MEDIASTINAL PARATHYROID ADENOMA MIMICKING CANCER METASTATIC TO BONE
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1 Case Report MEDIASTINAL PARATHYROID ADENOMA MIMICKING CANCER METASTATIC TO BONE Ping Yu Xiong, MD 1 ; Joshua Lakoff, MD, FRCPC 2 ; Robyn L. Houlden, MD, FRCPC 2 ABSTRACT Objective: Mediastinal parathyroid adenomas are rare in clinical practice. We report a case that mimicked cancer metastatic to bone on initial workup to increase awareness of this differential diagnosis in the evaluation of patients presenting with multiple foci of uptake on technetium bone scanning without an established primary neoplasm. We also outline other diagnostic pitfalls that may be encountered in the workup and management of this uncommon condition. Methods: A 26-year-old man presented with a several-month history of back and pelvic pain. Initial plain radiography showed multiple lytic lesions in the pelvis. Technetium bone scanning revealed multiple foci of increased uptake in the thoracic vertebrae, ribs, clavicles, pelvis, and extremities. Results: A computed tomography (CT) scan demonstrated a mediastinal mass and an initial diagnosis of metastatic disease from a mediastinal primary malignancy was entertained. Further workup revealed markedly elevated serum ionized calcium of 1.97 mmol/l (normal, 1.19 to 1.31 mmol/l) and parathyroid hormone (PTH) of Submitted for publication July 27, 2016 Accepted for publication December 15, 2016 From the 1 Department of Medicine, and 2 Division of Endocrinology, Queen s University, Kingston, Ontario, Canada. Address correspondence to Dr. Joshua Lakoff, Division of Endocrinology, Hotel Dieu Hospital, 166 Brock Street, Kingston, ON K7L5G2, Canada. jml7@queensu.ca DOI: /EP CR To purchase reprints of this article, please visit: pmol/l (normal, 2.0 to 9.4 pmol/l). Parathyroid scintigraphy showed intense tracer accumulation in the anterior mediastinal mass. A median sternotomy was performed and histopathology was consistent with a parathyroid adenoma. Postoperatively, the patient s ionized calcium and PTH levels normalized and pain resolved. Conclusion: This case illustrates two clinical pearls: (1) brown tumor secondary to hyperparathyroidism is an important differential in the evaluation of patients presenting with widespread lytic bone lesions on CT or multiple foci of uptake on bone scan; and (2) the mediastinum is a rare location but should be considered in the workup of primary hyperparathyroidism. (AACE Clinical Case Rep. 2017;3:e344-e348) Abbreviations: CT = computed tomography; PTH = parathyroid hormone INTRODUCTION Primary hyperparathyroidism has an incidence of 1 to 7 per 1,000, with the highest rates in older females where it is 2 to 3 times more common than in men (1,2). The most common cause is a single parathyroid adenoma, which occurs in 75 to 85% cases (3). An ectopic location in the mediastinum is rare. In one study of 922 patients undergoing parathyroidectomy for hyperparathyroidism, only 34 (3.5%) were found to have a mediastinal parathyroid adenoma (3). Because they are uncommon, diagnosis and management of a mediastinal parathyroid adenoma can be challenging. The brown tumor is a rare clinical consequence of untreated severe primary or secondary hyperparathyroidism and represents a region of osteitis fibrosa cystica (4). Typical locations include the pelvis, ribs, clavicles, and e344 AACE CLINICAL CASE REPORTS Vol 3 No. 4 Autumn 2017
2 Mediastinal Parathyroid Adenoma, AACE Clinical Case Rep. 2017;3(No. 4) e345 extremities (5). There are several case reports of brown tumors mimicking cancer metastatic to bone (6-10), but only a few reported cases of brown tumors associated with ectopic parathyroid adenomas (11,12). We present the case of 26-year-old male with primary hyperparathyroidism to illustrate a number of clinical pearls. Initial imaging, including technetium bone scanning to investigate back pain, revealed multiple areas of uptake and an initial diagnosis of cancer metastatic to bone was erroneously made. He was subsequently found to have elevated ionized calcium and parathyroid hormone (PTH) suggestive of primary hyperparathyroidism. Computed tomography (CT) and parathyroid scanning confirmed an ectopic location in the mediastinum, illustrating that brown tumors can be associated with ectopic parathyroid adenomas and can mimic cancer metastatic to bone. CASE REPORT A 26-year-old male presented to his family physician with a several-month history of pelvic and back pain that occurred after a fall. Past