Rare case of primary bone lymphoma of the femur

Abstract

Primary bone lymphoma is a rare type of lymphoma that arises from skeletal tissue. Most cases described are non-Hodgkin’s lymphoma with diffuse large B-cell lymphoma being the most common subtype. While it is common for non-Hodgkin’s lymphoma to have secondary skeletal system involvement, primary involvement of the skeleton is surprisingly rare. Primary bone lymphoma accounts for less than 5% of all primary bone malignancies, 4%–5% of extranodal lymphomas and less than 1% of all non-Hodgkin’s lymphoma. We present an interesting case of a young adult male who was diagnosed with primary bone lymphoma of the femur. Interestingly, his initial X-ray imaging revealed no osseous abnormality and subsequent MRI revealed an infiltrating mass. The patient was treated with chemotherapy of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone resulting in complete remission.

Background

Primary bone lymphoma (PBL) is one of the rarest primary bone malignancies and is characterised as a lymphoma that affects skeletal tissue.¹ Most cases are diffuse large B-cell lymphoma (DLBCL), a subtype of non-Hodgkin’s lymphoma (NHL).² DLBCL classically presents with a quickly growing mass evolving from one or multiple lymph nodes, although 40% of cases have a primary presentation of an extranodal location.³ PBL comprises 4%–5% of extranodal lymphomas and less than 1% of all NHL.^{2 4} While it is common for NHL to have secondary skeletal system involvement with disease progression, primary involvement of the skeleton is extremely rare. PBL accounts for less than 5% of all primary malignant bone tumours.^{2 4} We present an interesting case of a young adult male who was diagnosed with primary DLBCL of the femur.

Case presentation

A man in his late 20s with no significant medical history presented to the hospital with worsening left knee pain. His knee pain had been gradually worsening over the past year, but acutely worsened after a motor vehicle accident 3 months prior. X-rays were negative at the time of the crash. The left knee pain and swelling had become debilitating requiring crutches for ambulation and hospital admission. He denied fever, night sweats, weight loss or any other joint pain. The patient was afebrile and haemodynamically stable. His physical examination revealed tenderness to palpation of the medial aspect of the left knee, oedema of the knee joint, and severe pain with flexion of the knee.

Investigations

Initial laboratory results were unrevealing. X-ray of the left knee again revealed no osseous abnormality, prompting further investigation (figure 1). MRI of the left knee revealed an infiltrating mass extending from the left distal femur diaphysis to the epiphysis with cortical breakdown and soft tissue extension suspicious for osteosarcoma (figure 2). The femur bone lesion was biopsied and demonstrated focal sheets of large atypical lymphoid cells with irregular nuclear contours, fine chromatin and some with prominent nucleoli (figure 3). Immunohistochemical (IHC) studies of the large, atypical lymphocytes were positive for CD20, CD10, BCL2, BCL6 and Pax5 (figure 4). IHC testing was negative for CD5 and MUM-1. Additional testing revealed a Ki-67 proliferation index of 50%. Epstein-Barr encoding region in situ hybridisation testing was negative. Flow cytometry revealed atypical B-cell population (10%) identified with CD20 expression. Overall pathology findings were consistent with DLBCL, germinal centre subtype.

Figure 1.

Initial X-ray of left knee demonstrating no osseous or soft tissue abnormalities.

Figure 2.

Coronal T1 (A), sagittal T2 fat saturated (B) and axial T1 post-contrast (C) images of the knee demonstrating an avidly enhancing heterogeneously T2 hyperintense infiltrating mass extending from the distal femoral metadiaphysis to the epiphysis with cortical breakthrough (red arrow) and a soft tissue component (white arrow).

Figure 3.

Haematoxylin and eosin biopsy section from distal femur lesion showing sheets of large, atypical lymphocytes with irregular nuclear contours and prominent nucleoli, intermixed with histiocytes and other blood elements (40x magnification).

Figure 4.

Immunochemistry of the case showing positive staining for CD20 (A), PAX5 (B), CD10 (C), BCL6 (D), BCL2 (E) and Ki-67 highlighting >50% of neoplastic cells (F).

