploration, and treatment of hypercalcemic crisis. Surgical oncology clinics of
North America. 1998;7(4):721-48.
7.
Kassahun WT, Jonas S. Focus on parathyroid carcinoma. Int J Surg. 2011;9(1):13-9.
8.
Giorgadze T, Stratton B, Baloch ZW, Livolsi VA. Oncocytic parathyroid adenoma: problem in
cytological diagnosis. Diagnostic cytopathology. 2004;31(4):276-80.
9.
Paker I, Yilmazer D, Yandakci K, Arikok AT, Alper M. Intrathyroidal oncocytic parathyroid
adenoma: a diagnostic pitfall on fine-needle aspiration. Diagnostic cytopathology. 2010;38(11):833-6.
10.
Newey PJ, Bowl MR, Cranston T, Thakker RV. Cell division cycle protein 73 homolog (CDC73)
mutations in the hyperparathyroidism-jaw tumor syndrome (HPT-JT) and parathyroid tumors. Human
mutation. 2010;31(3):295-307.
11.
Szabo J, Heath B, Hill VM, Jackson CE, Zarbo RJ, Mallette LE, et al. Hereditary
hyperparathyroidism-jaw tumor syndrome: the endocrine tumor gene HRPT2 maps to chromosome 1q21q31. American journal of human genetics. 1995;56(4):944-50.
12.
Shattuck TM, Valimaki S, Obara T, Gaz RD, Clark OH, Shoback D, et al. Somatic and germ-line
mutations of the HRPT2 gene in sporadic parathyroid carcinoma. The New England journal of medicine.
2003;349(18):1722-9.
13.
Hundahl SA, Fleming ID, Fremgen AM, Menck HR. Two hundred eighty-six cases of parathyroid
carcinoma treated in the U.S. between 1985-1995: a National Cancer Data Base Report. The American
College of Surgeons Commission on Cancer and the American Cancer Society. Cancer. 1999;86(3):538-44.
14.
Harari A, Waring A, Fernandez-Ranvier G, Hwang J, Suh I, Mitmaker E, et al. Parathyroid
carcinoma: a 43-year outcome and survival analysis. The Journal of clinical endocrinology and metabolism.
2011;96(12):3679-86.
15.
Jackson CE, Norum RA, Boyd SB, Talpos GB, Wilson SD, Taggart RT, et al. Hereditary
hyperparathyroidism and multiple ossifying jaw fibromas: a clinically and genetically distinct syndrome.
Surgery. 1990;108(6):1006-12; discussion 12-3.
16.
Chen JD, Morrison C, Zhang C, Kahnoski K, Carpten JD, Teh BT. Hyperparathyroidism-jaw
tumour syndrome. Journal of internal medicine. 2003;253(6):634-42.
17.
Sciubba JJ FJ, Kahn LB. Tumors and Cysts of the Jaw. Atlas of Tumor Pathology, 3rd Series,
Fascicle 29. Armed Forces Institute of Pathology, Washington, DC, 2001, 1–275.
18.
Teh BT, Farnebo F, Kristoffersson U, Sundelin B, Cardinal J, Axelson R, et al. Autosomal
dominant primary hyperparathyroidism and jaw tumor syndrome associated with renal hamartomas and
cystic kidney disease: linkage to 1q21-q32 and loss of the wild type allele in renal hamartomas. The Journal
of clinical endocrinology and metabolism. 1996;81(12):4204-11.
19.
Haven CJ, Wong FK, van Dam EW, van der Juijt R, van Asperen C, Jansen J, et al. A genotypic
and histopathological study of a large Dutch kindred with hyperparathyroidism-jaw tumor syndrome. The
Journal of clinical endocrinology and metabolism. 2000;85(4):1449-54.
20.
Bradley KJ, Hobbs MR, Buley ID, Carpten JD, Cavaco BM, Fares JE, et al. Uterine tumours are a
phenotypic manifestation of the hyperparathyroidism-jaw tumour syndrome. Journal of internal medicine.
2005;257(1):18-26.
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