medical history included a 1-year history of hypertension well managed with bisoprolol 5 mg daily. Review of systems was otherwise unremarkable with no constitutional symptoms such as weight loss or night sweats. Physical examination was unremarkable. The pain was initially treated with over the counter analgesics. Due to the persistence of pain, plain radiography of the lumbar spine was obtained and revealed a cm lucency involving the lateral aspect of the left sacral wing. An urgent CT of the pelvis was performed and revealed multiple aggressive bony lesions throughout the pelvis most consistent with a metastatic process. A subsequent technetium bone scan showed numerous foci of intensely hypermetabolic bone lesions also suggestive of metastatic bone disease (Fig. 1). A follow-up CT scan of the chest, abdomen, and pelvis revealed a cm anterior mediastinal mass, abutting the ascending aorta, and widespread multifocal osteolytic lesions. Nonobstructing bilateral nephrolithiasis was noted (Fig. 2). Initial bloodwork demonstrated an elevated creatinine of 139 µmol/l (normal, 0 to 85 µmol/l), an estimated glomerular filtration rate of 60 ml/min/1.73 m 2 (normal, 60 to 150 ml/ min/1.73 m 2 ), elevated alkaline phosphatase of 917 U/L (normal, 45 to 129 U/L), and elevated ionized calcium of 1.79 mmol/l (normal, 1.19 to 1.31 mmol/l). PTH was not measured with initial testing. The patient was admitted to hospital with a presumptive diagnosis of metastatic malignancy with a suspected mediastinal primary. Further investigations revealed markedly elevated PTH of pmol/l (normal, 2.0 to 9.4 pmol/l), with an elevated serum ionized calcium of 1.97 mmol/l (normal, 1.19 to 1.31 mmol/l). A secondary review of radiographs revealed subperiosteal resorption and the differential of extensive brown tumors was raised. Parathyroid scintigraphy showed intense tracer accumulation in the anterior mediastinal mass (Fig. 3 A). Given the significant elevation in PTH, the possibility of parathyroid carcinoma metastatic to bone was considered. The patient underwent a median sternotomy with resection of the mediastinal mass. Histopathologic studies were consistent with a parathyroid adenoma measuring cm. Postoperatively, the patient was monitored in the intensive care unit (ICU). Serum PTH levels normalized immediately postoperatively to 3.9 pmol/l and reached a nadir of 2.6 pmol/l by postoperative day 2, but after 4 days became elevated again at 16.3 pmol/l with a low-normal ionized calcium (Table 1). The presumed cause of the elevated PTH was felt to be vitamin D deficiency as the pre-operative 25-OH vitamin D level was low at <11 nmol/l (normal, 75 to 225 nmol/l). With vitamin D supplementation, calcium and PTH levels normalized (Table 1). Family history was negative for known hypercalcemia, hyperparathyroidism, or multiple endocrine neoplasia (MEN) syndrome. Given his young age (under 45 years), he was referred to Medical Genetics; testing for mutations in MEN1 (menin) and CDC73 (cell division cycle 73, formerly HRPT2) is pending. DISCUSSION A number of diagnostic pitfalls were encountered in the workup of this young man with back and pelvic pain. Multiple lytic lesions on plain radiographs and increased uptake on bone scanning raised the possibility of cancer metastatic to bone. Further testing suggested biochemical evidence of primary hyperparathyroidism with elevated serum ionized calcium and PTH levels. In hindsight, several studies have indicated that brown tumors with primary hyperparathyroidism can mimic bony metastases (6-10). The next diagnostic pitfall was the identification of an ectopic parathyroid adenoma. In patients with primary hyperparathyroidism, about 6 to 16% of cases have ectopic parathyroid adenomas (13). Ectopic parathyroid glands are most commonly found in the thymus (38%), retroesophageal region (31%), and intrathyroidal (18%) (13). Imaging studies are often performed to aid diagnosis of an ectopic parathyroid adenoma. Commonly used modalities include ultrasound, CT or magnetic resonance imaging, and technetium sestamibi scintigraphy. Ultrasound is commonly used due to its low cost and convenience, but it has poor sensitivity ( 30%) for locating ectopic glands (14). Even the sensitivity for localization of enlarged parathyroid glands in the normal anatomical location varies greatly (44 to 87%) and depends on operator skill and experience (14). In comparison, parathyroid scintigraphy and CT imaging have a much higher sensitivity than ultrasound for localizing parathyroid adenoma (71 to 93% and 76 to 83%, respectively) (14) and the sensitivity can be up to 100%
