Lymphoma

Wakenda K. Tyler, MD, MPH, FAAOS

SOHEIL SABZEVARI, MD

Dr. Tyler or an immediate family member serves as a paid consultant to or is an employee of Johnson & Johnson and Stryker; serves as an unpaid consultant to Musculoskeletal Transplant Foundation; and serves as a board member, owner, officer, or committee member of American Academy of Orthopaedic Surgeons, J. Robert Gladden Society, and Musculoskeletal Tumor Society. Neither Dr. Sabzevari nor any immediate family member has received anything of value from or has stock or stock options held in a commercial company or institution related directly or indirectly to the subject of this chapter.

ABSTRACT

Lymphoma is a term used to describe a group of malignancies that derive from the lymphocytic cell lineage. Bone involvement is common in several subtypes of lymphoma and unfortunately can result in pathologic fracture. The appearance of lymphoma in bone radiographically can mimic other disease processes and can be subtle. The orthopaedic surgeon should be aware of the radiographic and clinical presentation for lymphoma involvement within bone and be hypervigilant about its presentation in patients. Lymphoma often responds well to systemic treatment, and the patient can often have long-term survival. Therefore, it is important that surgical indications are understood by practicing orthopaedic surgeons and that the surgical principles for management of this malignancy are understood, because they are distinct from the management of other systemic malignancies. New systemic therapies continue to improve overall and long-term survival in patients with lymphoma. Orthopaedic surgeons treating these patients should coordinate care with the medical and radiation oncology teams to optimize functional outcomes.

INTRODUCTION

Lymphoma is the terminology used to describe a broad category of malignancies that are thought to be derived from the lymphocytes of the normal human immune system. Lymphocytes are white blood cells that function to regulate and modulate the immune system. There are three main types of lymphocytes: T cells, B cells, and natural killer cells. Because lymphoma cells are derived from the hematopoietic cell line, there is a tendency for bone marrow involvement. This marrow involvement can lead to remodeling of both the medullary and cortical trabeculae, which can eventually lead to weakening of the bone and pathologic fracture. Lymphoma can present with a variety of radiographic appearances within the bone but tends to have features that are more specifically indicative of lymphoma. It is important to discuss the relevant biology, epidemiology, clinical presentation, and treatment considerations that orthopaedic surgeons need to be aware of for non-Hodgkin and Hodgkin lymphoma.

EPIDEMIOLOGY AND PROGNOSIS

Lymphomas are divided into two categories based on specific histologic and cytogenetic features: Hodgkin lymphoma and non-Hodgkin lymphoma.¹ Non-Hodgkin lymphoma is then further characterized based on presumed lymphocytic cell of origin, with further subclassification based on prognostic factors and location of involvement.² Hodgkin lymphoma is thought to be of the B cell lineage and is most notable on histologic analysis for its large Reed-Sternberg cells. It has an incidence in the United States of 2.7 per 100,000 people, with 7,400 new cases diagnosed each year. It has a bimodal age distribution with a peak at age 25 years and then a smaller peak again at age 75 to 80 years.³ It occurs across all nationalities and races. Most patients present with painless lymphadenopathy. They may also have
fever, chills, night sweats, and weight loss. Hodgkin lymphoma, unlike non-Hodgkin lymphoma, does not typically present with primary bony involvement. Bony involvement indicates widely metastatic stage IV disease. Patients with stage IV disease often have bone pain and impending pathologic fractures.

The prognosis for Hodgkin lymphoma has improved over the past several decades. Using modern combined treatment modalities, patients with stage I or II disease have a 5-year survival rate of 96% or higher.⁴ Even patients with advanced disease can still have a 5- to 10-year survival rate of 65% or higher.⁴ The high rate of remission with this lymphoma means that treatment of patients with bony involvement should be durable and potentially capable of lasting for 20 years or longer. Most patients with bony disease are treated with both systemic chemotherapy and local radiation therapy to the involved bone. Many patients also undergo monoclonal antibody treatment and/or autologous stem cell transplantation. Hodgkin lymphoma is extremely sensitive to radiation, and it is expected that local control of bone sites will be accomplished solely with radiation. Patients typically show significant bone reconstitution and remodeling posttherapy. As with radiation of bone in other diseases, high doses of radiation given either before or after treatment can lead to a high rate of fracture nonunion if a fracture is present at the time of treatment.

