Implant-Associated Diffuse Large B-Cell Lymphoma following Total Knee Replacement Arthroplasty: Case Report of a Non-EBV-Related Case with Review of Literature

Abstract

Implant-related sarcomas are infrequent but well-known complications following joint replacement surgery. Periprosthetic lymphomas are still rarer and difficult to diagnose as they can clinically mimic aseptic loosening or joint infection. A 68-year-old female who underwent knee replacement surgery 2 years earlier presented with pain in the left knee and thigh. Imaging findings were suggestive of prosthesis-related sarcoma. CT-guided biopsy revealed diffuse large B-cell lymphoma and Epstein − Barr virus-encoded RNA testing by in situ hybridization was negative. The patient received five cycles of chemotherapy, and post-therapy her radiographs showed complete resolution of the extraosseous soft tissue component in the suprapatellar recess and posterior aspect of the femur. Whole body PET-CT also showed complete resolution of metabolically active lesion in the left distal femur. Most metallic-implant-associated lymphomas are associated with Epstein − Barr virus infection. Non-Epstein-Barr virus-related lymphomas are rarer, and a high index of suspicion should be kept in mind in cases of prosthetic failure.

Keywords

implant-associated lymphomas - B-cell lymphoma - Epstein-Barr virus - in situ hybridization

Introduction

The use of orthopedic prosthetic devices in joint replacement surgery has transformed the treatment of patients with degenerative joint disease and fractures. It substantially improves the quality of life by providing symptomatic relief and quick restoration of joint function. Regular follow-up of these patients has resulted in increased detection of long-term complications and prosthetic failure. Although the number of implant surgeries has increased considerably in the recent times, cases of periprosthetic lymphomas remain rare.[1] Diagnosis is often challenging as it clinically mimics other conditions such as aseptic loosening or infection. It is important to distinguish periprosthetic lymphomas from other benign and malignant soft tissue tumors as improper management can lead to increased morbidity and poor outcomes. In this article, we report a rare case of implant-associated lymphoma following total knee arthroplasty in a 68-year-old female, in which prompt diagnosis resulted in an excellent patient outcome.

Case Report

A 68-year-old female presented with back pain radiating to the left lower limb for 1 month. On investigation, radiographs revealed age-related degenerative spine disease. MRI of the lumbosacral spine was suggestive of degenerative disk disease with diffuse disk bulge causing thecal sac indentation and neural foramina narrowing. Her pain was partially relieved after medical treatment. Ultrasound abdomen and pelvis showed no obvious abnormality except non-obstructing renal calculi measuring 5 mm. On high-resolution ultrasound of the neck, a tiny benign nodule measuring 2 mm was detected in the right lobe of thyroid, without any obvious lymphadenopathy. Two months later she complained of pain in the left knee and thigh of 10 days duration. The pain was sudden in onset, gradually progressive and localized to the knee. She had difficulty in walking, which aggravated with knee movements. She had a past history of total knee replacement performed 2 years earlier. She had also undergone laparoscopic-assisted vaginal hysterectomy 15 years earlier and closed mitral valvotomy 30 years earlier. On examination of her left knee, a well-healed surgical scar was noted with minimal swelling. She had tenderness over left distal femur extending along the joint line to the proximal tibia.

Active knee movements were painful at the terminal range. There was no evidence of crepitus or neurovascular deficits. Her general condition was fair with ECOG (Eastern Cooperative Oncology Group) Performance Status Scale Grade 2. Hemogram, routine urine examination, liver and renal function tests were within normal limits. However, she had elevated levels of erythrocyte sedimentation rate (130 mm in the first hour) and C-reactive protein (28 mg/L). There was mild elevation of LDH (262 U/L). Other laboratory parameters like serum procalcitonin, IL-6, and D-dimer levels were within normal range. Blood culture showed no growth after 36 to 48 hours of aerobic incubation at 37°C.

