Hypercalcemic Crisis in a Patient with a Huge Mediastinal Atypical Parathyroid Adenoma

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1 AACE Clinical Case Reports Rapid Electronic Articles in Press Rapid Electronic Articles in Press are preprinted manuscripts that have been reviewed and accepted for publication, but have yet to be edited, typeset and finalized. This version of the manuscript will be replaced with the final, published version after it has been published in the print edition of the journal. The final, published version may differ from this proof. Case Report EP CR Hypercalcemic Crisis in a Patient with a Huge Mediastinal Atypical Parathyroid Adenoma Jenna L. Sarvaideo, DO 1, Jennifer Clark, MD 2, Kathryn E. Coan, MD 3, Oleksandr Kravtsov, MD 4, Amanda Jacquart, MS, CGC 5, Paul Knudson, MD 1, Diana Maas, MD 1, Robert D. Blank, MD-PhD 1, Tracy S. Wang, MD 3 and Joseph L. Shaker, MD 1 From: 1 Division of Endocrinology, Metabolism and Clinical Nutrition at Medical College of Wisconsin, Milwaukee, WI; 2 Division of Internal Medicine at Mayo Clinic, Rochester, MN; 3 Division of Endocrine Surgery at Medical College of Wisconsin, Milwaukee WI; 4 Division of Pathology at Medical College of Wisconsin, Milwaukee, WI; 5 Human and Molecular Genetics Center at Medical College of Wisconsin, Milwaukee, WI Running title: Huge Atypical Parathyroid Adenoma Corresponding address: Dr. Jenna L. Sarvaideo, Assistant Professor of Medicine, Division of Endocrinology, Medical College of Wisconsin, 9200 W. Wisconsin Avenue, Milwaukee, WI jsarvaideo@mcw.edu

2 Abstract Objective: To describe a patient who presented with hypercalcemic crisis and severe hyperparathyroidism who had urgent surgery. She was found to have a huge mediastinal atypical parathyroid adenoma (APA). We discuss our case, the difficulty discriminating an APA from parathyroid cancer, and the tools that help differentiate these conditions. Methods: We present the clinical manifestations, laboratory results, radiologic and surgical findings, and management in a patient with hyperparathyroid crisis. Discussion follows. Results: We report a case of a 39-year-old woman who presented with symptoms of severe hypercalcemia. Her intact parathyroid hormone (PTH) level was found to be markedly elevated, consistent with primary hyperparathyroidism (PHPT). Imaging revealed an anterior mediastinal mass, suggestive of possible ectopic parathyroid tissue. Urgent surgery and subsequent pathological study of the excised mass revealed a supernumerary 37.5 g parathyroid gland within the mediastinum surrounded by a rim of thymic tissue. Histologically, the adenoma did not meet the World Health Organization criteria for the diagnosis of parathyroid carcinoma; however, the adenoma had atypical pathologic features given an abnormal mitotic figure. Parafibromin staining was performed and largely negative in the center of the tumor. Germline analysis of the MEN1 and CDC73 genes revealed no pathogenic variants. Her postoperative course was complicated by hypocalcemia, but took several days to develop.

3 Conclusion: The distinction between APA and parathyroid carcinoma may be difficult and parafibromin staining and genetic testing for CDC73 mutations should be considered, as the results have implications for patient follow-up as well as for patients relatives. Abbreviations: APA = atypical parathyroid adenoma; PTH = parathyroid hormone; PHPT = primary hyperparathyroidism; PGP9.5 = protein gene product 9.5.