Non-Hodgkin lymphomas are a group of hematologic malignancies that share a common T or B cell lineage, but otherwise differ in their response to treatment and long-term cure rates. The incidence of non-Hodgkin lymphoma is increasing throughout the world, at a rate of approximately 4% per year.⁵ In the United States, approximately 74,000 new cases were diagnosed in 2019, making non-Hodgkin lymphoma the seventh most common malignancy among adults.⁶ The median age at diagnosis is 66 years and the incidence dramatically rises with increasing age; however, non-Hodgkin lymphoma is reported in all age groups.⁷ Males have a slightly higher incidence than females. Diffuse large B-cell and follicular lymphoma (also B cell origin) are the two most common types of non-Hodgkin lymphoma, making up approximately two-thirds of all cases. Follicular lymphoma is considered an indolent form of lymphoma, which is often but not always incurable, with a slow progression of disease. Diffuse large B-cell lymphoma tends to be more aggressive but is considered curable and has a good prognosis when managed with modern chemotherapy and radiation modalities.

Like patients with Hodgkin lymphoma, patients with non-Hodgkin lymphoma often present with systemic signs, such as fever, chills, weight loss, and lymphadenopathy. Unlike patients with Hodgkin lymphoma, patients with non-Hodgkin lymphoma frequently present with bone involvement and even pathologic fracture. Approximately 25% to 30% of all non-Hodgkin lymphomas will have bone marrow involvement at presentation.⁸^,⁹ Only a fraction of these will develop or present with pathologic fracture, but bone or joint pain in a patient with non-Hodgkin lymphoma is cause for concern. Some of these patients will present with the initial report of musculoskeletal pain and in these cases, the orthopaedic surgeon will make the initial discovery and diagnosis (Figure 1). In a study of 238 patients with presumed osteoporotic vertebral compression fractures who presented to the orthopaedic surgeon for treatment of compression fractures, it was found that 1.3% of patients had an underlying undiagnosed lymphoma. In this small group of patients, the compression fracture and back pain were the initial presenting symptoms for their lymphomas.¹⁰

FIGURE 1 Three years after anterior cruciate ligament (ACL) reconstruction, an 18-year-old man reported left knee pain and a sense of instability.

A plain radiograph (A) was obtained, which was read as normal, and MRI was performed to assess ACL integrity. A T1-weighted magnetic resonance image (B) shows geographic edema in the distal femur. The patient was referred to an orthopaedic oncologist for evaluation and biopsy. The biopsy revealed diffuse large B-cell lymphoma.

The overall relative 5-year survival of patients with non-Hodgkin lymphoma is approximately 68%. Those with isolated localized disease have a 5-year survival of greater than 80%, whereas those with distant metastasis and stage IV disease still have a 5-year relative survival of approximately 60%.⁷ Prognosis can vary greatly depending on the type of lymphoma. For instance, the 5-year relative survival of patients with stage IV disease of T cell origin lymphoma is only 37% compared with 60% for B-cell origin lymphoma.⁷ Much like patients with Hodgkin lymphoma, many patients with non-Hodgkin lymphoma have a long life span and will ultimately be cured of their cancer, even with significant bony involvement. Non-Hodgkin lymphoma is well controlled with
systemic treatment (chemotherapy, monoclonal antibodies, steroids, and NSAIDs) and radiation treatment, and it is often the combination of these that is used by the oncology team to treat patients. Prophylactic fixation before fracture occurrence is the ideal treatment for patients with impending fractures.

