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We describe the fine-needle aspiration cytology features of a primary parathyroid cancer and of the local recurrent and distant metastatic lesions. The presence of prognostic factors Ki-67 and proliferating cell nuclear antigen (PCNA) was compared immunohistochemically between primary parathyroid carcinoma and related metastatic and recurrent foci. Flow cytometric DNA analysis was also performed to investigate any chromosomal abnormality of the parathyroid carcinoma. Cytologic examination of the endocrine tumor showed that it comprised a loose cohesive cluster and tumor cells with granular cytoplasm and mild nuclear atypia, but for purposes of cytodiagnosis, it is difficult to determine whether such a neoplasm is malignant on the basis of morphology alone. Immunohistochemical analysis showed that Ki-67 and PCNA labeling indices were higher in the recurrent and metastasized carcinomas than in the primary cancer, suggesting that neoplastic cells become more malignant in the recurrent and metastasized foci. To our knowledge, this is the first report describing not only cytopathologic but also immunocytologic differences between primary parathyroid cancer and the metastatic lesion.
UNLABELLED: Familial hyperparathyroid syndromes involving mutations of HRPT2 (also CDC73), a tumor suppressor, are important to identify because the relatively high incidence of parathyroid malignancy associated with such mutations warrants a specific surveillance strategy. However, there is a dearth of reports describing experience with surveillance and early detection informed by genetic insight into this disorder. INTRODUCTION: Familial isolated hyperparathyroidism (FIHP) is a rare cause of parathyroid (PT) tumors without other neoplasms or endocrinopathies. Germline mutations in CASR, MEN1, and rarely, HRPT2 have been identified in kindreds with FIHP. HRPT2 mutations may be enriched in FIHP families with PT carcinoma, underscoring the importance of identifying causative mutations. MATERIALS AND METHODS: A 13-year-old boy, whose father had died of PT carcinoma, developed primary hyperparathyroidism. A left superior PT mass was identified by ultrasonography and removed surgically. Aggressive histological features of the boy's tumor included fibrous trabeculae, mitoses, and microscopic capsular infiltration. Two years later, under close biochemical surveillance, primary hyperparathyroidism recurred 5 months after documentation of normocalcemia and normal parathyroid status. Ultrasound and MRI identified a newly enlarged right superior PT gland but indicated no recurrent disease in the left neck. Histologic features typical of a benign adenoma were evident after surgical extirpation of the gland. RESULTS: Leukocyte DNA analysis revealed a frameshift mutation in exon 2 of HRPT2. The initial tumor manifested the expected germline HRPT2 mutation, plus a distinct somatic frameshift mutation, consistent with the Knudson "two hit" concept of biallelic inactivation of a classic tumor suppressor gene. Genetic screening of the patient's 7 asymptomatic and previously normocalcemic siblings revealed three with the same germline HRPT2 mutation. One of the siblings newly identified as mutation-positive was noted to be hypercalcemic at the time of the genetic screening. He was found to have a PT adenoma with aggressive features. Two of the five children of another mutation-positive sibling also carry the same HRPT2 mutation. CONCLUSIONS: Despite the reported rarity of HRPT2 mutations in FIHP, a personal or family history of PT carcinoma in FIHP mandates serious consideration of germline HRPT2 mutation status. This information can be used in diagnostic and management considerations, leading to early detection and removal of potentially malignant parathyroid tumors.
Hyperfunctioning parathyroid carcinoma is a relatively rare endocrine tumor, accounting for approximately 1% of all cases of primary hyperparathyroidism. The diagnosis is suspected when the tumor is large, parathyroid hormone (iPTH) levels are high, and a palpable tumor is present in the neck. Patients who have recurrence of hyperparathyroidism several months after surgical treatment should be suspected of having a recurrent or persistent parathyroid carcinoma. At operation, a large invasive tumor is usually found. The fibrous, inflammatory-like reaction is the most characteristic indication of malignancy. Even in tumors with minimal invasiveness, the possibility of a carcinoma should be considered if the tumor has mitotic activity and a monotonous instead of a pleomorphic cellular population. If the surgeon can recognize the possibility of parathyroid malignancy and adequately treat the patient during the initial operation, more gratifying results should be obtained.
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Primary hyperparathyroidism is a common disorder characterized by aberrant growth and function of solitary or multiple parathyroid glands. Many, if not all, parathyroid adenomas are examples of benign clonal neoplastic growth. The molecular events associated with the development of parathyroid neoplasia have not been well characterized. We examined benign and malignant parathyroid tissues for structural abnormalities of the p53 tumor suppressor gene. To screen for mutations in the p53 gene, we analyzed polymerase chain reaction-amplified DNA by denaturing gradient gel electrophoresis. DNA was isolated from 26 benign parathyroid adenomas and 3 parathyroid carcinomas, and polymerase chain reaction was used to amplify DNA fragments corresponding to the 4 evolutionarily conserved domains within exons 5, 7, and 8 of the p53 gene in which the majority of point mutations have been identified. Amplified DNA fragments were electrophoresed through polyacrylamide gels with linearly increasing gradients of the denaturants urea and formamide. After electrophoresis, the gels were examined for the presence of abnormally migrating bands, which represent DNA with altered melting points due to nucleotide sequence changes. Amplified fragments were of the expected size in DNA from 26 parathyroid adenomas and 3 parathyroid carcinomas. Denaturing gradient gel electrophoresis studies failed to disclose evidence of mutations in exons 5, 7, and 8 of the p53 gene in these neoplasms. We conclude that p53 point mutations do not appear to be a primary event responsible for neoplastic growth in parathyroid tissue.
