Osteolytic bone lesions in patients with primary myelofibrosis: A systematic review.

Philadelphia negative myeloproliferative neoplasms (MPNs) are classically characterized by excess production of terminal myeloid cells in the peripheral blood. They include polycythemia vera, essential thrombocythemia, and primary myelofibrosis. Among this group, primary myelofibrosis is the least common and usually carries the worst prognosis. Bone involvement in primary myelofibrosis has many forms; it affects bone marrow leading to bone marrow fibrosis, it can cause periostitis, in addition to bone and joint pain. A common radiologic finding in primary myelofibrosis is the presence of osteosclerotic lesions. However, the presence of osteolytic lesions in bone imaging was described in few reports. In this review, we searched English literature using the PRISMA guidelines looking for patients with Primary myelofibrosis who had osteolytic bone lesions to assess the impact of such findings on the disease and its effect on prognosis. We found the vast majority of lesions were painful affecting most commonly the vertebral column, pelvis, and ribs, and were detected in patients above 50 years of age with no gender preference, unfortunately they represented advanced disease stages, resulting in inadequate treatment response and poor outcome.

Introduction

In 1879 Dr. Gustav Heuck reported the first case of myelofibrosis, Heuck described two cases of generalized osteosclerosis with remarkable hepatosplenomegaly, anemia, hyperplastic lymph nodes and extreme leukocytosis, which he called “splenic-medullary leukemia” and “pure splenic leukemia” respectively depending on his laboratory and post mortem observations (1). Later on, and exactly in 1951 Dr. William Dameshek formally classified primary myelofibrosis within myeloproliferative disorders (MPD) (2). Over a century of time, many nomenclatures have been used to describe the same entity, as agnogenic myeloid metaplasia, chronic idiopathic myelofibrosis, and osteosclerosis with splenomegaly (3), until the World Health Organization (WHO) utilized the name of primary myelofibrosis in 2008 (4).

PMF is a monoclonal stem cell proliferation (myeloid type) that results in bone marrow fibrosis. As per the WHO 2016 classification of hematopoietic malignancies, PMF categorized within Myeloproliferative Neoplasms (MPN) (5), PMF grouped together with Polycythemia vera (PV) and Essential thrombocythemia (ET) under the name of ‘JAK2-MPNs’ to ratify the relation among those disorders, where 15 % of ET and PV patients can end up with PMF like type, called as a post-ET or post-PV myelofibrosis (6,7). PMF has male predominance with the most affected age groups between 60s to 70s (8).

According to WHO 2016 guidelines PMF divided in two subtypes, pre-fibrotic and overt fibrotic, patients have to meet all the 3 major criteria with at least one minor criteria for diagnosis table 1 (9), in case of post-PV or post-ET myelofibrosis the criteria from the International Working Group for MPN Research and Treatment (IWG-MRT) should be followed table 2 (10).

Table 1.

2016 World Health Organization diagnostic criteria for primary myelofibrosis

	Primary myelofibrosis (PMF)
	Prefibrotic/early PMF (pre-PMF)	Overt PMF
Major criteria
1	Megakaryocytic proliferation and atypia b, without reticulin fibrosis > grade 1c, accompanied by increased age-adjusted BM cellularity, granulocytic proliferation and often decreased erythropoiesis	Megakaryocyte proliferation and atypiab accompanied by either reticulin and/or collagen fibrosis (grade 2 or 3)
2	Not meeting WHO criteria for BCR-ABL1 + CML, PV, ET, MDS, or other myeloid neoplasm	Not meeting WHO criteria for BCR-ABL1 + CML, PV, ET, MDS or other myeloid neoplasm
3	Presence of JAK2, CALR, or MPL mutation or in the absence of these mutations, presence of another clonal markerd or absence of minor reactive BM reticulin fibrosise	Presence of JAK2, CALR, or MPL mutation or in the absence, the presence of another clonal marker d or absence of evidence for reactive BM fibrosisf
Minor criteria
1	Presence of one or more of the following, confirmed in two consecutive determinations:	Presence of one or more of the following confirmed in two consecutive determinations:
	Anemia not attributed to a comorbid condition	Anemia not attributed to a comorbid condition
	Leukocytosis ≥ 11 × 109/L	Leukocytosis ≥ 11 × 109/L
	Palpable splenomegaly	Palpable splenomegaly
	LDH level above the upper limit of the institutional reference range	LDH level above the upper limit of the institutional reference range
		Leukoerythroblastosis

