The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 12 5948-5951
Copyright © 2004 by The Endocrine Society
Oxyphil Parathyroid Adenoma: A Malignant Presentation of a Benign Disease
Jessica Fleischer,
Carolyn Becker,
Diane Hamele-Bena,
Tracy L. Breen and
Shonni J. Silverberg
Departments of Medicine (J.F., C.B., T.L.B., S.J.S.) and Pathology (D.H.-B.), College of Physicians and Surgeons, Columbia University, New York, New York 10032
Address all correspondence and requests for reprints to: Shonni J. Silverberg, M.D., Professor of Clinical Medicine, College of Physicians and Surgeons, Columbia University, Department of Medicine, PH 8-864, 630 West 168th Street, New York, New York 10032. E-mail: sjs5{at}columbia.edu.
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Abstract
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Functioning parathyroid adenomas of the oxyphil cell type are rare, and the clinical characteristics of patients with these tumors have not been well defined. We describe two cases of severe primary hyperparathyroidism (PHPT) caused by benign oxyphil parathyroid adenomas. The patients’ clinical presentations mimicked parathyroid carcinoma. Both had very large tumors associated with marked elevations in PTH and serum calcium levels. Skeletal manifestations were also atypical for benign PHPT, with severe osteoporosis in one patient and osteitis fibrosa cystica in the other. These cases also highlight the remarkable capacity of the skeleton to recover after successful parathyroidectomy, previously reported in other forms of severe PHPT. Bone mineral density improved dramatically 1 yr after parathyroidectomy, with increases of 51% at the lumbar spine, 36% at the total hip, and 11% at the distal one third radius. Most of the increases occurred in the first postoperative months. Consistent with this early and accelerated skeletal response, markers of bone turnover were increased 2 months after surgery and normalized by 8 months postoperatively. In patients with PHPT who present with severe or atypical clinical features, oxyphil adenoma should be considered.
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Introduction
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THE MOST COMMON cause of primary hyperparathyroidism (PHPT) is a solitary adenoma composed mainly of chief cells (1). Oxyphil cells are also found in the parathyroid gland but were traditionally thought to be nonfunctional. Functioning oxyphil parathyroid adenomas do occasionally occur (1). Warren and Morgan (2) first described a pure functioning oxyphil cell adenoma of the parathyroid in 1935. Since then, a number of additional cases have been reported (3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16). In a retrospective review of 500 patients with neck explorations for PHPT, Wolpert et al. (15) found that oxyphil cell adenomas represented only 3% of cases. Indeed, review of the literature finds only 120 documented cases to date (3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16).
The literature on oxyphil cell parathyroid adenomas largely focuses on the pathologic features, whereas the clinical manifestations of patients with these tumors have not been well described. In this report, we describe two women with severe PHPT caused by oxyphil cell adenomas. Both patients had striking elevations in PTH, marked hypercalcemia, very large tumors, and overt clinical symptoms that rapidly improved after parathyroidectomy. This presentation is unusual in that the modern clinical profile of benign PHPT has shifted from a symptomatic disorder toward one that is most commonly asymptomatic (17, 18, 19). Indeed, the clinical features of these two patients suggested parathyroid carcinoma (20), which was the presumptive preoperative diagnosis in both cases.
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Case Reports
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Case 1
A 43-yr-old Hispanic female presented to our emergency room in August 2002 with posterior neck pain. She had a history of acute renal colic in 1995. Work-up at that time revealed PHPT with an intact PTH of 1071 pg/ml (normal, 10–65), serum calcium of 12.3 mg/dl (normal, 8.4–10.2), and serum phosphorus of 0.7 mg/dl (normal, 2.5–4.5). Due to financial and social constraints, she left the country and was lost to follow-up until 7 yr later when she was admitted with posterior neck pain. She denied stridor, shortness of breath, or hoarseness, but did report dysphagia. She denied symptoms of hypercalcemia, bone pain, or fractures. Her menstrual periods were normal, and her family history was negative for osteoporosis, renal stones, or parathyroid disease. She had two healthy children. She denied use of thiazide diuretics, lithium, herbal supplements, or vitamins. She did not smoke, drink alcohol, or use illicit drugs. On physical examination, she was 62 inches tall and weighed 132 pounds. Her blood pressure was 106/70 mm Hg. There were no palpable neck masses or lymphadenopathy, but the trachea was deviated to the right. Her thyroid gland was not enlarged. Cardiovascular, pulmonary, and abdominal exams were unremarkable. Motor strength and reflexes were normal. Serum biochemistries on admission (Table 1
) included: calcium, 12.4 mg/dl (normal, 8.4–9.8); albumin, 4.9 g/dl (normal, 4.0–5.0); phosphorus, 1.6 mg/dl (normal, 2.5–4.5); blood urea nitrogen, 7 mg/dl (normal, 7–20); and creatinine, 0.5 mg/dl (normal, 0.5–1.1). Intact PTH was 888 pg/ml (normal, 10–65). 25-Hydroxyvitamin D and 1,25-dihydroxyvitamin D levels were 18 ng/ml (normal, 10–68) and 166 pg/ml (normal, 15–60), respectively, and total alkaline phosphatase activity was 209 U/liter (normal, 33–96). Bone mineral density (BMD) by dual-energy x-ray absorptiometry (Hologic, Waltham, MA; model Delphi W) revealed a marked reduction in bone mass at all sites, with T-scores in the osteoporotic range at the lumbar spine and distal radius (Table 1). Computed tomography of the neck showed a very large mass posterior to the left lobe of the thyroid (Fig. 1). Radiographs of clavicles and hands showed no evidence of osteitis fibrosa cystica.
