Atypical with Findings of Severe Hypercalcemia and Hyperparathyroidism

Garrett Mockler, MD PGY-2 Faculty advisors: Dr Jeffrey Harrison, Dr Birgit Khandalavala Co-author of original paper: Dr Steve Miller and Dr Birgit Khandalavala Disclosures and conflict of interest: None Objectives

1) Evaluation of patients with thyroid and parathyroid masses 2) Evaluation of patients with hypercalcemia 3) Evaluation of patients with hyperparathyroidism Reminder!

It is easy to criticize in hindsight The best way to look at an error is through root cause analysis. We are not doing that today as the point of this lecture is not to focus on morbidity and mortality but to use this case as a learning point for assessing a patient with elevated calcium and parathyroid levels. We are here to learn! Case presentation

67 yo Asian F presented to ENT clinic for anorexia, fatigue, weakness, rib pain, constipation, malaise, a documented weight loss of 30 lbs over 7 months, and a large left neck mass. Prior history from PCP: 12/08/14- serum Calcium elevated 10.6 (8.6-10.2). TSH normal 12/09/15- Routine health maintenance. Osteoporosis noted. Ca 11.6 (8.7-10.3) 5/02/16- US for Lt thyroid mass: right lobe 1.6 cm and left lobe 3.3 cm. Left lobe had a 3 cm dominate, solid mass Case presentation (cont) PCP timeline (cont) 5/16/16- US guided FNA: lymphocytitic thyroiditis 4/27/16- Swollen glands, no mention in PE, given Biaxin 500 mg BIDx 7 days 7/27/16- Constipation, given Linzess and colonoscopy ordered 8/31/16- normal colonoscopy 12/16/16- Documented weightloss of 22 lbs in 5 months. No mention of thyroid mass in PE but mention in assessment. Ca 16.0 (8.5-10.1) Referral to ENT Case presentation (cont) 12/19/16 Repeat calcium 15.0 (8.5-10.1) 12/20/16 Sees ENT. Visibly enlarged left thyroid that is mobile anterior- posteriorly but not superior-inferiorly. Non-tender. Nasolaryngeal endoscopy performed which was normal. Repeat labs ordered and a left thyroid lobectomy recommended. FNA repeated as well. TSH was normal at 0.426 mIU/L. Free T4 normal at 1.02 ng/dL Calcium 11.6 mg/dL. Repeat calcium 3 days later 15.0 mg/dL Alkaline phosphatase 223 U/L. Repeat 3 days later 233 U/L Hypercalcemia Multiple causes – Primary hyperparathyroidism – Inherited: MEN, Familial isolated hyperparathyroidism, Hyperparathyroidism-jaw tumor syndrome – Familial hypocalciuric hypercalcemia – Renal failure – Malignancy – Vitamin D intoxication – Chronic granulomatous disorders – Medications – Pituitary or adrenal cause – Immobilization – Nutrition – Milk-alkali syndrome Work-up algorithm for hypercalcemia Back to our case

Repeat Calcium 16.0 mg/dL iPTH 1311 pg/mL

Creatinine normal

According to algorithm, DDx: primary hyperparathyroidism, MEN syndromes Primary Hyperparathyroidism

• “Stones, bones, groans with psychiatric overtones”

• Symptoms not necessarily due to hypercalcemia • Anorexia • Nausea • Constipation • Polydipsia • Polyuria

• Nephrolithiasis most common complication of primary hyperparathyroidism (15-20% of newly diagnosed patients)

• Patients with primary hyperparathyroidism and vitamin D deficiency have more significant disease with larger adenomas, increased PTH concentrations, increased bone turnover, and more frequent fractures Boonen, S & Vanderschueren, D & Pelemans, W & Bouillon, Roger. (2004). Primary hyperparathyroidism: Diagnosis and management in the older individual. European journal of endocrinology / European Federation of Endocrine Societies. 151. 297-304. 10.1530/eje.0.1510297. Primary Hyperparathyroidism DDx

Parathyroid adenoma Atypical parathyroid adenoma Familial hypocalciuric hypercalcemia Drugs: thiazides and lithium Differences between benign adenoma and parathyroid carcinoma Benign adenoma • Carcinoma Modest Ca elevation <15 Ca >15 Non-palpable neck mass PTH >3x upper limit of PTH <3x upper limit normal of normal Palpable neck mass

Symptoms more profound What now?

