Multiple primary bone lymphoma in children: a case description

Introduction

Bone lymphoma is a malignant tumor of lymphoid tissue that typically develops in the bone marrow or bone. Histologically, it is distinguished by abnormal proliferation of lymphocytes, histiocytes, and precursors (1). It is classified into primary and secondary. Primary bone lymphoma (PBL) is a rare type of lymphoma that affects only the bones or marrow. The main clinical manifestations are bone pain and accompanying symptoms, such as local bone pain, limited limb movement, decreased muscle strength, and local mass; the disease is rarely associated with the whole body symptoms, although pediatric patients with limb involvement may have generalized dysfunction (2). Imaging examination can show cortical bone destruction and soft tissue invasion and early changes of the medullary cavity. This case report describes the clinical symptoms and imaging findings of a child with multiple PBLs to guide clinical diagnosis and treatment.

Case presentation

A 12-year-old girl was admitted to the hospital with recurrent pain in her left knee and right shoulder for one year. The left knee pain had begun a year prior without apparent cause, and there was no obvious correlation between the pain and movement. The pain was associated with restricted joint movement. Resting could help relieve the pain. There was no dizziness or headache, no sensitivity to hot or cold, no chest tightness or palpitations, no abdominal pain or distension, and no limb spasms. During her hospitalization, she was treated with anti-inflammatory medications and traditional Chinese medicine physiotherapy at a local hospital, which helped to alleviate her symptoms. Following that, the symptoms returned, and the right shoulder pain gradually developed. The patient was then transferred to our hospital’s outpatient department for further evaluation and treatment. The outpatient department planned to admit the patient for “pain in the left knee and right shoulder”. Physical examination revealed that the upper and lower limbs were roughly equal in length. The skin temperature of both knees was slightly higher, the left knee joint was slightly swollen, and there was mild tenderness around the joint. There were no visible ulcers or pus discharge. The fingertips on both lower limbs had good blood supply without numbness, and a physical examination of the other limbs revealed no unusual findings. The muscle strength and tone in the limbs were normal. Blood routine revealed the following: white blood cell (WBC) count 10.13×10⁹/L; hemoglobin 116 g/L; high-sensitivity C-reactive protein (CRP) 44.56 mg/L; erythrocyte sedimentation rate (ESR) 46 mm/h; reticulocyte count 0.1×10¹²/L; platelet count 233×10⁹/L; serum lactate dehydrogenase (LD) 239 IU/L; Epstein-Barr virus nucleic acid testing (DNA) <500 copies/mL.

Radiological examination: X-ray showed multiple bone destruction of bilateral humeral head, femoral head, and tibia; bone destruction of the tibia was unilateral; computed tomography (CT) examination showed multiple osteolytic bone destruction of skull, mandible, sternum, sternal vertebra, and iliac bone, discontinuity of adjacent cortical bone, linear periosteum hyperplasia, and formation of masses in the surrounding soft tissue. Magnetic resonance imaging (MRI) examination showed multiple bone edema of the femur, tibia, ilium, and sacrum, surrounding soft tissue masses. Enhancement scans of the bone showed uneven enhancement (Figures 1-3).

Figure 1 X-ray showing bone destruction in the extremities and pelvis. (A) Bone destruction in the proximal humerus. (B) At the midshaft of tibia, eccentric bone destruction and adjacent cortical thickening can be observed. (C) Multiple bone destruction in the bilateral proximal femur, ilium, and sacrum.

Figure 2 CT examination showing bone destruction and surrounding soft tissue lesions. (A) Bone destruction in the skull. (B) Bone destruction and compression changes in the vertebrae. (C) Osteolytic bone destruction in the sacrum and ilium. (D) Soft tissue mass formation around bone destruction. CT, computed tomography.

Figure 3 MRI examination showing bone destruction and surrounding soft tissue lesions. (A) Decreased T1WI signal in the femur and tibia. (B) Heterogeneous slightly higher T2WI signal. (C) Slightly higher fat suppression signal (T2WI). (D) Heterogeneous enhancement on enhanced scan. MRI, magnetic resonance imaging; T1WI, T1-weighted image; T2WI, T2-weighted image.

