Management of polycythemia vera by endoscopic parathyroidectomy

Padmakumar R, Chiramel KJ, Pai M, Shams F, Subin P. Management of polycythemia vera by endoscopic parathyroidectomy. J Appl Hematol [serial online] 2020 [cited 2020 Nov 20];11:204-7.

Available from: https://www.jahjournal.org/text.asp?2020/11/4/204/300771

Contents

1. Abtract
2. Introduction
3. Case Report
4. Outcome
5. Discussion
6. Conclusion
7. References

Abstract

Polycythemia vera (PV) is a hemotologic disease. Majority of persons with PV, essential thrombocythemia and primary myelofibrosis show the Janus kinase (JAK) 2 gene– which is needed for the normal development of blood cells. PV is generally controlled with medication: hydroxyurea or pipobroman. Phlebotomy is the mainstay of therapy for PV. Association between hyperparathyroidism and PV has been very sparingly considered. Primary hyperparathyroidism may produce a growth factor, which induces pancytosis, especially in the presence of high levels of ionized calcium. It is found that parathyroid hormone levels (PTH) could influence hemopoiesis through a direct action on hemopoietic precursors. A 52-year-old female presented with complaints of fever associated with headache and generalized weakness.

On evaluation, her hemoglobin value was found to be high (Hb– 18.8 g/dl) with leukocytosis. She was evaluated for polycythemia, which showed JAK-2 mutation positivity. She was started on Enteric Coated Aspirin. She was managed initially with twice-weekly venesection to keep packed cell volume <45. It was observed that she was having very high PTH– 569.9 pg/ml and low Vitamin D levels– 8.41 mg/ml. She underwent a Technetium 99M Sestamibi Scan (TcMIBI), which showed a large adenoma involving the left inferior parathyroid gland. She was taken up for endoscopic parathyroid removal through the left axillo-breast approach. Intraoperatively, PTH value had dropped from 569.9 pg/ml to 62 pg/ml. Hemoglobin level decreased to normalcy by the 2^nd week of surgery without any medication or venesection.

Patients with polycythemia must be screened for hyperparathyroidism. Early treatment of hyperparathyroidism by parathyroid removal will take care of polycythemia as well. Endoscopic parathyroidectomy is very feasible, safe, and well accepted by patients.

Keywords: Hyperparathyroidism, Janus kinase-2 mutation, parathyroid adenoma endoscopic parathyroidectomy, polycythemia vera

Introduction

Polycythemia vera (PV) is a hemotologic disease. In PV hyperviscosity results from the increased red cell count. The associated increase in white cells and platelets can lead to headache, fatigue, and other symptoms. Thrombus formation of artery or vein may also be a feature. Majority of persons with PV, essential thrombocythemia (ET) and primary myelofibrosis show Janus kinase (JAK) 2 gene, which is needed for the normal development of blood cells. The presence of JAK-2 distinguishes the above disorders from other myeloproliferative disorders (MPD). Hence, it avoids the use of chemotherapeutic agents currently employed in the treatment of MPD.^[1] The identification of JAK-2 and increased RBC are the two significant components of making a diagnosis of PV. Ninety-five percent of PV cases show JAK-2 V617F. Other JAK–2 mutations located in axon 12 can be detected in 2%–5% of cases. JAK-2 V617F mutation-positive patients respond well to treatment compared to mutation-negative patients.

Phlebotomy is the mainstay of therapy for PV. It is done with the aim of keeping the packed cell volume (PCV) <45% in males and 42% in females. It is done with the aim of reducing problems associated with erythrocytosis. The administration of aspirin is advised to reduce ocular migraine and microvascular complications.

High calcium level in PV is generally believed to have a link with malignancies such as renal cell carcinoma. High red cell volume can also be induced by chronic lung disease, stenosis of the renal artery, hydronephrosis, chronic smoking, and hepatocellular carcinoma. The link of hyperparathyroidism to PV is generally not thought off. There is some functional relationship between parathyroid hormone levels (PTH), osteoblastic and osteoclastic activity as well as hematopoiesis.

