• Information
  1. Epidemiology
  2. Etiology
  3. Clinical Presentation
  4. Diagnosis
  5. Treatment

A. Epidemiology

1. Very rare tumors
2. Account for 1-5% of primary hyperparathyroidsm [1,3]
3. Affects men and women equally
4. Symptoms of hypercalcemia usually lead patients to seek medical care
5. Hyperparathyroidism - Jaw Tumor (HPT-JT) Syndrome [4]
   1. Due to mutations in HRPT2 gene which encodes parafibromin protein
   2. Rare autosomal dominant cause of HPT and parathyroid carcinomas
   3. HRPT2 maps to chromosome 1q25-32

B. Etiology

1. Parathyroid Adenomas
   1. Monoclonal or oligoclonal tumors
   2. Likely that two or more genes have mutated
   3. Somatic mutation of MEN1 gene (tumor suppressor) in ~20% of cases
   4. Small minority of single adenomas have activating mutations of Cyclin D1 (CCND1) gene
   5. Nearly all adenomas have overexpression of CCND1 (also called PRAD1)
   6. Abnormal cells have deficient sensitivity to inhibition by Ca2+
2. Parathyroid Carcinoma [4,5]
   1. No clear association with parathyroid adenomas, radiation, or exposures
   2. No clear association with chronic renal failure associated parathyroid hyperplasia
   3. MEN1 gene mutations have not been found in most parathyroid carcinomas
   4. Overexpression of CCND1 has been reported in ~90% of parathyroid carcinomas
   5. Loss of a region of chromsome 13 (gene unknown) implicated
   6. HRPT2 mutations found in 10 of 15 parathyroid carcinomas from patients without any familial or known genetic predisposition to the disease [4]
   7. Germline mutations in HRPT2 were found 3 of these 15 patients [4]

C. Clinical Presentation

1. Mainly due to excessive secretion of PTH by functioning tumor
2. Symptoms less often due to infiltration of vital organs by tumor mass
3. Mnemonic for hyperparathyroidism/hypercalcemia: "bones, stones, and groans"
4. Common Presentations
   1. Asymptomatic with mild hypercalcemia (<5% of cases)
   2. Moderate or severe hypercalcemia presnet with polydipsia, polyuria
   3. Severe or longer standing disease can present with pathologic fractures
5. Symptoms of longstanding hypercalcemia due to hyperparathyroidism:
   1. Renal: Polyuria, Nephrolithiasis, Nephrocalcinosis; Diabetes insipidus may occur
   2. Cardiovascular: Hypertension, Shortened QT interval on ECG
   3. Gastrointestinal: Anorexia, Nausea, Vomiting, Constipation, Pancreatitis
   4. Musculoskeletal: Myalgias, Weakness
   5. CNS: Apathy, Lethargy, Confusion, Delirium

D. Diagnosis

1. Hypercalcemia - often >14mg/dL
2. Hyperparathyroidism: markedly elevated parathyroid hormone (PTH)
3. Palpable neck mass
4. Renal involvement - ~50%
5. Skeletal complications ~50%
6. Both renal and skeletal disease common
7. Fine needle aspiration with biopsy for definitive diagnosis
8. Localizing studies required for recurrent disease to assess progression
9. Magnetic resonance imaging may be useful for bulkier disease

E. Treatment [1]

1. Surgery
   1. Complete resection of primary lesion is most effective
   2. Careful post-operative management of serum calcium (and phosphate) levels
   3. Postoperative hypocalcemia may be severe and may require intravenous calcium
   4. Supplemental calcium with calcitriol may be used
   5. Reoperation usually recommended for recurrent disease
2. Radiation therapy has been ineffective
3. Chemotherapy
   1. Generally poor response to chemotherapy
   2. Dacarbazine appears to be most effective single agent
   3. Combination chemotherapy with methotrexate, doxorubicin, cyclophosphamide, lomustine
4. Bone Disease [2]
   1. In patients with inoperable primary or recurrent tumor, long term bone prophylaxis required
   2. Bisphosphoanates are very effective
   3. Calcimimetics are also being developed for hyperparathyroidism

References

1. Shane E. 2001. J Clin Endocrinol Metab.
2. Kebebew E. 2003. Curr Treat Options Oncol. 2001. 2(4):347
3. Brown EM and Vickery AL Jr. 1996. NEJM. 335(16):1213
4. Shattuck TM, Valimaki S, Obara T, et al. 2003. NEJM. 349(18):1722
5. Weinstein LS and Simonds WF. 2003. NEJM. 349(18):1691