Legend and notes: Table adapted from: Barbui T, et al. Blood Cancer J. 2015; 5:e337, and Arber DA, et al. Blood 2016;127:2391–2405. BM, bone marrow; CML, chronic myeloid leukemia; MDS, myelodysplastic syndrome; LDH, serum lactate dehydrogenase. b Small-to-large megakaryocytes with aberrant nuclear/cytoplasmic ratio and hyperchromatic and irregularly folded nuclei and dense clustering. c In cases with grade 1 reticulin fibrosis, the megakaryocyte changes must be accompanied by increased BM cellularity, granulocytic proliferation, and often decreased erythropoiesis (that is, pre-PMF). d In the absence of any of the three major clonal mutations, the search for the most frequent accompanying mutations (ASXL1, EZH2, TET2, IDH1/IDH2, SRSF2, SF3B1) are of help in determining the clonal nature of the disease. e Minor (grade 1) reticulin fibrosis secondary to infection, autoimmune disorder or other chronic inflammatory conditions, hairy cell leukemia or other lymphoid neoplasm, metastatic malignancy, or toxic (chronic) myelopathies. f BM fibrosis secondary to infection, autoimmune disorder, or other chronic inflammatory conditions, hairy cell leukemia, or other lymphoid neoplasm, metastatic malignancy or toxic (chronic) myelopathies.

Table 2.

IWG-MRT recommended criteria for post-PV MF and post-ET MF

Criteria for post-polycythemia vera myelofibrosis
Required criteria:
1	Documentation of a previous diagnosis of polycythemia vera as defined by the WHO criteria1
2	Bone marrow fibrosis grade 2–3 (on 0–3 scale)3 or grade 3–4 (on 0–4 scale)4,a
Additional criteria (two are required):
1	Anemiab or sustained loss of requirement of either phlebotomy (in the absence of cytoreductive therapy) or cytoreductive treatment for erythrocytosis
2	A leukoerythroblastic peripheral blood picture
3	Increasing splenomegaly defined as either an increase in palpable splenomegaly of >5 cm (distance of the tip of the spleen from the left costal margin) or the appearance of a newly palpable splenomegaly
4	Development of >1 of three constitutional symptoms: >10% weight loss in 6 months, night sweats, unexplained fever (>37.5°C)
Criteria for post-essential thrombocythemia myelofibrosis
1	Documentation of a previous diagnosis of essential thrombocythemia as defined by the WHO criteria1
2	Bone marrow fibrosis grade 2–3 (on 0–3scale)3 or grade 3–4 (on 0–4 scale)4,a
Additional criteria (two are required):
1	Anemiab and a >2mg ml-1decrease from baseline haemoglobin level
2	A leukoerythroblstic peripheral blood picture
3	Increasing splenomegaly defined as either an increase in palpable splenomegaly of >5 cm (distance of the tip of the spleen from the left costal margin) or the appearance of a newly palpable splenomegaly
4	Increased LDH (above reference level)
5	Development of >1 of three constitutional symptoms: >10% weight loss in 6 months, nights sweat, unexplained fever (>37.5°C)

Abbreviations: IWG-MRT: International Working Group for Myelofibrosis Research and Treatment; LDH: lactate dehydrogenase; post-ET MF: post-essential thrombocythemia myelofibrosis; post-PV MF: post-polycythemia vera myelofibrosis.

