Int J Hematol (2014) 100:615–618 DOI 10.1007/s12185-014-1668-x
CASE REPORT
The role of parathyroidectomy in JAK2 mutation negative polycythemia vera Afif N. Kulaylat • Eric E. Jung • Brian D. Saunders
Received: 24 March 2014 / Revised: 2 September 2014 / Accepted: 2 September 2014 / Published online: 11 September 2014 Ó The Japanese Society of Hematology 2014
Abstract The relationship between polycythemia vera (PV) and primary hyperparathyroidism is not well understood. Remission or improvement of PV following parathyroidectomy in the setting of primary hyperparathyroidism has previously been described; however, longterm outcomes are not well characterized. We describe a patient with JAK2 mutation negative PV and primary hyperparathyroidism, with a dramatic, but ultimately transient, improvement in hemoglobin following resection of a parathyroid adenoma. While screening for hyperparathyroidism may be useful in the setting of PV, indications for parathyroidectomy should be driven by symptomatology or established criteria, not the desire to affect the clinical course of PV.
hyperparathyroidism is an endocrinologic disorder usually caused by a parathyroid adenoma, carcinoma, or hyperplasia, which may require surgical intervention [ 2]. While seemingly unrelated, a purported relationship between these two conditions has been explored as numerous cases have described the remission or improvement of PV following parathyroidectomy in the setting of concomitant disease [3–7]. However, the nature of this relationship remains obscure, and the long-term outcomes are not well characterized. We describe a patient with PV and primary hyperparathyroidism, with a dramatic, but ultimately transient, improvement in hemoglobin following resection of a parathyroid adenoma.
Keywords Primary hyperparathyroidism Polycythemia vera Parathyroidectomy Parathyroid adenoma Remission Hypercalcemia
Case report
Introduction Polycythemia vera (PV) is a myeloproliferative hematologic disorder, generally controlled with medication and phlebotomy to avoid the complications associated with pathologically elevated red blood cell mass [1]. Primary A. N. Kulaylat E. E. Jung B. D. Saunders Department of Surgery, College of Medicine, The Pennsylvania State University, Hershey, PA 17033, USA B. D. Saunders (&) Department of Surgery, Penn State Hershey Medical Center, Mail Code: H149, 500 University Drive, Hershey, PA 17033, USA e-mail:
[email protected]
An 84-year-old female with PV was referred to an endocrinologist with symptoms of constipation, musculoskeletal pain, and concentration difficulties. She was diagnosed with a myeloproliferative disorder most consistent with PV 4 years earlier based on established criteria and was followed regularly by a hematologist [8, 9]. Her Janus kinase 2 (JAK-2) V617F status was negative. Control of her PV was achieved with regular doses of hydroxyurea and periodic phlebotomy, with the goal of maintaining her hematocrit below 40 %. On further evaluation, her laboratory studies demonstrated a serum calcium level of 10.6 mg/dL (8.4–10.2 mg/ dL), parathyroid hormone (PTH) level of 70 pg/mL (9–65 pg/mL), and normal 25-hydroxy vitamin D levels. Bone densitometry demonstrated findings of osteoporosis [10]. She underwent a Technetium 99 m sestamibi nuclear medicine parathyroid scan, suggesting a left lower parathyroid adenoma, which was confirmed with surgeon-
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Fig. 1 Graph demonstrating patient hemoglobin and hydroxyurea dosing [cumulative weekly doses (mg)] in relation to the date of surgical intervention. The arrows indicate time points where a phlebotomy was performed
performed ultrasound. Following consultation with an endocrine surgeon, she elected to proceed with a parathyroidectomy. Intraoperatively, a substernal parathyroid adenoma within the superior aspect of the left thymus was resected. Intraoperative PTH levels decreased from 143 to 52 pg/mL. Her hospital course was uncomplicated and she was discharged uneventfully on post-operative day 1. After 1 year following her surgery, serum calcium and PTH levels were 9.1 mg/dL and 28 pg/mL, respectively. In subsequent visits to her hematologist, she was noted to have decreased hemoglobin and hydroxyurea requirements. A summary of her hemoglobin levels and hydroxyurea requirements are summarized in Fig. 1, with accompanying white blood cell counts and platelets summarized in Fig. 2. Her median hemoglobin decreased from 13.4 g/dL in the year prior to parathyroidectomy to 10.5 g/dL in the year following parathyroidectomy; her median hydroxyurea requirements decreased from 5,500 to 1,500 mg/week in the same interval [Mann–Whitney Test (MW): both p \ 0.01]. While phlebotomy (500 ml) was performed on three occasions in the year prior to surgery, she did not require any phlebotomy in the immediate post-operative year. However, in the beginning of her second post-operative year, her median hemoglobin levels began to rise and would exceed her pre-operative levels (13.9 vs. 13.4 g/dL, MW: p \ 0.01). Her hydroxyurea requirements also increased, although they have not yet met pre-operative levels (3,500 mg/ week vs. 5,500 mg/week, MW: p \ 0.01). Throughout this period, serum calcium levels remained within
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normal limits (calcium ranged between 8.5–9.1 mg/dL up to three years post-operatively).