Primary hyperparathyroidism generally results from an adenoma, hyperplasia, or carcinoma of parathyroid glands; that may require surgical intervention. The classical biological signs of hyperparathyroidism are hypercalcemia, hypophosphatemia, increased PTH in blood, and increased cyclic adenosine monophosphate urinary elimination. The parathyroid tumor may produce a growth factor which induces pancytosis, especially in the presence of ionized hypercalcemia. Hemopoietic precursors may be directly influenced by PTH, resulting in hemopoiesis. Moderate levels of PTH can induce hematopoiesis but maybe inhibitory at a high concentration. We are presenting a case of PV associated with primary hyperparathyroidism due to parathyroid adenoma.

Case Report

A 52-year-old postmenopausal female presented with complaints of fever associated with headache and generalized weakness. She was on treatment for systemic hypertension with telmisartan, chlorthalidone, and nifedipine. On evaluation, her hemoglobin value was found to be high (Hb– 18.8 g/dl) with neutrophilic leukocytosis and mild lymphocytosis. Peripheral smear showed normocytic normochromic blood picture with erythrocytosis. The Serum iron level was 65 mcg/dL. She was evaluated for polycythemia, which showed JAK-2 mutation positivity. She was started on enteric coated aspirin.

Elevated uric acid (10.2 mg/dL) and calcium (13.53 mg/dL) were initially taken as part of polycythemia. But when it increased to 13 and 14.9, respectively, she was evaluated in detail for any parathyroid pathology. It was observed that she was having very high PTH– 569.9 pg/ml and low Vitamin D levels (25-OH Vit. D)– 8.41 mg/ml.

She did not have any bone pain or features of stone diseases. She underwent a Technetium 99M Sestamibi Scan (TcMIBI) double phase parathyroid scintigraphy, which showed large adenoma involving the left inferior parathyroid gland, later confirmed with ultrasound. USG abdomen was unremarkable.

She was managed initially with twice-weekly venesection of 350 ml to 400 ml to keep PCV <45. She was then referred to our department to proceed with endoscopic parathyroidectomy. She was taken up for endoscopic parathyroid removal through the left axillo-breast approach under general anesthesia.

The procedure of endoscopic parathyroidectomy through axillo-breast approach is performed in the following manner. A 10-mm trocar was placed on the anterior axillary fold to introduce the telescope. In the beginning, the telescope aids in dissecting the space. Later, it shows the structure with magnification and delineation. Two working ports of 5 mm were placed in the subplatysmal area. This will expose the sternocleidomastoid and sternohyoid muscles.

The plain medial to the sternocleidomastoid (lateral to the strap muscles) was opened to expose the left lower lobe of the thyroid and the nearby parathyroid adenoma. A large left inferior parathyroid gland adenoma was identified. By blunt dissection, the parathyroid adenoma was mobilized, safeguarding the recurrent laryngeal nerve. The parathyroid vessels were sealed and divided using ultrasonic device. The gland was placed in a custom made endobag and removed in toto through the 10-mm trocar. The drainage tube was placed, and subcuticular closure was performed [Figure 1]. The parathyroidectomy specimen was given for histopathological assessment. Intraoperatively, PTH value had dropped from 569.9 pg/ml to 62 pg/ml. Her course in the hospital was uncomplicated.

Figure 1: Incisions for Endoscopic Parathyroidectomy on left side

HPE revealed a 3.5 cm × 3 cm × 2 cm parathyroid adenoma weighing 5 g. It had mitosis <1/10 HPF. The capsule was intact, and there was no capsular invasion [Figure 2].

Figure 2: Low power view showing perivascular arrangement of tumor cells

Outcome

Her wounds healed well with minimal scarring and the symptoms at the presentation– headache and weakness disappeared. Hemoglobin level decreased to normalcy by the 2^nd week of surgery. Antihypertensives were reduced to single drug– Telmisartan (compared to three drugs preoperatively). Six months following surgery, the PTH value is 28 pg/mL, serum calcium is 9.1 mg/dL, and Hb is 14.3 g/dL. She is continuing the enteric-coated Aspirin– 75 mg once daily.

Discussion

Chronic myeloproliferative neoplasms (CMPNs) are diseases of clonal multipotent stem cells. The four classical subgroups are: chronic myeloid leukemia, primary myelofibrosis (PMF), PV, and ET. Almost all patients having PV, 60%–65% of patients with ET have JAK2 V617F point mutation. JAK2 mutations cause hypersensitivity in hematopoietic progenitor cells towards growth factors and other cytokines. JAK2 V617F mutation-positive PV and ET patients had lower vitamin D levels.^[6] Other than the effects on calcium-phosphate metabolism and bone balance, Vitamin D has an impact on cell proliferation, differentiation and cell adhesion as well as proliferation and apoptosis of tumor cells. In a study on patients with CMPNs, it was observed that there was a high prevalence of Vitamin D deficiency in patients with PV and ET– more so with PV. Vitamin D deficiency was observed in our patient also.

