Elderly man presenting with asymptomatic hypercalcemia

Grand Rounds Elderly Man Presenting Hypercalcemia

Asymptomatic

Douglas A. Nuckols, MD, Terance T Tsue, MD, Janet M. Woodroof Daniel E. Bruegger, MD, and Larry A. Hoover, MD, FACS

An 81-year-old man was found to have an elevated serum calcium level (13.3 mg/dL) during routine health maintenance laboratory screening (reference range, 9 to 11 mg/dL). Repeat laboratory evaluation confirmed his calcium level to be elevated above the normal range (11.9 mg/dL). His documented serum calcium level 2 years before was 9.9 mg/dL. He had no complaints during his initial presentation. Review of systems showed a lo-lb weight loss in recent months. During further questioning he denied any bone, joint, or muscle aches; anorexia; dysphagia; abdominal pain; nausea; vomiting; constipation; polydipsia; nocturia; polyuria; dysequilibrium; fatigue; depression; confusion; headache; blurred vision; hoarseness; palpitations; or flushing. He admitted a distant history of peptic ulcer disease and mild hypertension but no history of renal calculi, pancreatitis, or neck masses. He had a 60 pack-year cigarette smoking history, although he had quit smoking 20 years before. He denied significant alcohol use. There was no history of head and neck irradiation or family history of head and neck malignancy. His past medical history was also significant for local resection of multiple skin cancers, hiatal hernia, hypercholesterolemia, colonic polyps, and paroxysmal atria1 fibrillation, for which he was orally anticoagulated. His past surgical history included an appendectomy many years ago and a transurethral resection of a bladder tumor 3 years before. Medications before surgery included digoxin, warfarin, quinapril HCl, quinidine gluconate, and pravastatin. He is allergic to iodinated contrast. During physical examination the patient was From the Departments of Otolaryngology-Head and Neck Surgery and Pathology, University of Kansas School of Medicine, Kansas City, KS. Address reprint reauests to Doualas A. Nuckols, MD, Department of Otolaryngology-Head and Neck Surgery; Universitv of Kansas School of Medicine. 3901 Rainbow Blvd, Kansas City, KS 66160. Copyright 0 1998 by W.B. Saunders Company 0196-0709/98/1905-0008$8.00/O American Journal of Otolaryngology,

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MD,

thin, well-nourished, and apparently healthy. His head and neck examination was unremarkable. Fiberoptic laryngoscopy showed symmetric-bilateral true vocal cord motion and no mucosal lesions or masses. His neck was supple without mass, lymphadenopathy, or thyromegaly. All cranial nerves were intact. His chest was clear to auscultation, and there were no abdominal masses or tenderness. There was no bone or muscle tenderness, and his strength was normal in all of his extremities. Laboratory tests showed his white blood cell and platelet count to be normal. His hematocrit was slightly low at 38% (reference range, 40% to 50%). Serum electrolyte, phosphorus (2.3 mg/dL), aspartate aminotransferase, alkaline phosphatase, uric acid, albumin, and digoxin levels were normal except for an elevated creatinine (1.4 mg/dL). Thyroid function tests, including thyroid stimulating hormone (TSH), thyroxine radioimmunoassay (RIA), and triiodothyronine (TJ uptake levels, were within reference limits. Anti-thyroglobulin and anti-microsomal antibodies were elevated at 28 U/mL (reference, 50.3 U/mL) and 3.4 U/mL (reference, 50.3 U/mL), respectively. Serum calcitonin level was 6.9 pg/mL (reference, 111.5 pg/mL). Parathyroid hormone immunoradiometric assay (PTH-IRMA) was found to be markedly elevated at 569 pg/dL (reference, 165 pg/dL). Repeat PTH-IRMA was 528 pg/ dL. The parathyroid hormone-related protein (PTHRP) level was 0.7 pg/mL (reference, 52.8 pg/mL). Subsequent iodine 131 radioisotope scanning of the thyroid gland showed a small, hypofunctioning left thyroid nodule. In addition, high-resolution thyroid sonography showed three isoechoic heterogeneous nodules in the medial left thyroid lobe. The largest nodule measured 1.1 cm and showed some cystic changes. There was a 6-mm hypoechoic right thyroid nodule. A 3.3-cm hypoechoic heterogeneous mass was also seen posterior to the right thyroid lobe. The inferior extent of the mass was at the right common carotid artery takeoff. No other extrathyroidal masses or cervical lymphadenopathy were observed (Fig 1). Thallium-sestamibi scanning failed to show uptake in the identified masses (Fig 2). Chest radiograph was without evidence of No 5 (September-October),