Parathyroid carcinoma is a rare cause of primary hyperparathyroidism with a prevalence ranging between 0.5 and 4%. Because of their aggressiveness, prompt diagnosis and treatment are mandatory. A parathyroid carcinoma was found in four patients (4.5%) of 88 patients who underwent surgical cervical exploration for primary hyperparathyroidism at the Institute Nacional de la Nutrición in a period of seven years. Our paper gives the clinical characteristics, diagnosis, treatment and outcome of the four patients.
Several advances have been achieved toward the goal of understanding the molecular basis of parathyroid tumorigenesis. The cyclin D1/PRAD1 oncogene has been identified, and is involved in the development of several different tumor types besides those of the parathyroid. The tumor suppressor RB gene has been linked to the pathogenesis of parathyroid carcinoma. The MEN-1 gene product has been identified and mutations in MENIN shown to contribute to sporadic tumors. An understanding of the functions of MENIN will provide further insights into parathyroid disease. Mutations in the RET gene have been identified as the causal agent in MEN-2 but this gene contributes rarely to development of sporadic parathyroid tumors. Ultimately, a description of parathyroid tumorigenesis will need to account for such features as the rarity of parathyroid carcinoma, the increased incidence of tumors after neck irradiation, and the increased frequency of hyperparathyroidism in postmenopausal women. In addition, the relationship between excessive cellular proliferation and an altered set-point in the mechanism linking extracellular calcium concentration to PTH secretion requires explanation. While mutations in the CASR gene itself play a critical role in familial disease, they do not appear to be involved in sporadic parathyroid tumorigenesis, and investigation of genes important for its expression is clearly warranted.
During recent years the total number of patients undergoing surgery for hyperparathyroidism has markedly increased, but the annual number of cases with substantial hypercalcemia has remained unchanged. Parathyroid carcinoma and water clear cell hyperplasia cause more severe hypercalcemia than other kinds of hyperparathyroidism. Grave hypercalcemia due to hyperparathyroidism is more common among the elderly, but can occur during pregnancy and also among children. Occasionally, a patient with hyperparathyroidism can also have another cause of the hypercalcemia and does not become normocalcemic until adequately treated for both. The suspicion of grave hypercalcemia should arise due to its clinical features. Determination of serum calcium and intact parathyroid hormone concentrations establishes the diagnosis. The basic treatment of grave hypercalcemia is to rehydrate the patient and to restore the sodium losses. To further lower the serum calcium value we have found bisphosphonates to be very effective. The definitive treatment of grave hypercalcemia due to hyperparathyroidism is surgery. As a last resort, frail patients with grave hyperparathyroidism can undergo surgery under local anesthesia. Repeat operations can improve the prognosis of patients with metastatic parathyroid carcinoma. Selective venous catheterization with blood sampling for determination of intact parathyroid hormone can be helpful in localizing recurrent disease.
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A 54-year-old man was admitted to our hospital because of dyspnea. Radiographic examination showed an anterior mediastinal mass and pericardial effusion. Serum calcium and parathyroid hormone-related protein (PTHrP) levels were elevated, and serum CYFRA 21-1 level was extremely high. Results of percutaneous needle biopsy under computed tomography guidance led to a diagnosis of moderately differentiated squamous cell carcinoma. Immunohistological staining showed the tumor cells to be positive for PTHrP and cytokeratin monoclonal antibodies. Postmortem findings were considered to indicate thymic carcinoma. Thymic carcinoma is rare, but our case indicates that thymic squamous cell carcinoma can be identified in terms of paraneoplastic hypercalcemia.
Between August 1975 and January 1981, 106 patients thought to have persistent or recurrent hyperparathyroidism underwent a total of 108 parathyroid re-explorations at the National Institutes of Health. These 106 patients had a total of 175 previous operations for hyperparathyroidism (156 cervical and 19 mediastinal). Nephrolithiasis (54% of patients) and bone disease (24% o patients) were the predominant symptoms. Arteriographic examination and selective venous sampling provided highly accurate localizing results in 33% of the patients, and were of some help in 64%. The final diagnoses after reoperation and re-evaluation were: single-gland disease in 58 patients, primary nonfamilial hyperplasia in 19 patients, familial hyperplasia in three patients, multiple endocrine neoplasia (MEN) Type I in ten patients, MEN Type II in two, parathyroid carcinoma in four patients, secondary hyperplasia in three patients, and familial hypocalciuric hypercalcemia (FHH) in two patients. The diagnosis was in doubt in five patients. In the 95 patients with unequivocal hyperparathyroidism, not due to parathyroid carcinoma, surgery eliminated hypercalcemia in 91 (96%). Two patients died after operation, one of disseminated candidiasis, and one patient, with an immunodeficiency, of sepsis. Five patients developed temporary, and one permanent, recurrent nerve damage; 41% of the patients were hypocalcemic, at the time of discharge from the hospital.