Oncology was consulted and the patient subsequently underwent staging to help guide treatment modalities. CT of the neck, chest, abdomen and pelvis had no pathologically enlarged lymph nodes. Nuclear medicine (NM) bone scan revealed an intense focal uptake within the distal left femur without additional focal areas of increased uptake to suggest further metastatic osseous lesions (figure 5). Bone marrow biopsy demonstrated normocellular marrow with no evidence of involvement by lymphoma. He was diagnosed with stage IV DLBCL with an International Prognostic Index (IPI) of 2 points.

Figure 5.

Planar Tc-99m-MDP bone scan demonstrating focal and asymmetrically increased tracer uptake in the distal left femur (red arrow).

Differential diagnosis

Differential diagnoses for bone masses can vary depending on age, morphology and location within the bone. Our case had imaging revealing an infiltrating mass extending from the distal femoral metadiaphysis to the epiphysis with cortical breakdown. Due to involvement of the metaphysis, additional differential diagnoses include osteosarcoma, chondrosarcoma, bone cyst and fibroma. Involvement of the diaphysis increases the differential to include Ewing’s sarcoma, osteoblastoma and fibrous dysplasia. Primary involvement of the epiphysis typically increases suspicion for giant cell tumour or chondroblastoma. In older patients, metastatic malignancy and multiple myeloma should always be ruled out. It is always important to consider infection, especially in patients with intravenous drug use and poorly controlled diabetes, as osteomyelitis can mimic a malignant bone tumour.

Treatment

He was treated with a chemotherapy regimen of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) for a total of six cycles. He did not receive any surgical or radiation intervention.

Outcome and follow-up

Our patient completed the six cycles of chemotherapy without any major complications. He tolerated the therapy well and had significant improvement in his initial presenting symptoms. His left knee pain alleviated to the point where he could ambulate without crutches. Follow-up positron emission tomography (PET) scan of the whole body obtained 6 weeks after completing chemotherapy demonstrated slightly increased metabolic activity within the distal left femoral metadiaphysis with a Deauville score of 2. Oncology deemed PET scan results indicative of a complete remission and did not recommend any further chemotherapy. He will continue to closely follow with oncology at regular intervals for continued disease monitoring.

Discussion

The definition of PBL can vary; although, it is generally defined as a malignant lymphoid neoplasm arising in an osseous site without regional lymph node or visceral involvement.⁵ PBL has a male preponderance and the median age for diagnosis ranges between 45 and 60 years.^{1 6} Patients most commonly present with localised bone pain and soft tissue swelling, while other symptoms include pathologic fractures or systemic B symptoms (fevers, night sweats, weight loss).1 2 4 6 PBL can present in any bone of the skeleton; however, the femur has been the most commonly reported site.1 2 5 6 Other commonly affected bones include the pelvis, tibia, humerus, vertebra, scapula, and mandible.^{2 5 6}

Diagnosis of PBL can be difficult as initial radiological findings are non-specific with a wide variety of findings. Radiographic findings can range from normal bone appearance to large infiltrative lesions.² PBL most commonly presents on plain radiologic films as extensive osteoblastic or osteolytic lesions involving the cortex with reactive periosteal findings.⁴ It can be challenging to distinguish PBL from other bone pathology given the non-specific imaging findings. For example, the periosteum reactive changes in PBL, such as onion skin layering or sunburst appearances, have findings similar to osteosarcoma.⁷ Differential diagnoses that appear similar on radiological imaging include Ewing’s sarcoma, chondrosarcoma, Langerhans cell histiocytosis, osteomyelitis, metastasis of solid tumours and secondary lymphoma.^5–7 Contrast-enhanced CT and MRI help to assist in diagnosis by providing greater detail to tumour boundaries and extent of disease.¹ Our patient’s case differed in the fact that original radiographs of the knee were entirely unrevealing, which prompted further evaluation with a more sensitive modality such as MRI. Although uncommon, it is important to recognise that PBL may not be detectable on plain radiographs, which are primarily used as a screening exam before more timely and expensive imaging methods are utilised.