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Fig 1. Real time gray scale sonography of the thyroid identifies a large extrathyroidal mass adjacent to, but separate from, the lower pole of the right lobe of the thyroid. The mass measures approximately 3.3 x 1 .l x 1.3 cm and shows moderate heterogeneity with focal cystic areas.

pulmonary mass or cortical osteopenia. A surgical procedure was then performed. PRELIMINARY

DIFFERENTIAL

DIAGNOSIS

Hypercalcemia can have many causes. Spurious results can result from inappropriate blood sample handling or hyperproteinemic or hemoconcentration states, but were ruled out in the present case by test repetition and normal albumin and electrolyte levels, Uncommon causes of hypercalcemia include the use of thiazide diuretics or lithium, vitamin A and D intoxication, milk-alkali syndrome, and immobilization, which were unlikely in this case, given the negative history. Hypercalcemia is usually a late manifestation of chronic granulomatous diseases (ie, sarcoid) and was unlikely in the present case because of the negative history and lack of protean physical findings. Familial predilection for hypercalcemia is usually autosomal dominant and includes familial hyperparathyroidism, familial hypocalciuric hypercalcemia (FHH), and multiple endocrine neoplasia (MEN) syndrome type I and IIA. These disorders were unlikely given the patients’ negative family history and his older age at presentation. FHH is usually associated with only mildly elevated PTH levels, unlike the markedly elevated levels detected in the present case. In addition, MEN type I was unlikely given the absence of evidence for concurrent pituitary or pancreatic neoplasms. MEN IIA was a possibility given the concurrent presence of a thyroid nodule (ie, medullary thyroid carcinoma) and

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potentially metastatic or parathyroid mass in a patient with hypertension. The normal serum calcitonin level and only mild hypertension, however, argue against this origin. The incidence of noncalcitonin-secreting medullary thyroid carcinomas tends to be very 1ow.l In patients with elevated calcium secondary to malignancy, clinically obvious disease is usually present. The mechanism for this calcium increase in serum is either metastatic or bulky disease with extensive boney involvement (ie, myeloma or breast carcinoma) or paraneoplastic humoral secretion of an osteolytic PTH-RP (ie, lung, head and neck, esophageal, and bladder carcinomas). Both of these possibilities were considered in the present patient because of the presence of a synchronous extrathyroidal nodule and because the majority of adult, nonthyroid neck masses are neoplastic in origin, with less than 15% congenital or inflammatory. Additionally, the pres-

Fig 2. Thallium sestamibi scanning shows normal uptake within the major salivary glands as well as the thyroid. No evidence of extrathyroidal uptake is noted on (A) initial scanning or (6) after pertechnetate subtraction.

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ence of a thyroid cold nodule and contralatera1 neck mass is certainly worrisome for a primary thyroid malignancy. Hashimoto’s thyroiditis, as confirmed by the antithyroglobulin and antimicrosomal antibodies found in the discussed case, has been associated with a higher incidence of papillary adenocarcinoma. However, the incidence of hypercalcemia due to papillary adenocarcinoma would not be expected to be significant. Arguments against the metastatic or paraneoplastic origins include the paucity of symptoms and lack of clinical findings of widely disseminated neoplastic disease, a negative head and neck examination, the abscence of osteolytic boney changes or masses on the chest radiograph, and normal alkaline phosphatase and PTH-FW levels. In addition, extraparathyroid PTHproducing tumors generally are not associated with an elevated serum PTH. Primary hyperparathyroidism is the most common cause of asymptomatic hypercalcemia in the outpatient setting3 and is usually the result of an isolated adenoma (83%) or four-gland hyperplasia (13%). Urolithiasis and osteopenia were the most common signs of primary hyperparathyroidism; however, now with the advent of routine blood chemistries asymptomatic hypercalcemia is the most common initial finding (18% to 51%) in the majority of patients.4 Secondary and tertiary hyperparathyroidism are rare in the absence of renal disease and normal phosphate levels, as in this case. Abnormal production of calcitriol or skeletal resistance to parathyroid hormone can be associated with secondary or tertiary hyperparathyroidism, although features of high-turnover bone disease (ie, pruritis, periartitular calcification) were not present in this particular patient. The preoperative ultrasonographic findings of a right extrathyroidal mass with elevated PTH-IRMA is highly suggestive of a primary process of the parathyroids, most likely a large adenoma or carcinoma. High resolution ultrasonography cannot reliably distinguish carcinomas from large adenomas, except in cases with extensive invasion of surrounding structures. 5 Other radiographic modalities (ie, magnetic resonance imaging and computed tomography) have not had better success making the preoperative distinction.6 Some uncertainty was raised as well following the absence of detection by both