X-ray was suggestive of pathological fracture at the periprosthetic region. Computed tomography showed cortical break along the anterior aspect of femur with associated extraosseous soft tissue. There was no evidence of mineralization and the lesion extended into the suprapatellar recess and the posterior aspect of the femur ([Fig. 1]). MRI of the left thigh and knee showed metallic artifacts around the knee joint, with irregular altered signal intensity in the diaphysis and metadiaphysis of the distal femur. The lesion was hypointense on T1-weighted images and hyperintense on T2-weighted and STIR (Short Tau Inversion Recovery) images with heterogeneous post-contrast enhancement. There was focal cortical discontinuity in the posterior cortex of the distal femur. The adjacent soft tissue component and anterior compartment of the thigh muscles (vastus intermedius and medialis) also showed altered signal intensity, appearing hypointense on T-weighted images and hypertense on T2/STIR images, with heterogeneous post-contrast enhancement, suggesting the possibility of a metal prosthesis-related sarcoma. A few enlarged popliteal nodes were also noted ([Fig. 2]). PET-CT imaging from the base of the skull to mid-thigh showed an FDG avid lytic destructive lesion in the distal end of the left femur with a soft tissue component, adjacent fat stranding and muscle edema (max SUV 24.6). In addition, FDG-avid enlarged ipsilateral popliteal and femoral nodes as well as bilateral pulmonary nodules were pointed out. CT-guided biopsy of the left distal femur was performed and the specimen was sent for histopathological examination. Biopsy showed large areas of coagulative necrosis with shadow outlines of necrotic cells, along with a viable cellular lesion. This lesion comprised sheets of polygonal cells with round to indented nuclei, distinct nucleoli, and abundant pale eosinophilic to clear cytoplasm. At some sites, there was entrapment of the host bony trabeculae by the tumor cells ([Fig. 3]). On immunohistochemistry, the tumor cells were positive for LCA and B-cell markers including CD20 and PAX5. The tumor cells were negative for other lymphoid-associated markers, such as CD3, CD30, CD138, and ALK. The tumor cells were also negative for epithelial markers like Pan CK, GATA3, TTF1, and the marker of osteoblastic differentiation SATB2. The Ki67 labeling index was 40% ([Fig. 4]). The histopathological features were suggestive of diffuse large B-cell lymphoma. Epstein-Barr-encoded RNA (EBER) testing by in situ hybridization (ISH) was negative.

Fig. 1 (A) Topogram image showing total knee replacement prosthesis. (B) Sagittal multiplanar reconstructed non-enhanced CT image, showing soft tissue density lesion in the distal end of femur (arrow). (C) Axial non-enhanced CT image showing cortical break along the anterior aspect of femur (dashed arrow) with extraosseous soft tissue with no mineralization extending into the suprapatellar recess anteriorly and along the posterior aspect of femur (arrows).

Fig. 2 (A) Sagittal T1-weighted MR image showing an isointense lesion in the marrow (arrow) with extraosseous soft tissue in the suprapatellar recess and posterior aspect of the knee (asterisks). (B) Subsequent sagittal T1-weighted MR image showing an enlarged popliteal node. (C) Sagittal T2-weighted image; (D) Sagittal STIR-weighted image; (E) Sagittal post contrast T1-weighted image showing the lesion is heterogeneous, of intermediate signal intensity and shows mild post-contrast enhancement (arrow) with associated extraosseous soft tissue (asterisks). STIR, Short Tau Inversion Recovery.

Fig. 3 Histological sections of core needle biopsy. (A) Cores of necrotic tumor with an adjacent core of viable tumor [H&E; ×20]. (B) Necrotic tumor on the right side showing shadow outlines of necrotic tumor cells surrounding a fragment of bone trabeculae. The adjacent viable area on left shows tumor cells arranged in a diffuse sheet [H&E; ×100]. (C, D) Viable tumor at higher magnification showing round to polygonal tumor cells with round, indented, or lobulated nuclei and moderate to abundant eosinophilic to clear cytoplasm [H&E; C × 200, D × 400].

Fig. 4 Immunohistochemistry findings. (A) Pan-cytokeratin negative in tumor cells [HRP-Polymer; ×400]. (B) Tumor cells showing positivity for vimentin [HRP- Polymer; ×400]. (C) LCA and (D) CD20 showing diffuse, strong membranous positivity in tumor cells [HRP-Polymer; ×400]. Tumors cells are negative for (E) CD3, (F) CD138, (G) CD30, and (H) ALK [HRP-Polymer; ×400].

Following the diagnosis of stage IVE lymphoma, the patient received five cycles of R-CHOP regimen, and her post-therapy radiographs showed reconstitution of the bony cortex at the site of the cortical break, with complete resolution of the extraosseous soft tissue in the suprapatellar recess and posterior aspect of the femur ([Fig. 5]). Additionally, follow-up whole body PET-CT performed after five cycles of chemotherapy showed complete resolution of metabolically active lesion in the distal left femur and associated lymph nodes. The patient has been on follow-up without any recurrence for 2 years.

Fig. 5 Follow-up radiograph of the left knee, post three cycles of chemotherapy. Anteroposterior (A) and lateral (B) radiographs of left knee show a total knee replacement prosthesis in situ. There is reconstitution of the bony cortex at the site of cortical break and complete resolution of extraosseous soft tissue in the suprapatellar recess and posterior aspect of femur. (C) Follow-up whole body PET-CT image, post three cycles of chemotherapy, showing complete resolution of the metabolically active lesion in the distal left femur.

