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Introduction

Osteolytic lesions of long bones are typical occurring pathological fracture. The most common bone disease pathological fracturse are metastatic tumors. About 10% of patients with primary malignant tumor will develop metastasis of the proximal femur. Common bone metastases are derived from breast, kidney, thyroid, prostate cancer, or myeloma (1,2).

Several studies have documented that patients with rheumatoid arthritis (RA) have an increased risk of developing a lymphoproliferative disorder (LPD). Patients with RA have a high risk of developing LPDs about two to four times compared to the general population (3). Methotrexate (MTX) is currently a widely used disease-modifying anti-rheumatic drug. MTX-associated LPD (MTX-LPD) is a lymphoid proliferation or lymphoma that occurs in patients immunosuppressed with MTX and classified as a part of the ‘other iatrogenic immunodeficiency-associated LPDs’ category by the World Health Organization (WHO) in 2001 (4). MTX-LPD have characteristics of elderly patients, more females, more Diffuse large B cell lymphoma (DLBCL), more EBV positivity, and poor prognosis (5).

Case report

A 46-year-old woman was admitted to our hospital complaining of right thigh pain and fatigue. She had a medical history of RA for 5 years and 2 months. She had been receiving MTX (8-10 mg/week) for 4 years and 11 months and etanercept (25 mg/week) for 3 years and 5 months. Her RA activity had been well controlled with these drugs. The laboratory data showed the following elevated values: Leukocyte, 8,200/µl (normal range: 4,300-8,000/µl); C-reactive protein (CRP), 10.07 mg/dl (normal range: 0-0.40 mg/dl); calcium, 11.5 mg/dl (normal range: 7.0-10.0 mg/dl); inorganic phosphorus, 6.0 mg/dl (normal range: 2.9-4.3 mg/dl); alkaline phosphatase, 442 U/l (normal range: 115-359 U/l); lactate dehydrogenase (LD), 466 U/l (normal range: 119-229 U/l); and soluble interleukin-2 receptor (sIL-2R), 2,900 U/ml (normal range: 124-466 U/ml). On examination for infection, serological tests revealed that the Epstein-Barr virus (EBV) viral capsid antigen immunoglobulin G titer was high, which indicated a current infection.

Hip X-ray image showed an ill-defined osteolytic lesion and pathological fracture of the right femoral trochanter (Fig. 1A and B, white arrows). Magnetic resonance imaging (MRI) showed that the masses in the bilateral femur and iliac had a low intensity on the T1-weighted image (T1WI) and high intensity on the T2-weighted image and were enhanced on gadolinium enhanced-T1WI (Fig. 2A-C). Whole-body computed tomography demonstrated axillary, mediastinal, and external iliac lymphadenopathies. Further, 18F-fluoro-deoxy-glucose positron emission tomography (18F-FDG-PET) showed some abnormal uptakes in the ribs, pelvis, femur, and lymph nodes (Fig. 3A-D).

Figure 1. Initial hip X-ray image. Ill-defined osteolytic lesion and pathological fracture of the right femoral trochanter were detected. (A) Anteroposterior view; (B) lateral view. The white arrows indicate pathological fracture of femoral neck.

Figure 2. Initial magnetic resonance imaging. The mass was detected diffusely at the bilateral femur and iliac. (A) T1-weighted image; (B) T2-weighted image; (C) contrast-enhanced T1-weighted image.

Figure 3. 18F-fluoro-deoxy-glucose positron emission tomography (PET). (A) Whole-body PET showed multiple abnormal uptakes. (B) PET-computed tomography (CT) of the thoracic level. The SUVmax was 21.6 at the right axillary lymph node. (C) PET-CT of the iliac bone. The SUVmax was 10.2 at the left iliac bone. (D) PET-CT of the ribs showed abnormal uptakes at some ribs. The SUVmax was 5.46-7.82.

We performed open biopsy and palliative surgery using an intramedullary nail, because we considered that complete resection was impossible. The specimen showed diffuse infiltration of monotonous lymphoid cells (Fig. 4A). Immunohistochemical studies demonstrated that the infiltrating mononuclear cells were predominantly positive for CD79a, CD20 and MUM-1. CD10 and B-cell lymphoma 6 were not detected (Fig. 4B-D). The histological diagnosis was diffuse large B-cell lymphoma (DLBCL) of non-germinal center B type (non-GCB type).

Figure 4. Histological findings. (A) H&E staining showed diffuse infiltration of monotonous lymphoid cells. (B-D) Immunohistological studies. Infiltrating mononuclear cells were predominantly positive for CD20 (B) and MUM-1 (C), but negative for B-cell lymphoma 6 (D).

We referred the patient to a hematologist. Following withdrawal of MTX, her LD and sIL-2R levels decreased gradually at 4 weeks. Furthermore, osteoblastic change in the iliac bone was observed on an X-ray image. Based on the overall clinical data, the multiple bone tumors were diagnosed as MTX-LPD.