Clinical manifestations

Fatigue represents the most common complaint (11); other symptoms like fever, weight loss, bone pain, night sweats, and pruritus are also reported (12). Classically splenomegaly presents in more than 90 % of cases, although the symptoms due to spleen enlargement like vague pain in the left upper quadrant and early satiety are quite less common (13), remarkable hepatomegaly with or without portal hypertension noticed as well (14).

Extra-medullary hematopoiesis can take place at any stage of the disease and notably can involve any organ; for example central nervous system involvement can lead to increased intracranial pressure, altered mental status, and cord compression (15,16) similarly can lead to pleural effusion (17), and ascites (18), lymphadenopathy is not uncommon and skin manifestations have also reported (19), bone also can be affected and many reviews in the literature have described the different types of bone pathology, and concluded that osteosclerosis is the most common radiological feature, which appears either as a diffuse hyperlucent lesions or less commonly as patches of sclerosis (20). In this review, we shed the light on the exceptional association between osteolytic bone lesions and primary myelofibrosis.

Risk stratification

Before the era of molecular and genetic studies, the outcome was poorly identified. Nowadays, with the utilization of the new cytologic technology, the door has been opened for advanced prognostic scoring systems which can stratify patient’s risk from day one of diagnosis. GIPSS (genetically inspired prognostic scoring system) is the most common risk estimation tool which categorizes patients into low, intermediate, and high risk, validated to predict overall survival and leukemia-free survival; the other predication tool and the more complicated one is MIPSS70+ v2.0 (mutation-enhanced international prognostic scoring system plus karyotype, 70+, version 2.0) which incorporates the clinical findings with the cytologic studies, it is advised as a two-step approach for better risk discrimination in patients with intermediate risk on GIPSS score (21,22).

Treatment usually depends on the risk stratification of each case. For high-risk patients: a bone marrow transplant is a good option (23), whereas medications like JAK2 inhibitors (24) and hydroxyurea can be considered in low and moderate cases.

Methods

We performed a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We searched the English literature (Google Scholar, PubMed, and SCOPUS) for studies, reviews, case series, and case reports about patient with myelofibrosis who develop lytic bone lesion. We used the terms in combination: “Myelofibrosis’” or “Primary myelofibrosis” OR “chronic idiopathic myelofibrosis” OR “agnogenic myeloid metaplasia” and “Osteolytic bone lesion”, “Osteolytic lesion”, “lytic bone lesion”. The review included patients with primary myelofibrosis confirmed by biopsy, and declining all cases with any possible secondary causes of myelofibrosis. The reference lists of the included studies were scanned for any additional articles. The search included all articles published up to 10th April 2021. Two independent reviewers screened the titles and abstracts of the records independently and papers unrelated to our inclusion criteria were excluded. A total of 10 articles were included in the review (Figure 1).

Figure 1.

The PRISMA flow diagram detailing the patients with myelofibrosis who developed osteolytic bone lesion.

Results

Clinical information for each patient is summarized in (Table 3). A total number 0f 10 patients were included in the review. Six patients out of 10 were females, the male:female ratio almost equal to 1:1. The mean age at time of diagnosis was 56.3 year, only two cases were diagnosed at young age, however the majority have osteolytic bone lesion at age above 40 years (8/10) of cases.

Table 3.

Clinical characteristcs, treatment received and outcome of patients with myelofibrosis secondary to polycythemia vera.

