Osteolytic lesion in polycythemia vera: First report and review of literature

Myeloproliferative neoplasms (MPNs) are a group of rare clonal disorders of hematopoietic progenitor cells that are associated with morbidity from disease-related symptoms, thrombotic events, and risk of transformation to acute myeloid leukemia (AML) [1]. The three most common MPNs are polycythemia vera (PV), essential thrombocytosis (ET), and myelofibrosis (MF). Patients withMPN can experience a constellation of debilitating symptoms that negatively impact their quality of life [2–5]. In prior surveys of patients withMPNs, bone pain was the fourth most common symptom reported by 44% of patients and rated as “very severe” in up to a third ofMF patients [2–5]. In very rare situations, patients with MPN can develop osteolytic lesions [6–21]. We report the first case of an osteolytic lesion in a chronic-phase PV patient, and review published case reports of MPN patients with osteolytic lesions to summarize the clinical characteristics and implications for patient care.


Case Report
In 2019, a 59-year-old woman was found on routine bloodwork to have elevated hemoglobin (185 g/L) and hematocrit (0.58). All other counts were within normal limits. Molecular testing confirmed JAK2 V617F mutation, erythropoietin level was < 2 IU/L, and bone marrow biopsy demonstrated a hypercellular marrow with increased erythropoiesis and granulopoiesis, establishing a diagnosis of PV. The patient was started on aspirin 81 mg daily with phlebotomies as needed. In 2020, she developed excruciating right hip pain, leading to multiple emergency department presentations. Magnetic resonance imaging (MRI) of right hip demonstrated T1 hypointense and T2 hyperintense signal in the right intertrochanteric region extending into the right greater trochanter measuring 3.9 × 3.5 × 2.6 cm ( Figure 1A). Computed tomography (CT) scan confirmed a lytic lesion within the right proximal femur.
Investigations for other malignancies including multiple myeloma were normal. 18 Fluorodeoxyglucose positron emission tomography (PET) scan confirmed the right femur lesion with increased metabolic activity, but found no other abnormalities. Subsequent CT-guided biopsy of F I G U R E 1 Magnetic resonance imaging (MRI) scans of the right femur the right proximal femur reported hematopoietic tissue with hypercellularity and panmyelosis consistent with PV.
Coinciding with the osteolytic lesion the patient lost phlebotomy requirements (hemoglobin 125 g/L, hematocrit 0.40). A repeat bone marrow biopsy had no significant changes from prior assessment (Table S1). She reported no constitutional symptoms, but impaired mobility related to right hip pain. Ruxolitinib was initiated at 5 mg BID as a trial for pain control based on prior case reports [2,18]. After 6 months of therapy, the hip pain improved on patient self-assessment from 10/10 to 3/10, blood counts remained stable, and follow-up MRI demonstrated decrease in edematous fluid surrounding the lesion ( Figure 1C).

LITERATURE REVIEW
We conducted an English literature search using Google scholar, PubMed, and Medline, for studies, reviews, case series, and case reports of patients with diagnosis of PV, ET, PMF, and MPNunclassified associated with osteolytic bone lesion from 1970 to July 2021.

Development of osteolytic lesions
The etiology of osteolytic lesions in MPN is not fully understood.
Activation of the JAK-STAT pathway leads to altered hematopoiesis and proliferation of one or more cell lines, associated with modifications to the microenvironment of the bone marrow [18-20, 22, 23].
Microenvironment changes in the bone marrow include abnormal production of granulocytes, megakaryocytes, fibroblasts, osteoblasts, and release of pro-inflammatory cytokines, which lead to marrow fibrosis, osteosclerosis, compressive atrophy, and bone destruction [
Reported medical and surgical therapies have demonstrated some temporary symptomatic benefit, though most patients have persistent or new lesions. Radiographic resolution of osteolytic lesions has only been reported in two of the 16 cases. One case had resolution following allogeneic stem cell transplant [12]. Bucelli et al. reported a patient with MF and osteolytic lesions to her left proximal humerus in whom ruxolitinib was started for symptomatic splenomegaly. After 9 months of treatment, spleen size was decreased and bone pain was improved; reimaging confirmed resolution of the osteolytic lesion [18]. This suggests ruxolitinib might have altered the microenvironment of the bone marrow leading to resolution of the osteolytic lesions, but further research is needed to explore this possibility [18,[25][26][27]. In our presented case, ruxolitinib has led to improved pain control and improvement on MRI after limited follow-up.

Implications for patient care
The presence of persistent worsening bone pain in patients with MPN should prompt imaging with CT scan followed by PET scan as needed to investigate for lytic lesions, especially with the poor prognosis associated with this finding. Given that osteolytic lesions can occur in other hematological malignancies (i.e., multiple myeloma), ruling out concurrent disease is necessary (i.e., serum protein electrophoresis, parathyroid hormone) [10,14,17]. If no other malignancy is found in an MPN patient, we recommend both biopsy of the osteolytic lesion to confirm etiology and repeat bone marrow biopsy to evaluate for disease progression.

CONCLUSION
We report the first case of chronic-phase PV with osteolytic lesion with clinical response to ruxolitinib. The occurrence of osteolytic lesions in MPN is rare and characterized by excruciating bone pain, aggressively behaving disease, and may indicate an overall poor prognosis. Further investigation and attention to bone pain with MPN is warranted to reduce symptom burden and identify patients at higher risk of progression.

ACKNOWLEDGMENTS
The authors would like to thank the Myeloproliferative Neoplasm team and Leukemia clinic nurses at Princess Margaret Cancer Centre for their ongoing support.

FUNDING INFORMATION
Funding support for this project from the Corresponding author Hassan Sibai.

CONFLICT OF INTEREST
Dawn Maze has research support, honoraria, advisory board, and consultancy for Novartis, Celgene/Bristol-Myers Squibb, PharmaEssentia, Takeda, and Pfizer. The other authors have no conflict of interest to disclose.

ETHICS STATEMENT
Written consent for the publication of a case report was obtained from the patient. In addition, Institutional Ethic Review was not required for case report by the University Health Network.