4 Introduction Hypercalcemic crisis due to PHPT is a rare, but life-threatening endocrine emergency, with serum calcium levels typically reaching >14 mg/dl. Presentation often involves mental status changes such as slurred speech or confusion. Other manifestations of hypercalcemia may also be present, including renal insufficiency, abdominal pain and nausea. Management of hypercalcemic crisis begins with aggressive volume resuscitation via intravenous hydration. Loop diuretics may be used once the patient is euvolemic, to prevent volume overload and to augment calciuresis. Calcitonin and bisphosphonates may also be administered to inhibit bone resorption; however, bisphosphonates do not reach peak effect until hours post infusion, should be used with caution in patients with renal impairment, and may interfere with normal bone remodeling once definitive treatment is undertaken. The calcimimetic agent, cinacalcet, which decreases calcium levels, may also be used, and has been shown to be useful as a bridge to definitive surgical management (1). Expeditious parathyroidectomy rapidly reduces serum calcium and PTH levels and may prevent or abate multisystem complications; it is, therefore, the definitive treatment and provides the best long-term outcomes (2). Herein, we report a patient with hypercalcemic crisis. Her clinical presentation is notable for an ectopic mediastinal parathyroid adenoma and its huge size. Interestingly, the histopathology was reported as atypical parathyroid adenoma.

5 Case Report A 39-year-old woman with a past medical history of obesity and in the first trimester of pregnancy presented to a community hospital with nausea and vomiting. Family history was notable for mother with diabetes mellitus type 2 and end-stage renal disease. On physical exam, she was alert and oriented. Thyromegaly without discrete nodules was noted. Vital signs were normal. The initial biochemical evaluation revealed a serum calcium level of 17.5 mg/dl, ionized calcium >2.05 mmol/l, PTH 812 and 1306 pg/ml, and creatinine level of 1.19 mg/dl (Table 1). Patient was found to have a fetal demise. She was treated with intravenous fluids and calcitonin, with a nadir of serum calcium of 13.9 mg/dl prior to discharge, with recommendations for outpatient follow-up with endocrinology. She re-presented one month later, having missed her scheduled follow-up appointments. She had persistent nausea, constipation, and developed slurred speech, dizziness and lethargy. Her serum calcium was >20.1 mg/dl, PTH 1,000 pg/ml, and creatinine 2.28 mg/dl. The patient was treated with intravenous normal saline, calcitonin, and cinacalcet, but her serum calcium levels remained elevated ( >20.1 mg/dl). Renal ultrasound demonstrated nephrocalcinosis. Preoperative imaging in anticipation of parathyroidectomy included Sestamibi-SPECT/CT, which revealed abnormal uptake in the superior anterior mediastinum only (Figure 1). The patient was subsequently transferred to our institution for definitive management. On admission, labs revealed a serum calcium of 17.8 mg/dl, ionized calcium 2.44 mmol/l, and PTH 1852 pg/ml. She had worsening renal function with creatinine 3.46 mg/dl and serum phosphorus 5.6 mg/dl. The 25-hydroxy vitamin D measured by

6 competitive electrochemiluminescence protein binding assay was low at 7.1 ng/ml. She was started on cautious vitamin D replacement of 2000 IU daily. Aggressive volume resuscitation and treatment with loop diuretics and cinacalcet was provided. Given previous imaging, CT of the neck and chest was performed, which confirmed the presence of a multi-lobulated anterior mediastinal mass. Cervical ultrasonography was non-localizing for parathyroid disease. The following day, the patient experienced worsening symptoms of nausea, vomiting, and debilitating joint pain, with persistent hypercalcemia ( mg/dl) and urgent parathyroidectomy was performed. Bilateral cervical exploration was performed, with identification and resection of an enlarged right superior parathyroid gland; right thyroid lobectomy was performed, given the presence of thyroid nodules on ultrasound. Both left-sided parathyroid glands appeared grossly normal. The mediastinal mass could not be reached via the cervical incision, and due to concern for a parathyroid carcinoma, median sternotomy was performed, so as not to rupture the parathyroid gland. This allowed for complete visualization of the mass directly anterior to the heart and its removal without intraoperative rupture. The mass was minimally adherent to the right pleura, but there was no evidence of invasion to the surrounding soft tissue (Figure 2). Immediately prior to surgery, the patient s PTH level was 2002 pg/ml. Intraoperative PTH levels were performed showing rapid decline of PTH levels upon removal of the anterior mediastinal mass (264 pg/ml and pg/ml). On postoperative day one, serum calcium decreased to mg/dl and PTH dropped to 26.6 pg/ml. The following day her serum calcium was mg/dl and PTH