Author	Age of PMF diagnosis and gender Presenting symptoms	Age (years) when the lytic lesion detected Lesion of osteolytic lesions	Lesion bx and JAK2V617F mutation	Treatment	Treatment response and outcome
1. Burnham, et al. Cureus 2020; 12 (3):e7475.	60 MLeft lateral hip and thigh pain	63Proximal left femur then right hip and femur. Rt calcaneus	MyelofibrosisPositive	BoneMarrow transplant then ruxolitinib	ImprovedDied after 10 months from the first osteolytic lesion
2. Bucelli et a1. Chemotherapy 2018; 63:340-4.	33 FLeft upper limb pain	59Left humerus	Grade 3 fibrosis positive	Hydroxyurea then ruxoliti nib 15 mg bid for 12 months	Full resoIution Aive after 1 year
3. Merry and Aronowitz.J Hosp Med 2010;5:E27-8.	7g M Weakness>>fall>>hand fracture	83Left hand, wrist, and forearm	Not doneN/A	Thalidomide and darbepoeti n	N/A Died after 1 month
4. Clutterbuck et a1.J Clin Pathol1995;48:867-8.	26 MPneumonia, flaccid paralysis of left foot	5.9Left femur	Hematopoietic cellsN/A	N/A	N/ADied due to septicemia after 6 months
5. Gruber et al. Med Oncol Tumor Pharmacother 1987;42: 107-9.	64 FBack pain with HF sx	64Ribs and the pelvis.Skull and scapula, spinal column	Hem atopoieticcellsN/A	Thioguanine and cytosine arabinoside then busulfan for lytic lesion	Partial response Died after 6 years form first symptomatic lytic lesion
6. Case records of the Massachusetts General Hospital.Case 39-1974Nengl J Med1974;29I:721-30.	66 FFatigue and anorexia	70 Clavicles, left. Scapula and humorous then ribs	N/AN/A	Busulfan	Mild improvement Died within a year due to sepsis
7. Rudders et al.Am J Clin Pathol 1974;6l:673-9.	72 FRight chest pain	72Right ribs, femur, pelvis and skull	Rib:Hematopoietic elementsN/A	Transfusion with. No treatment	No responseDied in the same year
8. French et al.South Med J1970;63:387-91.	67 MLower limbs swelling with left hip pain	671, 2 vertebra and right 8 th rib	Rib: fibrous replacement of the marrowN/A	Radiotherapy with testosterone enanthate 600 mg IM q week	Worsening Died within 6 months
9. Theodore et al. Radiology 1967;89:941-6.	55 FChest pain	68Ribs, clavicles,scapula and humerus	Hematopoietic stem cells front ribN/A	Transfusion with. No treatment	N/ADied in the same year
10. Case records of the Massachusetts General Hospital.Case 65-1963 N ENgI J Med 1963;269:854-63.	44 FAbdominal pain	62 Calvarium, ribs spine all bones, except tibia and fibula	N/AN/A	Fluoxymeste rone and conjugated estrogen	No response Died in one year due to pneumonia
11. Sideris et al. Ann Hematol 2006;85:555-6.	71 M Lower back pain with LL weakness	72 Ribs, sternum, vertebrae, pelvis, and calcaneus	Myeloid metaplasia N/A	N/A	N/A Died after 1 year
12. Kosmidis et al. Cancer 1980;46:2263-5.	69 F Acute pleuritic chest pain	71 AII homes (ribs and long bones)	Myelofibrosis N/A	N/A	N/A Died after 6 months
13. Leimert et al. Am J Clin Pathol 1978;70:706-8.	47 M Knee and ankle pain	49 Distal femurs, proximal tibias and fibulas, pelviS, and lumbar spine	Hematopoietic cells with fibrosis N/A	Radiotherapy	No respoiise Died within a year due to staphylococcal septicemia