thallium uptake and sestamibi scanning (Fig 2). The asymptomatic nature of the patient’s moderate hypercalcemia pointed toward a more benign adenomatous process. In contrast, the patient’s older age and extremely elevated PTH-IRMA were more characteristic of parathyroid carcinoma.7 PATHOLOGIC

DIAGNOSIS

The patient was brought to the operating room and underwent neck exploration through a standard thyroidectomy incision. Both recurrent laryngeal nerves were identified and preserved. The right neck mass was located posterior-lateral to the right thyroid lobe and was carefully removed with a surrounding cuff of normal tissue. The mass was firm with some fibrous adhesions noted to the surrounding tissue, but grossly, the mass did not appear to invade the surrounding structures. A soft ipsilateral paratracheal node was identified and removed. No other lymphadenopathy was palpable intraoperatively. A total thyroidectomy was performed to address the thyroid nodules. Three parathyroid glands, including the right superior and both left parathyroids were identified and were non-hyperplastic by appearance. Frozen section pathologic evaluation at the time of surgery showed the right neck mass to be suspicious for parathyroid carcinoma. Frozen section of the thyroid nodule showed chronic thyroiditis. The remainder of the specimens were sent for permanent section. Gross pathologic examination of the right extrathyroidal mass showed a 3.0- X 2.0- X 2.0-cm tan-brown mass weighing 4.5 g. Histopathologic examination of the extrathyroidal mass showed parathyroid cells arranged in nests and sheets, separated by fibrous septae (Fig 3). Cytologically, the cells were monomorphic with very little nuclear variation. Very rare mitotic figures were identified, and necrosis was absent. The capsule was focally thickened, and several sites of capsular invasion and infiltration into the surrounding adipose tissue were observed. Immunohistochemical stains were negative for calcitonin and thyroglobulin. These findings were interpreted as a low-grade parathyroid carcinoma. Histopathologic examination of the total thyroidectomy specimen showed typical features of Hashimoto’s thyroiditis, including prominent onco-

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Fig 3. Low power ence of a parathyroid adipose tissue (left graph shows nests that display minimal

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photomicrograph shows the presneoplasm invading the adjacent side). Higher power photomicroof monomorphic parathyroid cells cytologic atypia (right side).

cytic change of follicular cells (Hurthle cell change) and chronic inflammation with lymphoid follicles. The paratracheal lymph node was without histopathologic abnormality. CONCLUSION Parathyroid carcinoma is a rare, locally aggressive neoplasm. It is the rarest cause of primary hyperparathyroidism, accounting for 0.5% to 4.0% of patients presenting with hypercalcemia. 8,gThe presentation of parathyroid carcinoma is widely variable, and the preoperative distinction of parathyroid carcinoma from adenomatous primary hyperparathyroidism is seldom possible. Even postoperatively distinguishing benign from malignant disease is often difficult and is sometimes only possible in cases of tumor recurrence.1° The average age at presentation for parathyroid carcinomas is 44 years old, with 84% of the patients presenting in the 3rd to 6th decades.* Carcinomas tend to occur equally in both men and women, as opposed to adenomas, which have a female sex preponderance.” Parathyroid carcinomas also tend to be larger than adenomas, with the average size being 3.3 cm and weighing 12 g; nearly half of carcinoma patients present with a palpable neck mass.8J2J3 One should also suspect a parathyroid carcinoma when the serum calcium levels exceed 14 mg/dL. 7~12Approximately 90% of parathyroid carcinomas present with a serum calcium greater than 13 mg/dL.7 In addition, the PTH-IRMA rises to three to four times