7 decreased to 8.2 pg/ml. Her calcium along with her creatinine slowly normalized and her symptoms of joint pain, slurred speech, nausea and vomiting improved. At discharge, her serum calcium was 9.4 mg/dl and PTH 35.2 pg/ml. She was treated with calcium as carbonate and cholecalciferol. Patient was seen frequently upon discharge with laboratories about every 3 days. Her lowest serum calcium was 7.9 mg/dl on postoperative day 11. Her calcium carbonate was increased and calcitriol was added temporarily and calcium subsequently normalized. Unfortunately, patient was lost to follow-up. On histopathology, the anterior mediastinal mass weighed 37.5 grams and was well-circumscribed. There was no evidence of capsular or vascular invasion and only a single focus of abnormal mitosis, which is why this adenoma was deemed atypical. Parafibromin staining revealed strong nuclear positivity at the periphery of the nodule, but was largely negative for parafibromin at the center of the nodule. Germline genetic testing was performed on the patient; MEN1 and CDC73 gene sequencing and deletion/duplication analysis was completed, no pathogenic germline variants were identified. Furthermore, the right superior parathyroid gland was consistent with a parathyroid adenoma weighing 0.22 g. The resected right thyroid lobe revealed two microscopic foci of papillary carcinoma measuring <1 mm and 1.5 mm. Discussion We would like to highlight a few points from our case. We opted against the use of intravenous bisphosphonates because of our patient s renal impairment and because we did not want to interfere with normal bone remodeling after surgery. Postoperatively, we believe our patient s slow progression to hypocalcemia was because of kidney

8 disease and decreased renal clearance of calcium. We suspect the papillary thyroid cancer was an incidental finding as has been found in several autopsy studies (5,6). Finally, it is possible that severe hypercalcemia contributed to fetal demise. Although a discussion of mineral metabolism in pregnancy is outside the scope of this report, it is worth noting that total calcium levels may decrease in pregnancy due to decreased albumin. The ionized calcium does not change (7). There have been prior cases reporting hypercalcemic crisis secondary to ectopic parathyroid adenomas (3,4). Our patient not only had an ectopic mediastinal parathyroid adenoma causing hypercalcemic crisis, but it was deemed atypical due to abnormal mitosis. It can be difficult to truly distinguish an APA from parathyroid cancer. Fernandez- Ranvier et al. found that a palpable neck mass and hoarseness were almost exclusively present in patients with parathyroid carcinoma. Pathological diagnosis of parathyroid cancer usually includes capsular, vascular, and lymph node invasion, as well as distant metastasis (8). Our patient had no evidence of invasion, but because of marked cytological atypia, which can also be seen in parathyroid cancer, genetic analysis was pursued to further aid in our patient s diagnosis. Mutations in the CDC73 gene cause the hyperparathyroidism-jaw tumor syndrome, which is associated with a substantial risk for parathyroid cancer. Up to 70% of parathyroid carcinomas carry a CDC73 mutation, and in one-third of such cases, mutations are germline and have implications for relatives (9). Furthermore, prior to genetic analysis, immunostaining for parafibromin can be completed as tumors with CDC73 mutations are frequently associated with a loss of parafibromin. Staining for

9 parafibromin is relatively affordable and can easily be used in a pathology laboratory. Our patient s tissue sample was reported as largely negative for parafibromin, which further prompted us to recommend genetic analysis. Although not available to us, positive staining for protein gene product 9.5 (PGP9.5) is also associated with an increased risk of parathyroid malignancy (10). Other pathological markers have been used to predict parathyroid malignancy, but overlap with parathyroid adenomas has limited their utility. There have been reports of increased expression of Ki-67, cyclin D1 and Galectin-3 and decreased expression of p27 in parathyroid cancer as compared to parathyroid adenoma (1). PHPT due to an APA is a challenging diagnosis as this is a rare and ill-defined entity (11). Unfortunately, there are conflicting data in the literature on whether APAs recur (11,12,13). Further study in this area will provide valuable information in the classification of these tumors, their potential for recurrence or malignant transformation, and the most efficient monitoring for our patients. Finally, parafibromin staining and genetic testing for CDC73 mutations should be considered, as the results have implications for patient follow-up as well as for patients relatives.