Legend.’ NSA: not available

The mean time between the diagnosis of primary myelofibrosis until the osteolytic bone lesion capturing was approximately 10.1 years. Seven out of 10 patients had painful bone lesion. Others were incidental findings during a scan for other reasons. All patients have significant splenomegaly. All patients had the lytic lesion detected on X- ray, and 2 patients had confirmed findings on magnetic resonance imaging (MRI). The most commonly affected bones were the vertebrae, pelvis, ribs, humerus then the scapula, femur and skull and less frequently wrist bones and calcaneus. The shape, the extension and the numbers of lesion were variable, some showed cortical sparing and others come with cortical destruction. Two cases were positive for JAK2 mutation. Two patients had received ruxolitinib (one of them before bone marrow transplantation), two patients were treated with busulfan, one patient received radiotherapy, one patient had thalidomide and another one thioguanine with cytosine arabinoside. The rest of patients received non-specific treatments like erythropoietin analogues or supportive blood transfusion. Few cases responded well to treatment, only one patient survived one year after the detection of bone lesions. Our search also detected three patients with myelofibrosis secondary to polycythemia vera who also developed lytic lesions table 2 (patients no. 10-13).

Discussion

Since primary myelofibrosis has been reported, many theories describing the underlying mechanism have come to light; up to date, the pathophysiology of myelofibrosis is still not clear (Figure 2). However, the new targeted sequencing methods improved our understanding of the somatic mutation’s role in PMF phenotype. Likewise, the karyotypic studies did show the implication of chromosomal abnormalities in the disease development and prognosis, as a result the auto-activated gene in muted megakaryocyte or lymphocyte brings on a wide spectrum of cytokines and growth factors production leads to irregular clonal cell proliferation and fibroblasts stimulation. This constitutive activation of fibroblasts fills the bone marrow with reticuline and collagen leading to ineffective hematopoiesis (25, 26).

Figure 2.

JAK-STAT pathway. Ligand binding to cytokine and growth factor receptors activates JAKs, which are receptor tyrosine kinases that subsequently phosphorylate STAT transcription factors. Activated STATs translocate to the nucleus to stimulate the transcription of genes involved in cell proliferation and survival. The JAK-STAT pathway is dysregulated in MF, making JAKs targets for therapeutic intervention. (Reproduced with permission from Incyte Corp.
JAK: Janus-associated kinase; MPL: Myeloproliferative leukemia virus (oncogene); STAT: Signal transducer and activator of transcription).

The studies have showed that almost 60 % of PMF patients carry clonal karyotypic abnormalities, and the most common ones are deletion of a segment of the chromosomes (13q-) and (20q-) respectively (27, 28).

Although only 50 % of PMF patients have JAK2 mutation, activation of the JAK2-STAT pathway has a tremendous effect in cell proliferation and survival (29), the other mutations include the calreticulin gene (CALR) and the thrombopoietin receptor (MPL) are reported in 35 % and 5 % respectively in JAK2V617F-negative MF patients (30–32).

All these factors eventually result in a fibrous bone marrow that incapable of providing the tissues with blood cells. Subsequently, other organs like the liver and spleen take over the steering wheel to keep an adequate production of blood cells to ensure proper body function. This phenomenon is called extramedullary hematopoiesis, which is a defense mechanism from the embryonic phase that the body develops to maintain the hemostasis. It can explain the extra-osseus manifestations of myelofibrosis like hepatosplenomegaly, lymphadenopathy, and others (33, 34).

The hyperdynamic ineffective bone marrow can have a negative impact on the bone structure resulting in different types of bone pathology including lytic and sclerotic lesions. Studies have shown that 30–70 % of bone changes are osteosclerotic lesions, those changes can be observed in the long bones due to endosteal sclerosis which obliterates the margin between the cortical and medullary bone (Figure 3). However, in the vertebral column a mixed picture of condense alternatively with hyperlucent areas have been encountered (35), while in the ribs it is more homogenous and gives a view like the ‘jail bars’, later on, in the advanced stages we can notice the complete destruction and obliteration of medullary space with preserved cortex out borders (36).

Figure 3.

Left femur imaging. A plain radiograph of the left proximal femur identifies a sub-trochanteric permeative, lytic bone lesion with cortical destruction (A), which is also documented after T2-weighted fat-saturated MRI of the left proximal femur with notable intramedullary fibrosis, marked heterogeneity of the marrow, and associated soft tissue edema surrounding the proximal femur (B) (From ref. 47; Reproduced with permission of Editor).