Pathological examination: samples for pathological examination were obtained from the bone tissue of the right iliac crest lesion, measuring 1.0 cm × 1.0 cm × 0.3 cm. Tumor cell invasion was observed in the lesion bone tissues, with high magnification revealing the following: the cells were uniform, medium-to-large, with round nuclei, some nucleoli around the nuclear membrane, less cytoplasm, and basophilic. Immunohistochemical analysis: LCA(+), CD99(+), Ki67(+, 95%), CK-Pan(−), EMA(−), SMA(−), MoyD1(−), CD56(−), Vim(−), CD34(−), S-100(−), HMB45(−), NSE(−), Syn(−), and CgA(−). Special staining: periodic acid-Schiff (PAS) staining was normal and reticular fibers staining was positive. Fluorescence in situ hybridization (FISH) analysis revealed MYC gene rearrangement. A pathological diagnosis was made of diffuse large B cell lymphoma with MYC gene rearrangement (Figure 4).

Figure 4 Pathological findings of tumor cell invasion were observed in the lesion bone tissues. (A) Stained with HE ×400, (C) stained with HE ×200 magnification: the cells were uniform, medium to large, with round nuclei, some nucleoli around the nuclear membrane, less cytoplasm, and basophilic. (B) Ki67 ×200, immunohistochemical: LCA(+), CD99(+), Ki67(+, 95%), CK-Pan(−), EMA(−), SMA(−), MoyD1(−), CD56(−), Vim(−), CD34(−), S-100(−), HMB45(−), NSE(−), Syn(−), CgA(−), special staining, PAS stain was normal, and reticular fibers staining was positive. HE, hematoxylin and eosin; PAS, periodic acid-Schiff.

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was provided by patient’s legal guardians for publication of this article and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

Giudici et al. (3) first proposed the criteria for the diagnosis of PBL: (I) the primary lesion was bone; (II) histological evidence was obtained from bone rather than other metastatic sites; and (III) no other extraosseous lesions were found within 6 months of the onset of symptoms of primary bone lesions. PBL is classified into non-Hodgkin’s lymphoma (NHL) and Hodgkin’s lymphoma (HL) based on clinical symptom classification, morphology, immunology, and genetics. Most PBLs are NHL, there are more B cell types, followed by T cell types, and the diffuse large B-cell lymphoma (DLBCL) is the most common pathological type, which may remain confined to one or more bone tissues for several years (4). Bone lymphoma is relatively rare, accounting for only 7% of bone malignant tumors and 5% of extranodal lymphomas. It is more common in adults, peaking between the ages of 50 and 70 years (5,6). The ratio of male to female in PBL patients was 1.5:1. Although PBL in children is rare, it has a better prognosis than that in adults, and the complete remission rate is more than 95%. The treatment of PBL is mainly chemotherapy and radiotherapy; the role of surgery in the management of PBL is generally limited. Most surgical procedures have been performed for diagnostic purposes, namely biopsy. When PBL involves areas associated with significant bone marrow production, such as the pelvis, or extensive areas of bone, the application of radiation therapy should be carefully considered to avoid hematopoietic-related complications. Multiple bone malignant lymphoma in children is uncommon, and it is difficult to distinguish other bone malignant tumors in children due to similar symptoms, which was the original purpose of this case report.