However, her LD and sIL-2R levels increased rapidly after 2 months. Further, 18F-FDG-PET revealed progressive disease. She received a total of five cycles of R-CHOP (rituximab, 375 mg/m2; cyclophosphamide, 750 mg/m2; doxorubicin, 50 mg/m2; vincristine, 1.4 mg/m2; and oral prednisolone, 225 mg) on days 1-5 on a 21-day schedule. After chemotherapy, she experienced nausea and headache. Thus, she underwent MRI of the head, and intracranial dissemination of the DLBCL was observed. Then, she also underwent cranial irradiation, one cycle of mini MEAM (ranimustine, 50 mg/day; etoposide, 100 mg/day; cytarabine, 200 mg/day; and melphalan, 20 mg/day) on days 1-3, and two cycles of IT triple (MTX, 15 mg; cytarabine, 40 mg; and prednisolone, 10 mg). After the three cycles of chemotherapy, she received haplo-peripheral blood stem cell transplantation (haplo-PBSCT). After haplo-PBSCT, her intracranial lesion disappeared, and her symptoms improved.

At the final follow-up, tumor condition was no evidence of disease. She had no pain of her lower legs, and walking alone. X-ray showed sclerotic change of bilateral proximal femurs were observed (Fig. 5).

Figure 5. At the final follow-up, X-ray shows sclerotic change of bilateral proximal femurs. (A) Anteroposterior view; (B) Lateral view.

Discussion

The prevalence of RA is slightly different among countries worldwide; however, the prevalence is ~0.5%, and the estimated number of affected patients is 800,000 in Japan (6). RA is a systemic inflammatory disease characterized by the destruction of the articular structures and synovitis in multiple joints. MTX is an anti-rheumatic drug that is expected to have an excellent suppressive effect on articular destruction (7). For this reason, MTX is currently a widely used key drug for the treatment of patients with RA. However, patients with RA have a high risk of developing LPDs (3). Furthermore, LPD in patients with RA treated with MTX is defined as MTX-LPD in the 2001 WHO classification of tumors of hematopoietic and lymphoid tissues (4). Although the detailed mechanism of the occurrence of MTX-LPD is unknown, it is considered that MTX is involved as an etiology because there are cases where LPD had a complete regression after withdrawal of MTX alone (8). Furthermore, patients with RA treated with high-dose MTX (over 8 mg/week) are at a high risk of developing LPDs (9).

The clinical findings of MTX-LPD include fever, weight loss, and swelling of superficial lymph nodes. In the blood sampling data, high levels of CRP, LD, and sIL-2R are observed. In MTX-LPD, lymphomas occur in half of the lymph nodes and half of the extranodal lesions, such as the skin, gastrointestinal tract, salivary gland, thyroid, and nasal cavity (4,10). As in this case, multiple bone lesions accompanying a pathological fracture were not detected. The percentage of the pathological diagnosis of lymphomas in patients with RA is 35 to 60% for DLBCL and 12 to 25% for Hodgkin's lymphoma (5). In our case, the pathological diagnosis was DLBCL.

EBV is a known oncogenic virus involved in lymphomagenesis. An immunodeficiency status is considered to provide the basis for the onset of malignant lymphomas through the activation of EBV. The EBV-positive rate in MTX-LPD is 27.6 to 95%, which is significantly higher than that in sporadic LPD (9.9%) (3,11,12). Kamel et al (13) reported that MTX-LPD was associated with EBV because some cases of EBV-positive MTX-LPD spontaneously regressed after the withdrawal of MTX. Further, Feng et al (14) showed that MTX directly releases infectious virions and induces reactivation of EBV infection. No case of non-MTX-LPD showed spontaneous regression. In our case, the EBV result was positive; thus, she stopped using MTX. However, her condition did not improve, and the LD and sIL-2R levels in her blood sampling data increased rapidly after 2 months. Miyazaki et al (8) reported that the complete remission rate of MTX-LPD was ~30% with MTX withdrawal; however, the complete remission rate was as high as 60% in their EBV-positive cases. Therefore, many cases resulted in complete remission within 2 weeks. In this case, temporary improvement was obtained after MTX withdrawal; however, complete remission was not achieved within 2 weeks. Therefore, the patient was determined to have progressive disease after 2 months. For cases wherein complete remission cannot be obtained within 2 weeks, we should consult with hematologists and need to introduce chemotherapy.

Since DLBCL of a non-GCB type diagnosed on immunohistochemistry usually has a poor prognosis (15), we need to consider introducing chemotherapy. In summary, we experienced an MTX-LPD case with a pathological fracture. We need to consider MTX-LPD when pathological fractures occur in patients with RA treated with MTX.

Acknowledgements

The authors would like to thank Dr Yuko Kuwae of the Department of Diagnostic Pathology, Osaka City University Graduate School of Medicine (Osaka, Japan) for their assistance with pathological examinations and interpretations.

Funding

No funding was received.

Availability of data and materials

All data generated or analyzed during this study are included in this published article.

Author's contributions

NO designed the study and wrote the initial draft of the manuscript. MH contributed to analysis and interpretation of data and assisted in the preparation of the manuscript. MI, TI, ST, MO and HN contributed to data collection and interpretation, and critically reviewed the manuscript. All authors approved the final version of the manuscript.

Ethics approval and consent to participate

The patient provided consent.

Patient consent for publication

The patient and her family were informed that the data from her case would be submitted for publication and provided consent.

Competing interests

The authors declare that they have no competing interests.

Glossary

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References