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normal range, whereas benign causes of primary hyperparathyroidism typically have less elevated levels.7J2 Some have found PTH levels to be on average 10.2 times the upper limit of normal.14 Preoperative localization is similar to that used for other causes of primary hyperparathyroidism. Various methods of imaging have been tried, such as computed tomography magnetic resonance imaging, ultrasound, selective venous catheterization and sampling, thallium-technetium subtraction, and digital subtraction angiography; however, no single modality is completely satisfactory. In addition to ultrasonography, magnetic resonance imaging has excellent specificity for identifing parathyroid abnormalities; however, neither study is useful in differentiating benign from malignant disease unless gross local invasion can be shown.” As seen in our patient, thallium-sestamibi scanning does not visualize all parathyroid abnormalities. Primary medical therapies in the treatment of parathyroid carcinoma, including chemotherapy and radiation therapy, have been largely unsuccessful .7J5 The main therapeutic modality is complete surgical extirpation with adequate surgical margins.16J7 The success of adjuvant radiation and chemotherapy has been difficult to assess accurately given the relatively rare incidence of this disease.7J5 Neutron beam irradiation is more effective in slow-growing tumors and should be considered as an adjuvant if complete en bloc resection is not possible. l6 Monitoring for recurrence of this disease is typically performed by following serum calcium and PTH-IRMA levels. Thirty percent of all patients develop metastasis, which most commonly recur in the regional lymph nodes (15%) lung (12%) liver (8%), and bone (8%).* The time until recurrance appears to be variable.14 If the tumor does recur within 2 years after resection, the prognosis is poor.a Local resection of recurrence is palliative but indicated to control hypercalcemia. l6 Long-term survival is generally poor without complete surgical excision.8J2 Most patients succumb to the effects of hypercalcemia rather than the spread of the disease locally or distantly. If the tumor is removed completely at initial surgery, there is a 50% to 70% chance of finding no evidence of disease at 5 years8J2

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Postoperatively, our patient was started on thyroid hormone replacement. He required transient oral calcium supplementation. Because of close surgical margins, he underwent adjuvant photon radiation therapy. Follow-up examination showed no recurrent neck masses. Postoperative serum calcium and PTH-IRMA levels have been normal. REFERENCES 1. Schifter S, Williams ED, Craig RK: Calcitonin generated peptide and calcitonin in medulary thyroid cancer. Clin Endocrinol (OxfJ 25:703-710, 1986 2. Wirtschafter A, Schmidt R, Rosen D: Expression of the RET/PTC fusion gene as a marker for papillary carcinoma in Hashimoto’s thyroiditis. Laryngoscope 107:95100,1997 3. Belezikian JP: Management of acute hypercalcemia. N Engl J Med 326:1196-1203,1992 4. Heath H, Hodgson SF, Kennedy MA: Primary hyperparathyroidism: Incidence, morbidity, and potential economic impact on the community. N Engl J Med 302:189193,198O 5. Edmonson GR, Charboneau JW, James EM, et al: Parathyroid carcinoma: High frequency sonographic features. Radiology 161:65-67, 1986 6. Spritzer CE, Gefter WB, Hamilton R, et al: Abnormal-

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parathyroid glands: High-resolution MR imaging. Radiology 162:487-491,1987 7. Holmes EC, Morton DL, Ketchum AS: Parathyroid carcinoma: A collective review. Ann Surg 169:631-640, 1969 8. Schantz A, Castleman B: Parathyroid carcinoma. Cancer 31:600-605,1973 9. Pyrah LN, Hodgkinson A, Anderson CK: Primary hyperparathyroidism. Br J Surg 53:295-316, 1966 10. Levin KE, Gafante M, Clark OH: Parathyroid carcinoma versus parathyroid adenoma in patients with profound hypercalcemia. Surgery 101:649-660,1987 11. Blacker JE, Hoover LA, Zuckerbraun L, et al: A svstematic approach to parathvroid surgerv. Clin Otolarvn&111:4354>i,l986 _ ” - _ 12. Warm CA, Gaz RD: Natural historv of narathvroid carcinoma.“AmJ Surg 97:522-526,1985 a A i 13. Washburn MA, Chonkich GD, Chase DR, et al: Parathyroid carcinoma: Two new cases-diagnosis, therapy, and treatment. Laryngoscope 97:215-218,1987 14. Wynne AG, Heerden JV, Carney JA, et al: Parathyroid carcinoma: Clinical and pathologic features in 43 patients. Medicine 71:197-205,X992 15. Anderson BJ, Samaan NA: Parathyroid carcinoma: Features and difficulties in diagnosis. Surgery 94:906-915, 1983 16. Fyfe ST, Hoover LA, Zuckerbraun L, et al: Parathyroid carcinoma: Clinical presentation and treatment. Am J Otolaryngol11:268-273, i990 17. Jarman WT, Myers RT, Marshall RB: Carcinoma of the parathyroid. Arch Surg 113:123-125, 1978