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FIG. 1. Computed tomography of the neck showing a 2.8- x 6.0-cm heterogeneous mass posterior and adjacent to the left lobe of the thyroid, with substernal extension and displacement of the trachea.
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At surgery, a large neck mass was resected, measuring 6.0 x 3.8 x 2.1 cm and weighing 24.8 g. Pathology revealed a benign parathyroid adenoma consisting primarily of oxyphil cells. Immunohistochemical stains were positive for PTH. Twelve hours postoperatively, the serum calcium fell to 5.9 mg/dl and the PTH dropped to 8 pg/ml. Chvostek’s sign was negative, but carpal-pedal spasms were present. She was treated with intravenous calcium gluconate and then with oral calcium carbonate (3 g daily). Four days after the parathyroidectomy, serum calcium had increased to 8.2 mg/dl, and she was discharged on 2 g of supplemental calcium and 1600 IU of vitamin D daily.
Two months after surgery, the patient’s serum calcium remained low at 7.4 mg/dl, and there was evidence of secondary hyperparathyroidism (PTH of 151 pg/ml). Bone turnover markers were elevated (Table 1
), with a disproportionate increase in markers of bone formation (osteocalcin) over bone resorption (N-telopeptide). By 8 months after surgery, both osteocalcin and urinary N-telopeptide had normalized (Fig. 2). Over the 1st postoperative yr, BMD increased dramatically at the lumbar spine and total hip (Fig. 3). By 5 months, lumbar spine bone mass increased 41% (0.568–0.801 g/cm2) with the T-score improving to above the osteoporotic range (–4.4 to –2.2). At the total hip, BMD increased 29% (0.722–0.928 g/cm2; T-score, –1.8 to –0.3). Distal forearm BMD showed a much more modest increase of 6.2% (0.394–0.418 g/cm2; T-score, –5.0 to –4.6). Bone density continued to increase during the rest of the year with cumulative bone mass increases of 51% at the lumbar spine, 36% at the total hip, and 11% at the distal forearm.
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FIG. 2. Markers of bone turnover after parathyroidectomy. Shaded areas represent the normal range for each marker.
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FIG. 3. Changes in BMD at lumbar spine, hip, and distal one third radius sites following parathyroidectomy. A, Percent increase in BMD. B, Change in T-scores.
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Case 2
A 63-yr-old woman from Barbados with no prior medical history presented to an outside institution in February 2003 with fatigue and hoarseness. She had no family history of nephrolithiasis or hyperparathyroidism. Physical examination was unremarkable. Serum biochemistry studies revealed a calcium of 13.9 mg/dl (normal, 8.4–9.8); albumin, 4.3 g/dl (normal, 4.0–5.0); phosphorus, 1.6 mg/dl (normal, 2.5–4.5); blood urea nitrogen, 15 mg/dl (normal, 7–20); and creatinine, 1.1 mg/dl (normal, 0.5–1.1). Intact PTH was 616 pg/ml (normal, 10–65). Bone turnover markers were elevated with total alkaline phosphatase activity of 597 U/liter (normal, 33–96), bone-specific alkaline phosphatase activity of 1445 U/liter (normal, 24–146), and osteocalcin of 189.6 ng/ml (normal, 7.2–27.9). 25-Hydroxyvitamin D was 9 ng/dl (normal, 10–68) and 1,25-dihydroxyvitamin D was 43 pg/ml (normal, 15–60). There was mild subperiosteal resorption on hand x-rays. She was referred to our medical center for parathyroidectomy. Neck exploration revealed a well-encapsulated and nonadherent parathyroid mass measuring 4.7 x 2.7 x 1.0 cm and weighing 7.1 g. Pathologic examination showed a benign oxyphil cell adenoma that stained positively for PTH. The patient was maintained on oral calcium (4 g daily) and calcitriol (0.5 µg daily) while in the hospital. Four days after surgery, serum calcium was 8.5 mg/dl, and she was discharged on 3 g of supplemental calcium and 1.5 µg of calcitriol daily. The patient was lost to follow-up after discharge.