3 e346 Mediastinal Parathyroid Adenoma, AACE Clinical Case Rep. 2017;3(No. 4) A B C D Fig. 1. (A) Front and (B) back images of the bone scan showing numerous foci of intensely hypermetabolic bone lesions. (C) and (D) showing repeat bone scan 5 months after surgery. A B Fig. 2. Selected computed tomography images showing (A) sagittal cross section of the anterior mediastinal mass (circled in green) and (B) bone lesion in the lumbar spine. when parathyroid scintigraphy and CT imaging are used in combination (15). The next diagnostic pitfall was the consideration that this young man might have metastatic parathyroid carcinoma. The incidence of parathyroid cancer is rare; it accounts for between 0.5 and 5% of all cases of primary hyperparathyroidism (16). It poses a diagnostic challenge due to the lack of features that can definitively distinguish malignant from benign disease early in the clinical course (17). PTH levels are typically 5 to 10 times higher than the upper range of normal in malignant cases, while benign disease usually shows a more modest increase (18). Our patient s high PTH level contributed to the consideration that he might have parathyroid carcinoma. However, only 4.5% of patients with parathyroid cancer present with distant metastasis (16), likely because most patients present earlier from symptoms of hypercalcemia, bone pain, and renal stones. Brown tumors are commonly mistaken as bony metastases (6-10). Subperiosteal bone resorption is the most specific finding commonly seen in patients with brown tumors secondary to hyperparathyroidism. Roughly two thirds of patients with hyperparathyroidism have subperiosteal resorption seen on radiography (19,20). In this case, the patient s bony lesions were initially thought to be metastatic lesions from an unknown primary neoplasm. It was
4 Mediastinal Parathyroid Adenoma, AACE Clinical Case Rep. 2017;3(No. 4) e347 A B Fig. 3. Parathyroid scintigraphy showing (A) intense tracer accumulation in the anterior mediastinal mass (circled in green) and (B) repeat parathyroid scintigraphy after resection of the mediastinal mass. Table 1 Parathyroid Hormone and Ionized Calcium Levels Pre and Post Anterior Mediastinal Mass Resection Date Parathyroid hormone a (normal, pmol/l) Ionized calcium a (normal, mmol/l) Preoperative Immediately postoperatively Postoperative day Postoperative day Postoperative day Postoperative day Postoperative day Postoperative day Postoperative day Postoperative day months postoperative a Values in bold are outside of normal range. not until later, after more detailed review, that subperiosteal resorption was noted. The presence of subperiosteal resorption supports the diagnosis of hyperparathyroidisminduced bone disease, but its absence does not rule out the presence of hyperparathyroidism. The last diagnostic pitfall was the initial rebound elevation of PTH levels postoperatively, raising the consideration that another parathyroid adenoma might exist. PTH rebound effect has been reported to occur in approximately 30% of patients undergoing resection of parathyroid adenoma (21); and is associated with higher pre-operative PTH and calcium levels, lower vitamin D levels, and larger parathyroid adenomas (22). In this case, the rebound elevation of PTH postoperatively in the presence of low-normal calcium levels was felt to be from secondary hyperparathyroidism related to low vitamin D levels. The patient was carefully monitored in the ICU postoperatively due to concerns that he was at high risk for hungry bone syndrome. Risk factors for this condition include larger volume adenomas, older age, associated bone disease, and vitamin D deficiency (23). Fortunately, the patient did not develop this complication with the lowest postoperative ionized calcium level occurring on postoperative day 6 at 1.17 mmol/l (normal, 1.19 to 1.31 mmol/l). During postoperative follow-up, calcium and PTH levels stabilized within the normal range once vitamin D was adequately replaced. A bone scan 5 months post-surgery showed persistent multiple lesions varying in osteoblastic activity; however, most demonstrated interval reduction in activity. Genetic testing is pending and is recommended in such cases of young age of onset (<45 years) given the 10% risk of sporadic germline mutation detectable in 1 of 11 genes associated with hyperparathyroidism (24,25). CONCLUSION This case of a 26-year-old man who presented with back and pelvic pain illustrates two clinical pearls. Bone scanning revealed multiple areas of uptake raising an initial