10 References 1. Cetani F, Pardi E, Marcocci C. Update on parathyroid carcinoma. J Endocrinol Invest. 2016;39: Cannon J, Lew Jl, Solorzano CC. Parathyroidectomy for hypercalcemic crisis: 40 years experience and long-term outcomes. Surgery. 2010;148: Gratian, LF, Hyland, KA, Scheri, RP. Hyperparathyroid Crisis Due to Asymmetric Parathyroid Hyperplasia with a Massive Ectopic Parathyroid Gland. Endocrine Practice. 2014;20: Wang J, Murugan P, Amin K. et al. Brown Tumors and the Atypical Parathyroid Adenoma. AACE Clinical Case Reports Summer Harach, H. R., Franssila, K. O. and Wasenius, V.-M. Occult papillary carcinoma of the thyroid. A normal finding in finland. A systematic autopsy study. Cancer. 1985;56: Sampson RJ, Woolner LB, Bahn RC et al. Occult thyroid carcinoma in Olmsted county, minnestoa: Prevalance at autopsy compared with that in Hiroshima and Nagasaki. Japan. Cancer. 1974;34: Kovacs, CS. Maternal Mineral and Bone Metabolism During Pregnancy, Lactation, and Post-Weaning Recovery. Physiological Reviews Apr; Fernandez-Ranvier, G. G., Khanafshar, E., Jensen, K., Zarnegar, R., Lee, J., Kebebew, E., Duh, Q.-Y. and Clark, O. H. (2007), Parathyroid carcinoma, atypical parathyroid adenoma, or parathyromatosis?. Cancer.110:

11 9. Li Y, Simonds WF. Endocrine neoplasms in familial syndromes of hyperparathyroidism. Endocr Relat Cancer. 2015; Howell VM, Gill A, Clarkson A, et al. Accuracy of combined protein gene product 9.5 and parafibromin markers for immunohistochemical diagnosis of parathyroid carcinoma. J Clin Endocrinol Metab. 2009;94: McCoy KL, Seethala RR, Armstrong MJ, et al. The clinical importance of parathyroid atypia: is long-term surveillance necessary? Surgery. 2015;158: Ippolito G, Palazzo FF, Sebag F, et al. Intraoperative diagnosis and treatment of parathyroid cancer and atypical parathyroid adenoma. British Journal of Surgery. 2007; Kruijff S, Sidhu SB, Sywak MS, et al. Negative parafibromin staining predicts malignant behavior in atypical parathyroid adenomas. Ann Surg Oncol. 2014;

12 Table 1. Laboratory Data Variable Reference ranges at outside hospital Reference ranges at our institution Outside hospital, first visit**, T*=0 Outside hospital, first visit, T=5 Outside hospital, second visit, T=27 Outside hospital, second visit, T=32 Upon transfer to our institution, T=32 Day of surgery at our institution, T=34 T=27 T=32 T=39 Day of discharge at our institution, Calcium (mg/dl) > Albumin (g/dl) Intact PTH (pg/ml) Creatinine (mg/dl) Ionized calcium (mmol/l) > OH Vitamin D (ng/ml) Phosphorus (mg/dl) < TSH (uiu/ml) Alkaline Phosphatase unit/l *T= day since presentation **patient was in her first trimester of pregnancy

13 Figure 1: Single-photon emission computed g g p p tomography (SPECT) acquisition obtained at 3 hours demonstrating increased uptake in a lobulated mass in the anterior upper mediastinum

14 Figure 2: The anterior mediastinal mass weighed 37.5 grams. It was minimally adherent to the right pleura, but there was no evidence of invasion i to the surrounding soft tissue.