Literature Review

Multiple postoperative complications, such as aseptic loosening, osteolysis, dislocation, fractures, infection, and tumors are associated with implant surgery. Prosthesis-related infection is a serious and the most common complication after joint replacement.[2] Implant-related sarcomas are infrequent but well-recognized complications. The majority of cases documented in literature are osteosarcoma and undifferentiated pleomorphic sarcoma, followed by rare instances of synovial sarcoma, angiosarcoma, fibrosarcoma, Ewings sarcoma, chondrosarcoma, and malignant peripheral nerve sheath tumor.[3] Primary non-Hodgkin lymphoma of bone is uncommon accounting for less than 5% of all extranodal non-Hodgkin lymphomas.[4] To date, only 14 cases of primary non-Hodgkin lymphoma associated with orthopedic metallic implants have been reported in the literature.[1] [5] The time interval between the insertion of the metallic implant and the diagnosis of lymphoma in these cases has ranged from 14 months to 32 years.[6] [7] [8] The present case had a shorter latency period of 2 years. Among the reported cases, the age at diagnosis ranged from 25 to 85 years with no gender predilection. Most patients had undergone hip arthroplasty prior to the diagnosis of lymphoma. A subset of patients presented following knee arthroplasty and insertion of internal fixation devices, such as plate and screws, for the treatment of fracture.[1]

Discussion

Metallic implant-associated lymphoma is a distinctive subgroup of EBV-associated diffuse large B-cell lymphoma arising in a setting of long-standing chronic inflammation.[9] Studies by King et al, Ladon et al, and Coen et al have explored the carcinogenic potential of wear particles from orthopedic implants.[10] [11] [12] Chronic antigenic stimulation and immunosuppression play an important role in the development of these tumors. Metal particles are antigenic and incite chronic inflammation by the release of proinflammatory mediators from the damaged cell membrane of the macrophages. Chronic inflammation within a closed space leads to immunosuppression. Immune dysregulation promotes the proliferation of EBV-transformed B cells, which escape host immune surveillance, leading to the development of lymphoma.[10] Other etiological factors, such as the long-term carcinogenic effects of exposure to high concentrations of metal ions, which may predispose to an increased risk of malignancy, do not have conclusive evidence. Wear particles from the implant show genetic instability through chromosomal injuries.[11] [12] Most cases are associated with concomitant EBV infection.[13] Cheuk et al demonstrated EBV infection by ISH in a 78-year-old male patient who developed lymphoma after a latency period of 22 years.[4] One of the published cases was negative for EBV by in-situ hybridization but showed positivity on polymerase chain reaction.[14] The present case was negative for EBV by EBER ISH. However, EBV negativity cannot be completely ruled out as polymerase chain reaction was not performed. Two other cases of EBV-negative metallic implant-associated lymphoma were reported in an 80-year-old female and a 76-year-old male, involving the left distal femur and right proximal tibia, respectively.[1] [7] The absence of a lesion at any site other than the vicinity of the joint replacement strongly indicates that the metallic prosthesis was responsible for the development of lymphoma in this case. However, the possibility of a primary bone tumor cannot be ruled out.

Imaging provides a baseline tool for the evaluation of prosthesis-related complications. Serial radiographs assessed over a period of time are useful for detecting prosthesis loosening.[15] CT and MRI are helpful in correctly identifying most causes, except infection. Periprosthetic fluid collection is indicative of infection. Other radiological features suggestive of infection, such as marrow edema, cortical destruction, and inflammatory changes in adjacent soft tissue, can overlap with bone tumors. Periprosthetic sarcomas are destructive bone lesions with associated soft tissue masses, showing variable signal intensity and heterogeneous enhancement on contrast.[16] [17]

Patients typically present with pain, lytic bone lesions, and prosthetic loosening. Some patients may present with a discharging sinus, clinically mimicking osteomyelitis.[13] In the present case, the imaging was indicative of a periprosthetic sarcoma and the diagnosis was later confirmed on biopsy. In contrast to the anaplastic large cell lymphoma associated with breast implants, most non-Hodgkin lymphomas associated with metallic orthopedic implants are large B-cell lymphomas. One case of ALK-negative anaplastic large cell lymphoma was reported 10 years following knee arthroplasty.[18] Another case of anaplastic large cell lymphoma has been published following the implantation of a plate for tibial fracture.[19] Parkhi et al reported a case of systemic anaplastic large cell lymphoma involving a metal rod implanted two decades prior for a femur fracture.[20] This study was thoroughly worked up with complete follow-up details. The only limitation of this study was that molecular work-up was not done for this study.

Conclusion

Non-Hodgkin lymphoma occurring in the vicinity of metallic implants is rare, and even more so for the non-EBV-associated cases. These lesions are diagnostically challenging, as they often mimic aseptic loosening, infection, or rarely, implant-associated sarcoma. They should be considered in the differential diagnosis for all patients presenting with pain, swelling, and lytic lesions following arthroplasty.

Conflict of Interest

None declared.

Patient Consent

The patient consent form is obtained.

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Publication History

Article published online:
05 February 2026