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 with MPN can experience a constellation of debilitating symptoms that negatively impact their quality of life [2-5]. In prior surveys of patients with MPNs, bone pain was the fourth most common symptom reported by 44% of patients and rated as “very severe” in up to a third of MF 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. The MPN program at the Princess Margaret Cancer Centre is the largest MPN program in Canada. The MPN program has surveyed 1096 MPN patients regarding their symptoms, 208 MPN patients reported experiencing bone pain. Among these 208 patients, 17% have PV, 15% have ET, and 50% have MF (which includes post PV/ET-MF, prefibrotic-MF or PMF). Of 208 patients, 76 (37%) reported moderate or higher levels of bone pain (5/10 or greater based on the MPN-symptoms survey). 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. 18Fluorodeoxyglucose positron emission tomography (PET) scan confirmed the right femur lesion with increased metabolic activity, but found no other abnormalities. Subsequent CT-guided biopsy of 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). 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 MPN-unclassified associated with osteolytic bone lesion from 1970 to July 2021. In total, 16 case reports were found, highlighting that osteolytic lesion secondary to MPNs is rare (Table 1) [6-21]. All patients reported new or worsening bone pain as a presenting symptom. Osteolytic lesions were solitary in five patients; while 11 had multiple concurrent lesions. In 15 of 16 cases, patients had an established diagnosis of MF; PMF in 7 and secondary MF in 8 patients. One patient with an established PV diagnosis presented with osteolytic lesion concurrently with progression to secondary AML [17]. Median age of diagnosis was 62.5 (range 30–83 years of age), with nine female and seven male patients. The time between diagnosis and the onset of an osteolytic lesion ranged from immediately to 33 years. Symptom burden was significant with patients requiring multiple hospital admissions and interventions following identification of osteolytic lesions. Treatments provided for bone pain included palliative radiation [8, 20], orthopedic surgery for pathological fracture [11, 19], steroid therapy [6, 16], JAK-inhibitor [18], and chemotherapy [6, 10, 14]. In 14 cases, therapies only provided temporary symptomatic relief; and the osteolytic lesions either remained unchanged [6-11, 13, 15-17, 19, 21] or additional osteolytic lesions developed [20]. Bone biopsy (site not specified) confirmed hematopoietic cells Myeloma work-up negative Cytosine-arabinoside, did not achieve remission Subsequently treated with hydroxyurea did not achieve remission Cast to left arm and wrist Transfusion support Bone marrow biopsy confirmed PV transform to AML Myeloma work-up negative Bone biopsy of an osteolytic lesion (no further specification) - grade 3 MF Bone marrow biopsy confirmed AML Bone biopsy (pelvic) confirmed MPN with fibrosis No evidence of Merkel cell carcinoma cytogenetics: del 5q and 17p In all 16 cases investigations revealed progressive disease (i.e., worsening fibrosis, accelerated phase MPN or AML) along with the presence of osteolytic lesions; though diagnostic procedures were often delayed until further symptoms or cytopenias developed [6-16, 18-21]. Chambers et al. reported a patient with longstanding history of PV managed with hydroxyurea who presented to her local hospital after a fall and imaging revealed the presence of an osteolytic lesion [17]. A bone marrow biopsy performed to investigate new anemia demonstrated transformation from PV to AML [17]. Disease progression or death was observed within 12 months of identification of osteolytic lesion in nine cases [6-9, 11, 13, 15, 19, 20]. 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 [18, 22-24] Osteosclerosis can be seen in 40%–70% of patients with MF, and less commonly in other MPNs [18, 23, 24]. The literature suggests that osteolytic lesions occur in areas where there has been significant osteosclerosis and bone destruction [18, 23, 24]. Another possible cause for osteolytic lesions may be as a result of leukemic transformation of MPN from leukemic bone infiltration or focal bone destruction by tumor necrosis factor-alfa released by leukemic cells [14, 22, 24]. The occurrence of osteolytic lesion in MPN patients, independent of another malignant process, is rare. The summarized experience from the literature raises the concern that osteolytic lesions are a sign of disease progression and denote a poorer prognosis [6-21]. Although high-risk mutations and/or unfavorable cytogenetics can also drive disease progression in MPN [1, 23], extended molecular mutation were not provided in the 16 case reports. One case report did describe a patient with unfavorable cytogenetics [7]. 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, 25-27]. In our presented case, ruxolitinib has led to improved pain control and improvement on MRI after limited follow-up. Based on the 16 case reports, and our institute's experience, the occurrence of osteolytic lesion in MPN patients is rare. However, the occurrence of osteolytic lesions is associated with significant bone pain, declined quality of life, aggressively behaving disease, an increased risk of disease progression or leukemic transformation, and limited survival [6-21]. 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. 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. The authors would like to thank the Myeloproliferative Neoplasm team and Leukemia clinic nurses at Princess Margaret Cancer Centre for their ongoing support. Funding support for this project from the Corresponding author Hassan Sibai. 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. 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. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. 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