In this study, the majority of bone lymphoma were osteolytic bone destruction lesions, with local large lytic bone destruction that was infiltrative or cannibalized and had unclear boundaries. Soft tissue mass was observed around the cortical bone destruction, which was larger than the bone destruction area. The periosteal reaction was fairly mild. The longest-occurring sites were the bones of the limbs, and the spine, pelvis, sternum, and bones of the head and face may also be involved. The affected bone usually contained red bone marrow, which originated in the medullary cavity and spread throughout the long bone shaft. The lesions generally exhibited eccentric bone destruction, which means that the bone destruction significantly dominated on one side. Furthermore, other studies have also discovered that PBL spread primarily along the long axis of the diaphysis in tubular bone, with most of them growing laterally (7), indicating that eccentric bone destruction has specific characteristics. On CT examination, PBL demonstrated relatively mild “worm erosion”, with multiple small bone destruction foci gradually fused and extensive (8); infiltrative bone destruction and bone morphology were relatively complete when infiltrated along the Harvard canal, also known as cortical fenestration sign (9). Among the large masses surrounding the tumor bone, also known as wrapping sign, more than half showed a slight periosteal reaction and long bones were more common. Periosteal reaction is uncommon or absent in the spine and flat bones (8). Yu et al. (10) described the “ice floe sign” as a unique sign seen in PBL, indicating that the lesion exhibits a wide range of erosive bone destruction, blurred boundaries, and uneven increase in residual bone density. The original shape and contour of the affected bone were still preserved, resulting in bone destruction similar to newly melted floating ice, which has some significance for the diagnosis of PBL. This case was defined by widespread bone destruction throughout the body. Previous cases have reported that children with bone lymphoma had only one or two bone lesions, usually on long bones, but this case involved long bones, flat bones, and irregular bones. The “floating ice sign” could also be found in the iliac lesions. The MRI revealed equal/low signal on T1-weighted image (T1WI), variable medium/high signal on T2-weighted image (T2WI), and limited diffusion on diffusion-weighted imaging (DWI). The lesions were enhanced to varying degrees, and the enhancement range was larger than the routine scanning; the extent of peripheral soft tissue invasion is clearly demonstrated. MRI revealed a much wider range of lesions than plain film or CT findings. It is critical to investigate cases with abnormal bone lesions on MRI but mild or no visible bone destruction on plain film and CT.

Bone lymphoma should be distinguished from pyogenic osteomyelitis, Langerhans histiocytosis (LCH), osteosarcoma, leukemia infiltration, multiple myeloma, and bone metastatic cancers. Pyogenic osteomyelitis is usually caused by a bacterial infection. In this group of cases, the blood sedimentation rate and CRP levels were elevated, and MRI revealed an edema-like T2WI high signal in the bone that was easily confused with inflammatory lesions. However, osteomyelitis can cause osteoporosis, bone destruction, bone sclerosis, sequestrum formation, and peripheral soft tissue swelling in contrast to soft tissue mass formation (11). It has been hypothesized that persistent inflammatory stimulation in the tumor area and surrounding local area causes some inflammatory cells to accumulate more mutations over time, resulting in lymphoma. It has also been proposed that long-term chronic osteomyelitis makes a specific area of bone more susceptible to secondary lymphoma (12). LCH may also have multiple bone lesions throughout the body, which is more common in children. The periosteal reaction is more visible; the bone exhibits expansive bone destruction, the bone cortex thins under pressure, and lamellar periosteal proliferation can be seen. Osteosarcoma develops at a younger age than does bone lymphoma. Osteosarcoma typically develops in the metaphysis of long bones, but diaphysis is uncommon. Tumor bone formation can be seen, and the periosteal reaction is more severe than that of bone lymphoma. Leukemic bone infiltration is the most common type of malignant tumor in children. The clinical symptoms are obvious, and the diagnosis can be confirmed through laboratory and bone marrow aspiration tests. Multiple myeloma typically presents as a round osteolytic bone destruction with little surrounding sclerosis and no periosteal reaction. Bence-Jones (13) was found to be positive in urine in 50% of the patients, and the age of onset was over 40 years. Bone metastases often have a history of primary tumors, with obvious bone destruction and small surrounding soft tissue masses; soft tissue masses are frequently more localized than PLB.

In this case, the patient had an increased ESR without a fever, an elevated CRP level in laboratory tests, bone destruction in multiple bones throughout the body, and the formation of soft tissue masses. Pathology confirmed that the patient had bone lymphoma, which was treated with radiotherapy and chemotherapy. Radiotherapy and chemotherapy are highly effective against bone lymph node tumors. If patients’ prognoses can be improved through early and accurate diagnosis, as well as timely radiotherapy and chemotherapy, approximately 4 out of 5 patients can live for up to 5 years. Currently, it is difficult to distinguish between bone lymphoma and osteomyelitis in clinical, laboratory examination, and imaging. The diagnosis is primarily based on pathological findings, so a pathological biopsy is required for patients with suspected osteomyelitis.

Acknowledgments

None.

Footnote

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-24-945/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was provided by the patient’s legal guardians for publication of this article and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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