It has been described that PTH may induce hemopoiesis by a direct action on hemopoietic precursors– at a low concentration. It may be inhibitory at a high concentration. In our patient, we found that she had very high PTH but still had erythropoiesis. An article in the Journal of Endocrinology and Metabolism has mentioned about parathyroid adenoma being a risk factor for PV.^[7] Weinstein, in his study, has mentioned that reduction in calcium level in the postoperative period was associated with remission of PV. When the hypercalcemia recurred at a later time, it was again accompanied by pancytosis.^[8] In 4 out of 5 cases, parathyroidectomy resulted in complete and stable remission of PV even without any treatment.^[5] Godeau et al. also reported a case of PV with primary hyperparathyroidism, which responded successfully with the removal of parathyroid adenoma.^[9]

In a case reported in the International Journal of Haemotology, the patient had a JAK-2 status negative and they observed only transient (<1 year) control of PV following parathyroidectomy.^[4] George M Rogers has observed that PTH increases ferric chloride Fe 59 incorporation into erythrocytes of polycythemic mice. He also stated that PTH might increase erythropoiesis not only in pathological situations but also may play a role in the regulation of normal erythropoiesis.^[10]

Multiple endocrine neoplasias (MEN) I and II will have multiple adenomas or hyperplasia of the parathyroid glands. Parathyroid tumor, along with pancreatic and pituitary tumors, is the typical pattern of MEN1. The lesions in MEN-2A are pheochromocytoma, medullary carcinoma thyroid, parathyroid adenoma, or hyperplasia. In addition to the components of MEN-2A; MEN-2B will have oral and submucosal tumors. Detailed evaluation to look for these lesions is essential once a parathyroid adenoma is encountered. We also evaluated our patients fully and excluded MEN.

The surgical results of our patients were excellent is in terms of resolution of PV and hyperparathyroidism. As we proceeded with endoscopic parathyroidectomy the patient was very comfortable and could get excellent cosmetic outcomes without any neck scars. It also encouraged the patient to undergo the procedure at an early stage. It will also motivate her to undergo another procedure in case other parathyroids go in for hyperplasia or adenoma later.

Conclusion

Patients with polycythemia must be screened for hyperparathyroidism. Early treatment of hyperparathyroidism by parathyroid removal will take care of polycythemia as well. Endoscopic parathyroidectomy is very feasible, safe, and well accepted by patients.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

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Kulaylat AN, Jung EE, Saunders BD. The role of parathyroidectomy in JAK2 mutation negative polycythemia vera. Int J Hematol 2014;100:615-8

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Yikilmaz AŞ, Akinci S, Bakanay ŞM, Dilek İ. Vitamin D Deficiency and Janus kinase 2 V617F Mutation Status in Essential Thrombocythemia and Polycythemia Vera. Malays J Med Sci. 2020 ;27:70-7. doi:10.21315/mjms2020.27.1.7. Epub 2020 Feb 27. PMID: 32158346; PMCID: PMC7053540

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

Weinstein RS. Parathyroid carcinoma associated with polycythemia vera. Bone 1991;12:237-9

Godeau P, Bletry O, Brochard C, Hussonois C. Polycythemia vera and primary hyperparathyroidism. Arch Intern Med. 1981 ;141:951-3. PMID: 7235821

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About Dr. R. Padmakumar

Dr. R. Padmakumar is one of the Best Hernia Surgeon in India. He has been changing lives through Keyhole Surgery. He has got more than 30 years of hands-on experience in laparoscopic Surgery in major hospitals across India and has completed more than 7000 cases of Laparoscopic Hernia Surgeries. Dr. Padmakumar has trained more than 300 surgeons from all over the world the art of laparoscopic surgery especially Laparoscopic Hernia Surgery. Dr. Padmakumar is also hailed as one of the Best Bariatric Surgeon in India & UAE. He is renowned for new and improved treatment techniques and the first in the World to perform Scarless Bariatric Surgery with Tummy Tuck / Abdominoplasty. He is also one of the very few thyroid surgeons in India doing Endoscopic Thyroidectomy (scarless thyroid surgery).