Discussion The unclear relationship between PV and primary hyperparathyroidism continues to be of interest as a limited number of reports describe the remission or improvement of PV following parathyroidectomy [3–7]. In fact, in one unique case, a physician requested screening for primary hyperparathyroidism upon receiving a diagnosis of PV, aware of the described relationship in the literature [5]. A parathyroid adenoma was subsequently discovered and following parathyroidectomy, his PV resolved [5]. In our case, the patient experienced a significant improvement in her hemoglobin levels and hydroxyurea requirements following parathyroidectomy for symptoms of hyperparathyroidism. However, this improvement in the patient’s hemoglobin proved to be transient. Standard criteria guiding parathyroidectomy in primary hyperparathyroidism include the presence of any symptoms consistent with the effects of hypercalcemia and hyperparathyroidism [2]. These symptoms include nephrolithiasis, bone disease (e.g., osteoporosis), and neuromuscular symptoms, among others. In asymptomatic patients, surgery is guided by the presence of measurable laboratory derangements consistent with consensus statements for intervention (e.g., serum calcium [1.0 mg/dL above normal, reduced creatinine clearance) [11]. In our patient,
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Fig. 2 Graph demonstrating patient white blood cell and platelet counts in relation to the date of surgical intervention
parathyroidectomy in the setting of primary hyperparathyroidism was driven by osteoporosis and neuromuscular pain, both of which improved following surgery, with additional amelioration of her concentration difficulties also noted. Associations between PV and hyperparathyroidism have been described in the literature [12–15]. Several studies have demonstrated an increased risk of neoplastic processes, particularly PV, following the development of hyperparathyroidism due to parathyroid adenoma [13, 14, 16, 17]. Conversely, increased risk of developing hyperparathyroidism secondary to parathyroid adenoma has also been reported following the diagnosis of PV in a Swedish population study [14, 17]. Recent reports have elucidated functional relationships between major calcium regulating hormones such as PTH, osteoclastic/osteoblastic activity and the regulation of hematopoiesis [18–21]. These relationships suggest possible biological mechanisms linking PV and primary hyperparathyroidism. The reported cases have been heterogeneous with regard to the temporal relationship between PV and hyperparathyroidism, as well as duration of follow-up. In the previously described case reporting resolution of PV following parathyroidectomy, follow-up was only limited to 3 months [5]. In our patient, with continued follow-up, we discovered that the duration of her remission of PV was approximately 1 year. However, sustained remission of PV has been described following parathyroidectomy for hyperparathyroidism in a 2-year follow-up period [3]. Notably, in these cases, there was a close temporal
relationship between development of hyperparathyroidism and PV. In contrast, in another case, with a 4-year interval between the diagnosis of PV and development of hyperparathyroidism (similar to ours), a temporary period of remission was achieved; however, in a 2-year follow-up period, the patient continued to require regular phlebotomy every 60 days, compared to every 30 days previously [4]. Our case provides further evidence of a relationship between PV and primary hyperparathyroidism and suggests that patients do not respond uniformly to parathyroidectomy in this setting. Unlike previous reports, our report calls into question the sustained benefit of this intervention on the clinical course of PV. There may be certain mechanisms that compensate for, or overcome, the initial improvement or remission. Alternatively, there may be unique aspects of our patient’s case distinguishing it from previously reported cases, such as negative JAK-2 V617F status or timing of polycythemia relative to symptoms of hyperparathyroidism. Therefore, we recommend patients with PV be screened for hyperparathyroidism. However, given the risks inherent in any operation, motivation for parathyroid exploration should be driven by symptomatology or established criteria, not the desire to affect the clinical course of PV [2]. Acknowledgments The authors would like to thank Monali Vasekar, MD for her insight and Chelsea Stephens for her assistance in the preparation of this manuscript. Conflict of interest All authors declare that they have no conflict of interest.