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Discussion
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Parathyroid adenomas of the oxyphil cell type are rare, and until the late 1970s, these tumors were considered to be nonfunctional (1). Since then, several reports have demonstrated that oxyphil cells do produce PTH and may be involved in the pathogenesis of PHPT (3, 8, 10).
In this report, we describe two cases of oxyphil parathyroid adenomas that presented with clinical features of parathyroid carcinoma. In contrast to patients with mild, asymptomatic PHPT, those with parathyroid carcinomas tend to have significantly higher serum calcium levels. Moreover, serum PTH levels in parathyroid carcinoma are often 3–10 times the upper limit of normal, whereas in typical benign PHPT, values are frequently less than twice normal (20). The classical target organs of PTH, the skeleton and kidney, are also affected with greater frequency and severity in parathyroid carcinoma than in the modern presentation of benign PHPT (20, 21). The osteitis fibrosa cystica of case 2 is distinctly unusual in benign PHPT today.
Although pathologically benign, the size of the adenomas in the cases reported herein also resemble parathyroid cancer. The normal parathyroid gland weighs 25–35 mg, and the average parathyroid adenoma weighs 0.5 g (22), making the size of these oxyphil tumors (7 and 25 g) very atypical for benign parathyroid disease. Although the average size of oxyphil cell adenomas has been reported to be double that of the chief cell adenomas (6), the tumors in our patients are large even for this histologic type. Oxyphil cells are larger than chief cells and filled with abundant eosinophilic cytoplasm rich in mitochondria. The rate of PTH production from oxyphil cells is low, and it has been suggested that oxyphil adenomas causing hyperparathyroidism must be relatively large to overcome this inefficient hormone production (8).
Although the literature consistently shows that oxyphil cell adenomas are larger than chief cell adenomas, the biochemical features of patients with these tumors have not been well described. Most existing reports date from the 1980s and earlier, when PTH assay technology was less developed. In our cases, the PTH levels were exceptionally high for patients with normal renal function and were consistent with the PTH level in another recent report of an oxyphil adenoma (PTH of 1291 pg/ml, normal 10–54) (5). The mechanism by which adenomas of this cell type produce such high levels of PTH is unclear and warrants further investigation.
The marked elevation in PTH could account both for the extent of hypercalcemia and the degree of skeletal involvement in these patients. Although patient 1 did not have osteitis fibrosa cystica, there was evidence of severe demineralization at all measured sites on BMD. This differs from the usual pattern of skeletal involvement in benign PHPT, in which there is preferential loss of cortical bone mass (e.g. forearm) and relative sparing of cancellous bone (e.g. lumbar spine) (19). The extent of postoperative improvement in BMD also differed from that seen in patients with mild PHPT in whom modest increases (<10%) are expected at the spine and hip in the 1st postoperative yr (19). In our patient, the BMD increases were much more dramatic with gains of 51% at the lumbar spine and 36% at the total hip. Almost all of this increase occurred in the first few months after surgery. Impressive improvements in BMD after parathyroidectomy have previously been reported in patients with other forms of severe PHPT (23, 24), with most of the gains occurring by 1 yr after surgery. This report documents that most of the gain in bone mass occurs very early, during the first several months after surgery. Consistent with this, markers of bone turnover, which were increased 2 months after surgery, normalized by 8 months postoperatively. Most of the literature on bone turnover markers after parathyroidectomy describes patients with mild disease. Seibel et al. (25) found significant declines in markers of bone resorption (urinary pyridinoline and deoxypyridinoline) as early as 2 wk after successful parathyroidectomy. In contrast, alkaline phosphatase, a marker of bone formation, did not decrease significantly until 7 months after surgery. All markers of bone turnover returned to the normal range by 12 months (25). In another study describing a typical cohort of patients with benign PHPT, all markers of bone turnover declined by 3 months postoperatively. In contrast to our case, however, some markers were within the normal range preoperatively, and those that were abnormal were only slightly elevated (26). Taken together, the bone density and bone marker data are consistent with early and accelerated postoperative mineralization of the markedly increased mineralization space found in patients with severe PHPT.
In summary, benign oxyphil parathyroid adenomas may mimic parathyroid carcinoma both in terms of clinical features and tumor size. Cure may be associated with dramatic improvement in bone mass, evident within in the first several postoperative months. Oxyphil parathyroid adenomas should be considered in the differential diagnosis of patients with PHPT who present with severe or atypical biochemical and clinical manifestations.
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Footnotes
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We thank Dr. Virginia LiVolsi for confirming the diagnosis of oxyphil parathyroid adenoma.
Abbreviations: BMD, Bone mineral density; PHPT, primary hyper-parathyroidism.
Received August 13, 2004.
Accepted September 9, 2004.
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References
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Abstract
Introduction