5 e348 Mediastinal Parathyroid Adenoma, AACE Clinical Case Rep. 2017;3(No. 4) diagnosis of cancer metastatic to bone. It is important to recognize that brown tumors secondary to hyperparathyroidism can mimic this condition, and serum ionized calcium and PTH levels should be measured. This man was subsequently found to have a biochemical picture compatible with primary hyperparathyroidism. Investigations revealed a mediastinal location illustrating that although rare, this location must be considered in the workup of primary hyperparathyroidism. DISCLOSURE The authors have no multiplicity of interest to disclose. REFERENCES 1. Yeh MW, Ituarte PHG, Zhou HC, et al. Incidence and prevalence of primary hyperparathyroidism in a racially mixed population. J Clin Endocrinol Metab. 2013;98: Fraser WD. Hyperparathyroidism. Lancet. 2009;374: Nilubol N, Beyer T, Prinz RA, Solorzano CC. Mediastinal hyperfunctioning parathyroids: incidence, evolving treatment, and outcome. Am J Surg. 2007;194: Parisien M, Silverberg SJ, Shane E, Dempster DW, Bilezikian JP. Bone disease in primary hyperparathyroidism. Endocrinol Metab Clin North Am. 1990;19: Proimos E, Chimona TS, Tamiolakis D, Tzanakakis MG, Papadakis CE. Brown tumor of the maxillary sinus in a patient with primary hyperparathyroidism: a case report. J Med Case Rep. 2009;3: Meydan N, Barutca S, Guney E, et al. Brown tumors mimicking bone metastases. J Natl Med Assoc. 2006;98: Ullah E, Ahmad M, Ali SA, Redhu N. Primary hyperparathyroidism having multiple brown tumors mimicking malignancy. Indian J Endocrinol Metab. 2012;16: Morán LM, Moeinvaziri M, Fernández A, Sánchez R. Multiple brown tumors mistaken for bone metastases. Computed tomography imaging findings. Egypt J Radiol Nucl Med. 2016;47: Su AW, Chen CF, Huang CK, Chen PCH, Chen WM, Chen TH. Primary hyperparathyroidism with brown tumor mimicking metastatic bone malignancy. J Chin Med Assoc. 2010;73: Sager S, Aliyev A, Halac M, Oztürk T. Positron emission tomography/computed tomography imaging of brown tumors mimicking multiple skeletal metastases in patient with primary hyperparathyroidism. Indian J Endocrinol Metab. 2012;16: Mohan M, Neelakandan RS, Siddharth D, Sharma R. An unusual case of brown tumor of hyperparathyroidism associated with ectopic parathyroid adenoma. Eur J Dent. 2013;7: Bernal P, Ucros G, Mejia A. Mediastinal parathyroid adenoma and brown tumors. World J Nucl Med. 2012;11: Roy M, Mazeh H, Chen H, Sippel RS. Incidence and localization of ectopic parathyroid adenomas in previously unexplored patients. World J Surg. 2013;37: Haber RS, Kim CK, Inabnet WB. Ultrasonography for preoperative localization of enlarged parathyroid glands in primary hyperparathyroidism: comparison with (99m)technetium sestamibi scintigraphy. Clin Endocrinol (Oxf). 2002;57: Lumachi F, Tregnaghi A, Zucchetta P, et al. Technetium-99m sestamibi scintigraphy and helical CT together in patients with primary hyperparathyroidism: a prospective clinical study. Br J Radiol. 2004;77: Lee PK, Jarosek SL, Virnig BA, Evasovich M, Tuttle TM. Trends in the incidence and treatment of parathyroid cancer in the United States. Cancer. 2007;109: McClenaghan F, Qureshi YA. Parathyroid cancer. Gland Surg. 2015;4: Sharretts JM, Kebebew E, Simonds WF. Parathyroid cancer. Semin Oncol. 2010;37: Weiss A. Incidence of subperiosteal resorption in hyperparathyroidism studied by fine detail bone radiography. Clin Radiol. 1974;25: Wang CA, Guyton SW. Hyperparathyroid crisis: clinical and pathologic studies of 14 patients. Ann Surg. 1979;190: Ferrer-Ramirez MJ, Arroyo Domingo M, López-Mollá C, et al. Transient rise in intact parathyroid hormone concentration after surgery for parathyroid adenoma. Otolaryngol Head Neck Surg. 2003;128: Biskobing DM. Significance of elevated parathyroid hormone after parathyroidectomy. Endocr Pract. 2010;16: Witteveen JE, van Thiel S, Romijn JA, Hamdy NAT. Hungry bone syndrome: still a challenge in the post-operative management of primary hyperparathyroidism: a systematic review of the literature. Eur J Endocrinol. 2013;168:R45-R Eastell R, Brandi ML, Costa AG, D Amour P, Shoback DM, Thakker RV. Diagnosis of asymptomatic primary hyperparathyroidism: proceedings of the Fourth International Workshop. J Clin Endocrinol Metab. 2014;99: Thakker RV. Genetics of parathyroid tumours. J Intern Med. 2016;280:
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