Histopathology of the bone lesion biopsy remains the gold standard for diagnosis; although, it is still necessary to obtain comprehensive imaging and bone marrow biopsy for complete staging. The majority of PBLs are DLBCL, the most common subtype of NHL.² Jawad et al⁸ performed a large cohort study analysis of 1500 patients with PBL, which showed that 66.3% of PBL cases were DLBCL.⁹ Histologically, DLBCL is characterised by a diffuse pattern of large atypical lymphoid cells with large nuclei with prominent nucleoli. Immunochemistry of the neoplastic DLBCL cells express B-cell antigens such as CD19, CD20, CD22 and CD79a.^{2 8} Immunochemical profiling is also used for prognostication, where the expression of BCL2, BCL6, MUM-1 and MYC is considered poor prognostic factors.^{2 8}

Staging of PBL is based on the Lugano Classification System¹ (table 1). Stage IE represents disease limited to a single extranodal site, while stage IIE disease is characterised by a single bone lesion and regional lymph node involvement. Stage IV disease is defined by multifocal disease of the skeleton. Prognosis is based on stage of disease, with a 5-year overall survival rate of 38% for stage IV and 82% for stage IE.¹ IPI is a scoring system for conventional lymphomas based on age, performance status, lactate dehydrogenase level, number of extranodal sites and clinical stage.¹⁰ IPI has little prognostic value in PBL because staging and extranodal site involvement are unique characteristics of this type of lymphoma.¹

Table 1.

Staging of PBL based on the Lugano Classification System

Stage	Involvement
IE	Limited to a single extranodal site.
IIE	Single bone lesion and regional lymph node involvement.
III	Lymph nodes on both sides of diaphragm.
IV	Multifocal disease of the skeleton.

PBL, primary bone lymphoma.

Treatment options available for PBL include chemotherapy, immunotherapy, surgery and/or radiation. The role of surgery is limited to bone biopsy for histopathology evaluation, bone stabilisation and fixing pathological fractures.⁷ Since most cases of PBL are DLBCL, the cornerstone treatment is immunochemotherapy with R-CHOP.^{1 7} According to the IELSG-14 study, patients treated with anthracycline-based chemotherapy tend to have a favourable prognosis, regardless of receiving radiation therapy or not.¹¹ A retrospective multicentre Rare Cancer Network study by Cai et al¹² showed PBL treated with chemotherapy followed by radiotherapy had superior overall survival and better outcomes. Radiation therapy for treatment of PBL is debated and is given based on risk–benefit evaluation.

PBL is a rare diagnosis. This case describes a young adult man presenting with knee pain who was diagnosed with primary bone DLBCL. His initial knee X-ray revealed no osseous abnormality and subsequent MRI confirmed an infiltrating left femur mass. It is essential to have a high clinical suspicion for underlying malignancy even with negative initial radiologic imaging. Although PBL is uncommon, it is important to consider PBL as a differential diagnosis in patients presenting with a bone mass.

Patient's perspective.

• I never thought I would be diagnosed with cancer so young. I am thankful that they found the cancer early before it spread through my body. Going through chemotherapy is difficult, but I am hopeful that I will have a full recovery and I will be a cancer survivor.

Learning points.

• Primary bone lymphoma (PBL) is a rare type of lymphoma that accounts for less than 5% of all primary bone malignancies.

• PBL typically presents with localised bone pain, soft tissue swelling, fracture or B symptoms.

• PBL most commonly presents on plain radiograph with osteoblastic or osteolytic lesions; however, initial radiologic findings can also appear normal making diagnosis difficult.

• This case highlights a diagnosis of PBL of the femur after initial radiograph imaging was negative and further imaging with MRI revealed an underlying infiltrative mass.

• It is essential to have a high clinical suspicion for underlying malignancy even with negative initial radiologic imaging.

Ethics statements

Patient consent for publication

Consent obtained directly from patient(s).