As described in a 2020 study, primary lymphoma of bone is a distinct pathologic entity defined as lymphoma involving a single bony site or multiple bony sites without evidence of nodal or extranodal involvement for 6 months from diagnosis.¹¹ The Ann Arbor classification is used to stage primary bone lymphoma, with solitary osseous lesions being classified as stage I E and multifocal bone disease being classified as stage IV.¹²

Because of the small disease burden, these patients often lack systemic symptoms of disease. Most instances of primary lymphoma of bone are diffuse large B cell type. As discussed in a 2023 study, primary lymphoma of bone accounts for less than 2% of all lymphomas and approximately 7% of all primary malignancies of bone.¹³ There is a slight male predominance (male-female ratio: 1.2 to 1.8) and the median age at diagnosis is approximately 60 years.¹⁴ Although primary lymphoma of bone tends to occur in middle-aged males, young adults and even children can present with this form of lymphoma. The axial skeleton is a common site of involvement.¹⁴ Primary lymphoma of bone is also frequently seen in the metaphyseal region of long bones, such as the femur, humerus, and tibia. In general, the skeletal distribution tends to follow areas of increased hematopoietic activity. Patients with early-stage primary lymphoma of bone usually have an excellent prognosis, with up to a 90% 5-year survival rate when chemotherapy can be administered. That prognosis decreases with increasing stage of disease, as with the other forms of lymphoma.

Clinical Presentation

Most patients who present with lymphoma involvement of bone also have significant pain during activity and at rest. Patients will often report night pain that keeps them from falling asleep or awakens them from sleep. Patients will sometimes report that the pain is relieved with NSAIDs or corticosteroids, but this relief is usually short-lived or only a partial response. This occurs because the lymphoma cells (B cells and T cells) are often extremely responsive to agents that inhibit the normal inflammatory cascade. Some patients will present with pathologic fracture (Figure 2) after normal activity. It is common for patients to also present with abnormal MRI findings when imaging is performed for what is thought to be a different diagnosis, such as meniscal tear or rotator cuff pathology.

FIGURE 2 Plain radiograph shows pathologic fracture of the left femur in a 70-year-old patient, in whom this fracture had developed through primary lymphoma of bone in the femur when rising from a sitting position in a chair.

It is important in patients in whom any type of malignancy is expected or who are being evaluated for an abnormality on imaging that questions regarding constitutional systems are asked. For lymphoma, a history of night sweats, fever, weight loss, and/or prolonged swollen lymph nodes is concerning for lymphoma or some other systemic process. Patients with isolated primary lymphoma of bone are less likely to have these symptoms but will still present with isolated bone pain and findings on imaging to suggest an abnormal process within the bone marrow. Because of the nonspecific presentations, an elevated level of suspicion is required. According to a 2020 study, on average there is a delay of 8 months from the onset of symptoms to diagnosis for patients with primary lymphoma of bone.¹⁵

Imaging Characteristics

The plain radiograph presentation for lymphoma involvement of bone can vary. Because lymphoma is an infiltrative process of the marrow space, the lesion of interest is often poorly defined in its geographic borders. It is extremely rare to find a well-defined border around lymphoma lesions on both plain radiography and MRI. Plain radiographs can be completely normal in a patient with early lymphoma of bone (Figure 1, A), but when more than 30% of the bone’s mineral component is lost, a permeative pattern of bone lysis is often seen (Figure 3). The tumor will often permeate through the cortex and cause extreme weakening of the bone. Often, once treatment is started, the lytic areas will undergo remodeling and become more sclerotic with time. Aggressive periostitis may indicate a poor prognosis.¹⁶ Some lymphomas present with a mixed lytic-sclerotic process before treatment or even an all-sclerotic process, although these lymphomas are seen much less frequently. It has been shown in the setting of lymphocyte-induced bone resorption that receptor activator of nuclear factor kappa B (RANK) is activated on the osteoclast.¹⁷ There is also evidence that the tumor cells suppress the production of osteoprotegerin, which is the primary inhibitor of RANK ligand (RANKL) binding to RANK. The net result is a state of bone resorption by osteoclasts likely mediated by RANKL binding to RANK. Osteoclast-stimulating proteins, such as parathyroid hormone-related protein and macrophage inflammatory protein 1 alpha, have been shown to be upregulated in the malignant lymphocytes and could be the secreted factors that lead to RANKL-RANK-mediated activation of the osteoclasts.¹⁷

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