FNA – Can use to determine origin of the mass- in our sample case, the mass was found to be parathyroid tissue with positive test for parathyroid hormone and negative tests for TTF1, calcitonin, and thyroglobulin – Pathology could not determine if mass was malignant or benign in this case

MRI- r/o MEN – Patient had 2 x 4 mm area of hypoenhancement along right pituitary which was read as volume averaging or cystic microadenoma – Abdominal MRI negative for any pathology Treatment options

Medical – Asymptomatic – Non-surgical candidate • Avoid thiazides or lithium, eat low calcium diet, maintain exercise, stay hydrated, moderate calcium and vitamin D intake • Medications can include cinacalcet or bisphosphonates • Estrogen-progestin therapy- raloxifene • Denosumab- investigational Treatment options

Surgery – Who is a surgical candidate when asymptomatic? • Serum Ca 1.0 mg/dL or more above upper limit of normal • Skeletal indications – Bone density at the hip, lumbar spine, and/or distal radius T- score <-2.5 • Renal indications • Age <50 years old Case surgery

Pre-op PTH >2000 pg/mL Mass was mildly adherent to SCM and firm attachment to the left thyroid lobe Mass was 7.2 x 4.0 x 3.5 cm and was 42.2 gms No metastasis to lymph nodes 15 minutes after removal, PTH was 213 pg/mL Parathyroid hormone level remained >100 pg/mL months after surgery Histology

Hypercellular tissue with mild pleomorphism and solid to glandular archicture. Thick acellular fibrous bands throughout the parathyroid tissue and abundant hemorrhage. No necrosis, lymphovascular invasion, or surrounding tissue invasion noted. Tissue positive for pnaacytokeratin. TTF-1 and chromogranin negative Gross specimen Fibrous bands with hemorrhage and thick acellular fibrous bands Solid pattern Pseudofollicular pattern and thick fibrous capsule What to make of this?

Labs had features of carcinoma Presentation had features of carcinoma Surgery had features of benign adenoma due to there being a thick fibrous capsule and relative non-adherence to surrounding tissue Size consistent with carcinoma Histology has a mixed picture but does not meet the pathologic diagnosis of carcinoma Final diagnosis