The exact mechanism beyond developing lytic lesion is not fully studied, the observation from the above mentioned cases and post mortem reports suggest the following etiologies.

First, Raia et al. (37) noticed in his case after autopsy multiple nodules arising from the bone and the soft tissue around, compressing the adjusting bone causing area of lucency, similarly in Kosmidis et al. (38) case where he noticed areas of necrosis due to the extensive fibrotic tissue expansion toward the cortex. The second theory is the inflammatory theory in which lytic lesions manifest as a result of local bone destruction by tumor necrosis factor due to leukemic transformation of myelofibrosis (39).

In primary myelofibrosis there is slight male dominance, the searched literature showed that osteolytic lesions tend to happen in equal distribution between genders. Obviously, we need larger sample size to tell if there is difference between gender. Looking at patients’ characteristics, the patients with lytic bone lesions have mean age of 56 years at the presentation. This means that patient who developed lytic bone lesions are slightly younger compared to the other patients diagnosed with MF as the usual age of presentation for patients with MF is usually average 67 years (40).

It is easy to notice that most of the patients were in advanced stages when the lytic lesions discovered, this observation can be explained by the time needed to generate extramedullary hematopoiesis and subsequent effect on bone structure revealing the lytic lesions. PMF is associated with a median overall survival of around six years, and our patients had the lytic lesions detected after average 8.8 years. However, 7 patients had the osteolytic lesion detected within three years of PMF diagnosis and most patients who were young developed the osteolytic lesions after longer time compared to elder patients. This variation in age and the time to development of lytic lesion could be due to a long asymptomatic, indolent phase of the disease, in which patient can survive for decades without even knowing he or she is ill (41) or it can be due to age related factors. Because of the few number of reported patients, it is difficult to conclude if the lytic lesions are by themselves a sign of poor prognosis or they are a sign of advanced disease.

The majority of the lesions were painful and pain was the chief complaint that pushed people to seek medical advice. Since the bone is a highly innervated tissue and the nerve endings are distributed between the bone marrow trabeculae and the periosteum area, this fact can explain the pain even before detecting any bone destruction or periosteum inflammation (42). However, 3 patients came with asymptomatic lesions, this can be linked to the early presentation due to other complaints (fall, pneumonia and profound fatigue) (43,44). It is not surprising to perceive that the most affected bones are the same bones responsible for hematopoiesis. Since the initial response will be as a compensatory hyperfunctioning of the bone marrow, and once it fail the process will be continued in other organs.

The JAK/STAT pathway and its role in oncogenesis becomes well-established in the last decade (45). And more importantly after 2008 when the WHO guidelines highlighted the diagnostic value of JAK2 mutation in the diagnosis of PMF (46), this explains the reason why only 2 patients had JAK2 test as other cases were reported much earlier. In the same context, those two patients were treated with JAK inhibitor (Ruxolitinib) an FDA approved medication with proved efficacy in controlling (PMF) symptoms and improving overall survival. However, the case described by Burnham et al. (47) died within the first year of treatment due to renal failure related complications.

Our group is studying the unmet clinical needs in Myeloproliferative neoplasms and CML like cost effective analysis for second generations TKIs when used as upfront (48), the association of tuberclosis with CML (49), the reactivation of hepatitis B with CML (50), ophthalmic manifestations as initial presentation in patients with CML (51), Effects of intermittent fasting on CML (52), autoimmune hemolytic anemia and its association with different therapies in CML (53), priapism (54,55) and male fertility (56), obesity (57) and obesity related surgeries in patients with CML (58) as well as effects of environmental factors in MPNs(59).

Conclusion

Osteolytic bone lesions in patients with primary myelofibrosis is extremely rare finding, and noticed shortly after diagnosis in elderly and after longer duration in young patients. The lytic lesion seems to have a bad prognostic value as we can notice 11 out of 13 patients have died within one year of detection.