BACKGROUND: Uncontrolled hyperparathyroidism (HPT), particularly HPT resulting from chronic kidney disease (CKD), is associated with significant morbidity and cardiovascular mortality. Traditional medical therapy (eg, vitamin D sterols, calcium, phosphate binders) has been inadequate for the management of HPT and its vascular and skeletal complications. OBJECTIVE: : The goal of this article was to review the efficacy and safety profile of cinacalcet, a second-generation calcimimetic, in the management of HPT secondary to CKD, primary HPT, and parathyroid carcinoma. METHODS: MEDLINE, Web of Science, and International Pharmaceutical Abstracts were searched from 1995 to July 2005 using the terms cinacalcet, AMG 073, KRN 1493, calcimimetics, hypercalcemia, and hyperparathyroidism. RESULTS: Compared with placebo, cinacalcet significantly reduced parathyroid hormone levels within 2 to 4 hours after administration (P < 0.05). In Phase III trials involving 1136 patients with secondary HPT, 56% of those who received cinacalcet achieved the National Kidney Foundation Kidney Disease Outcomes Quality Initiative target of a reduction in parathyroid hormone to <300 pg/mL, 65% achieved a calcium-phosphorus product <55 mg2/dL2, and a respective 49% and 46% achieved normalized serum calcium and phosphorus levels (P < 0.001). Cinacalcet's effects were similar regardless of patients' demographic characteristics, duration or mode of dialysis, severity of HPT, or use of concomitant medical therapy. Preliminary evidence suggests that cinacalcet may reverse cortical bone loss. Cinacalcet was well tolerated, with nausea (31%) and vomiting (27%) being the most commonly reported adverse effects. Hypocalcemia was transient in 5% of patients, was usually asymptomatic, and was corrected by dose reduction. CONCLUSIONS: Based on the available evidence, cinacalcet is effective and well tolerated in the treatment of secondary HPT and refractory parathyroid carcinoma. Its use in primary HPT appears promising. Further investigations are needed to determine if cinacalcet can prevent the long-term complications of HPT and reduce mortality.
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The concentration of subunits of hCG (hCG alpha and hCG beta) was determined in plasma or serum from 70 patients with primary hyperparathyroidism (1 degrees HPT). Two of three patients with parathyroid carcinoma showed elevation in plasma concentrations of both subunits, which fell after surgical removal of the tumor. An extract prepared from the tumor of 1 of these patients contained the subunits in high concentrations, whereas in extracts similarly prepared from tissues removed from 7 patients with benign 1 degrees HPT, the subunits were not detectable or were present in much lower concentrations. In 42 cases of benign 1 degrees HPT, samples from veins containing a 10-fold gradient of parathyroid hormone obtained during selective venous catheterization and peripheral samples from the same patients were analyzed for hCG subunits. Only 1 patient demonstrated a mild elevation of hCG alpha in parathyroid venous effluent alone that may have represented subunit release by apparently benign parathyroid tissue. Thirty patients with multiple endocrine neoplasia type I were tested; 8 evidenced clinically active islet cell tumors, and 6 of these 8 showed high circulating concentrations of hCG alpha (and hCG beta in 1 case). Patients in the multiple endocrine neoplasia type I group with 1 degrees HPT or pituitary tumors, but no evident pancreatic islet disease, did not show elevations in subunit concentrations. Thus, in patients with 1 degrees HPT, determination of subunits of hCG may be helpful in making the diagnosis of parathyroid carcinoma or in screening for associated (and probably malignant) pancreatic islet disease.
Recurrent or persistent primary hyperparathyroidism (HPT) is a rare occurrence requiring generally a careful reoperation. From 1980 to 1992 a total of 192 patients underwent bilateral cervical exploration following a diagnosis of primary hyperparathyroidism. Persistent of recurrent HPT was found in 6 (3.04%) of our cases. In two patients a subtotal parathyroidectomy was performed (parathyroid hyperplasia) and hyperfunctioning parathyroid tissue was found at neck exploration. In one case an ectopic adenomatous fifth gland was found in mediastinum at reoperation. Three patients with recurrent HPT had a parathyroid carcinoma but in only two cases it was possible to identify and remove the pathologic tissue preoperatively localised in mediastinum by double-tracer scintigraphy and CT scan 6 and 15 months after first operation respectively. The third patient with parathyroid carcinoma was inoperable on account of multiple metastases both cervical and thoracic.