Atypical parathyroid adenoma Patient’s PTH remained elevated and she desired medical management with endocrinology versus more surgery. Patient lost to follow-up References Adam, M. A., Untch, B. R., & Olson Jr, J. A. (2010). Parathyroid Carcinoma: Current Understanding and New Insights into Gene Expression and Intraoperative Parathyroid Hormone Kinetics. The Oncologist, 61-72. Baser, H., Karagoz, A. C., Karanis, M. I., Sevimli, F., & Baser, S. (2013). Differential DIagnosis of Atypical Parathyroid Adenoma and Parathyroid Carcinoma in a Case with Severe Hypercalcemia. Journal of Medical Cases, Vol 4, No. 6, June 2013, 357-361. Cakir, B., Polat, S. B., Kilic, M., Ozdemir, D., Aydin, C., Sungu, N., & Ersoy, R. (2016). Evaluation of Preoperative Ultrasonographic and Biochemical Features of Patients with Aggressive Parathyroid Disease: Is There a Reliable Predictive Marker? Arch Endocrinol Metab, 537-544. Calson, D. (2010). Parathyroid Pathology. Archives of Pathological Lab Medicine, 1639-1644. Cao, J., Chen, C., Wang, Q.-l., Xu, J.-J., & Ge, M.-H. (2015). Parathyroid Carcinoma: A Report of Six Cases with a brief Review of the Literature. Letters, 3363-3368. DeLellis, R. (2011). Parathyroid Tumors and Related Disorders. Modern Pathology, S78-S93. Duckworth, L. V., Winter, W. E., Vaysberg, M., Moran, C. A., & Al-Quran, S. (2013). Intrathyroidal Parathyroid Carcinoma: Report of an Unusual Case and Review of the Literature. Case Reports in Pathology, Vol 2013, 1-5. Fernandez-Ranvier, G. G., Khanafshar, E., Jensen, K., Zarnegar, R., Lee, J., Kebebew, E., . . . Clark, O. H. (2007). Parathyroid Carcinoma, Atypical Parathyroid Adenoma, or Parathyromatosis? Cancer, Vol 110 Number 2, 255-264. Gill, A., Clarkson, A., Gimm, O., Keil, J., Dralle, H., Howell, V. M., & Marsh, D. J. (2006). Loss of Nuclear Expression of Parafibromin Distinguishes Parathyroid Carcinomas and Hyperparathyroidin-Jaw Tumor (HPT-JT) Syndrome-related Adenomas From Sporadic Parathyroid Adenomas and Hyperplasias. American Journal of Surgical Pathology, Vol 30 Issue 9, 1140-1149. Haglund, F., Juhlin, C. C., Kiss, N. B., Larsson, C., Nilsson, I.-L., & Hoog, A. (2016). Diffuse PTH Experssion in Parathyroid Tumors Argues Against Important Functional Tumor Subclones. European Journal of Endocrinology, 583-590. Halenka, M., Karasek, D., & Frysak, Z. (2012). Four Ultrasound and Clinical Pictures of Parathyroid Carcinoma. Case Reports in Endocrinology, 1-5. Harari, A., Waring, A., Fernandez-Ranvier, G., Hwang, J., Suh, I., Mitmaker, E., . . . Clark, O. (2011). Parathyroid Carcinoma: A 43-year Outcome and Survival Analysis. Journal of Clinical Endocrinology and Metabolism, 3679-3686. Hosny Mohammed, K., Siddiqui, M. T., Willis, B. C., Zaharieva Tsvetkova, D., Mohamed, A., Patel, S., . . . Cohen, C. (2016). Parafibromin, APC, and MIB-1 Are Useful Markers for Distinguishing Parathyroid Carcinomas from Adenomas. Applied Immunohistochemistry and Molecular Morphology. Ioannis Christakis, N. B., Clarke, C., Kwatampora, L. J., Warneke, C. L., Silva, A. M., Williams, M. D., . . . Perrier, N. D. (2016). Differentiating Atypical Parathyroid from Parathyroid Cancer. Annal of Surgical Oncology, Vol 23, Issue 9, 2889-2897. Kim, H. K., Oh, Y. L., Kim, S.-H., Lee, D. Y., Kang, H.-C., Lee, J. I., . . . Kim, S. W. (2012). Parafibromin Immunohistochemical Staining to Differentiate Parathyroid Carcinoma from Parathyroid Adenoma. Head and Neck, 201-206. Ng, S.-H., & Lang, B. H.-H. (2013). Parathyroid Carcinoma in a 30-year-old Man: A Diagnostic and Management Challenge. World Journal of Surgical Oncology, 1-4. Ozolins, A., Narbuts, Z., Vanags, A., Simtniece, Z., Visnevska, Z., Akca, A., . . . Goretzki, P. E. (2016). Evaluation of Malignant Paraythyroid Tumours in Two European Cohorts of Patients with Sporadic Primary Hyperparathyroidism. Langenbecks Arch Surgery, 943-951. Shah, B. G. (2010). Parathyroid Carcinoma. Clinical Oncology, 498-507. Boonen, S & Vanderschueren, D & Pelemans, W & Bouillon, Roger. (2004). Primary hyperparathyroidism: Diagnosis and management in the older individual. European journal of endocrinology / European Federation of Endocrine Societies. 151. 297-304. 10.1530/eje.0.1510297.