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References 1. Pearson TC, Messinezy M, Westwood N, Green AR, Bench AJ, Green AR. A polycythemia vera updated: diagnosis, pathobiology, and treatment. Hematol Am Soc Hematol Educ Program. 2000;1:51–68. 2. Yeh MW, Wiseman JE, Ituarte PH, Pasternak JD, Hwang RS, Wu B, et al. Surgery for primary hyperparathyroidism: are the consensus guidelines being followed? Ann Surg. 2012;255:1179–83. 3. Godeau P, Bletry O, Brochard C, Hussonois C. Polycythemia vera and primary hyperparathyroidism. Arch Intern Med. 1981; 141:951–3. 4. Tiryakioglu O, Kadioglu P, Ongoren S, Acbay O, Ferhanoglu B, Gu¨ndoglu S, et al. An unusual cause of hypercalcemia in polycythemia vera: parathyroid adenoma. Acta Med Okayama. 2002; 56:167–70. 5. Silverberg LI, Weigel RJ. Effect of parathyroidectomy on polycythemia vera. Surgery. 2005;137:102–3. 6. Weinstein RS. Parathyroid carcinoma associated with polycythemia vera. Bone. 1991;12:237–9. 7. Bae EH, Kim HS, Kim MJ, Kang YU, Kim YH, Kim CS, et al. Hypercalcemia in a patient with polycythemia vera. Chonnam Med J. 2012;48:128–9. 8. Pearson TC. Evaluation of diagnostic criteria in polycythemia vera. Semin Hematol. 2001;38:21–4. 9. Thiele J, Kvasnicka HM. The 2008 WHO diagnostic criteria for polycythemia vera, essential thrombocythemia, and primary myelofibrosis. Curr Hematol Malig Rep. 2009;4:33–40. 10. Assessment of fracture risk and its application to screening for postmenopausal osteoporosis. Report of a WHO Study Group. World Health Organ Tech Rep Ser. 1994;843:1–129 11. Khan AA, Bilezikian JP, Potts JT Jr. Guest editors for the third international workshop on asymptomatic primary h. the diagnosis and management of asymptomatic primary hyperparathyroidism revisited. J Clin Endocrinol Metab. 2009;94:333–4.
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A. N. Kulaylat et al. 12. Kurosawa M, Iwasaki H. Megakaryoblastic transformation of polycythemia vera with hypercalcemia. Ann Hematol. 2002;81: 668–71. 13. Pizzolito S, Barbone F, Rizzi C, Scott AC, Piemonte M, Beltrami CA. Parathyroid adenomas and malignant neoplasms: coincidence or etiological association? Adv Clin Pathol. 1997;1: 275–80. 14. Fallah M, Kharazmi E, Sundquist J, Hemminki K. Higher risk of primary cancers after polycythaemia vera and vice versa. Br J Haematol. 2011;153:283–5. 15. Hemminki K, Sundquist J, Bermejo JL. Associated cancers in parents and offspring of polycythaemia vera and myelofibrosis patients. Br J Haematol. 2009;147:526–30. 16. Meytes D, Bogin E, Ma A, Dukes PP, Massry SG. Effect of parathyroid hormone on erythropoiesis. J Clin Investig. 1981;67: 1263–9. 17. Fallah M, Kharazmi E, Sundquist J, Hemminki K. Nonendocrine cancers associated with benign and malignant parathyroid tumors. J Clin Endocrinol Metab. 2011;96:E1108–14. 18. Kollet O, Dar A, Shivtiel S, Kalinkovich A, Lapid K, Sztainberg Y, et al. Osteoclasts degrade endosteal components and promote mobilization of hematopoietic progenitor cells. Nat Med. 2006; 12:657–64. 19. Kawamori Y, Katayama Y, Asada N, Minagawa K, Sato M, Okamura A, et al. Role for vitamin D receptor in the neuronal control of the hematopoietic stem cell niche. Blood. 2010;116: 5528–35. 20. Adams GB, Martin RP, Alley IR, Chabner KT, Cohen KS, Calvi LM, et al. Therapeutic targeting of a stem cell niche. Nat Biotechnol. 2007;25:238–43. 21. Kode A, Manavalan JS, Mosialou I, Bhagat G, Rathinam CV, Luo N, et al. Leukaemogenesis induced by an activating betacatenin mutation in osteoblasts. Nature. 2014;506:240–4.
