Osseous manifestations of non-Hodgkin ’ s lymphoma in Human Immunodeficiency Virus ( HIV ) infection and Acquired Immunodeficiency Syndrome ( AIDS )

Background: Lymphoma is the second most common Acquired Human Immunodeficiency Syndrome (AIDS)associated neoplasm, the commonest being Kaposi sarcoma. The diagnosis and treatment of bone lymphoma still remains a challenge in our environment. Materials and methods: This is a retrospective chart review of 105 patients who were diagnosed histopathologically with lymphoma involving the bone over a period of 11 years in six local hospitals. Results: Forty-five (42.9%) patients with bone lesions and who were positive for Human Immunodeficiency Virus (HIV) formed the cohort. Clinical manifestations varied from swelling and pain in all patients to pathological fractures (n = 5, 11.1%) and paraplegia (n = 11, 24.4%) due to cord compression. Common sites included the spine, pelvis, femur, humerus, ribs, tibia and mandible. Treatment included chemotherapy and radiation, splinting or surgical fixation of pathological fractures and decompression of the spine with or without fusion. Conclusion: Bone lymphoma should be considered in any HIV-positive patient presenting with unexplained swelling and pain. The radiological picture may mimic bone infections like chronic pyogenic osteomyelitis, tuberculosis and fungal infections, other systemic disorders like Paget’s disease, blood-related tumours such as leukaemia and other primary and metastatic bone neoplasms.


Introduction
Lymphoma, commonly associated with congenital and acquired immune deficiency, is the second most common neoplasm associated with HIV and AIDS, and non-Hodgkin's lymphoma (NHL) is an AIDS-defining condition according to the World Health Organisation (WHO). 1,2With more than six million South Africans infected with HIV and 60 per cent of them already receiving highly active antiretroviral therapy (HAART), HIV-associated morbidity and mortality have decreased significantly. 3However, the incidence of AIDS-related lymphoma has not decreased as much and remains a major therapeutic problem. 3 Skeletal manifestations of this entity in patients with HIV infection are rarely reported in the literature.Any bone, except small bones of hands and feet, can be involved and radiological manifestations are variable making diagnosis difficult and sometimes missed. 4This is a retrospective review of clinical records and radiographs of patients who were HIV-positive and diagnosed with lymphoma affecting bone either as primary or secondary involvement.The aim is to highlight the spectrum of bone lesions in NHL and increase awareness of its occurrence in patients with HIV infection.

Materials and methods
The medical records of all patients who were diagnosed histopathologically with lymphoma involving the musculoskeletal system seen from September 2002 to December 2013 in six local hospitals were reviewed retrospectively.The clinical data recorded included clinical presentation, age, gender, HIV status, antiretroviral treatment, laboratory analysis and CD-4 count.Work-up of these patients included blood analysis (full blood count and differential, erythrocyte sedimentation rate, C-reactive protein, liver enzymes and calcium, magnesium and phosphate).Imaging included computerised tomograph of the chest, ultrasound of the abdomen and bone scan.The radiological patterns of bone lymphoma were assessed on plain radiographs mainly, and on magnetic resonance scans (MRI) when the spine was involved.Open biopsy of the most accessible lesion was performed to confirm the diagnosis.All HIV patients who presented with lymphoma involving bone either as primary or secondary lesions were included.The patients were classified according to the World Health Organisation (WHO) into four groups: 1 1.Lymphoma with a single bone site with or without regional lymph node involvement

Results
In a period of 11 years, 105 patients were diagnosed histologically with lymphoma involving bone.Of these 45 (42.9%) were confirmed HIV-positive and had lymphoma.Their ages ranged from 5 to 60 years (mean 24.4) (Figure 1).

Lymphoma is an AIDS-defining condition according to the World Health Organisation
Treatment was multidisciplinary and included orthopaedics, neurosurgery and haematology/oncology.
All patients received CHOP regimen chemotherapy (cyclophosphamide, doxorubicin, vincristine and prednisolone) except for four (8.9%) patients who died of pneumonia after biopsy while awaiting histology results and referral to oncology.Nine patients (20%) did not complete the minimum of six cycles of chemotherapy because they became very debilitated and abandoned therapy and demised after 3 months.Twenty patients (44.5%) received a combination of chemotherapy and radiotherapy.
Most long bone pathological fractures were treated surgically in adults [plating of the humerus (n = 1, 16.6%) and intermedullary nailing of the femur (n = 2, 33.3%)] and immobilised in a plaster in children (n = 2, 33.3%).One femoral (16.6%) nail was later removed and an external fixator applied after development of deep infection post-operatively and the patient demised 2 months later due to septicaemia.Two patients (33.3%) with pathological fractures of the femur and humerus were treated with skeletal traction and backslab immobilisation, respectively, because they were not fit for surgery.They demised of complications 4 weeks later.
Patients who presented with cord compression were treated by surgical decompression with or without spinal fusion (decompression alone, n = 8, 34.8% and decompression and fusion n = 6, 26.1%).Within the first 18 months of treatment a total of 28 (62.2%)patients had demised.Currently five (11.1%) patients have been disease-free for 2 years, seven (15.6%) have had recurrence, and five (11.1%) are lost to follow-up.The minimum follow-up was 6 months (range: 6 months to 2 years; mean: 12 months).

Discussion
Reports on bone lymphoma in HIV-positive patients are rare in the literature, with the exception of a few case reports. 5,6Lymphoma is a haematopoietic neoplasm composed of malignant lymphoid cells affecting different parts of the body.The most common areas of involvement include lymph nodes, spleen, central nervous system, bone marrow and gastrointestinal tract.Malignant lymphomas are classified as Hodgkin's lymphoma (the pathognomonic feature being the presence of Reed-Sternberg cells) and non-Hodgkin's lymphoma. 1,2,7

Treatment was multidisciplinary and included orthopaedics, neurosurgery and haematology/oncology
The current World Health Organisation (WHO) classification of non-Hodgkin's lymphoma (NHL) is based mainly on the B-cell and T-cell origins of the neoplasm. 1In HIV infection the majority of these lymphomas are highgrade B-cell lymphoma: Burkitt lymphoma, diffuse large B-cell lymphoma and diffuse large B-cell lymphoma with immunoblastic features. 7,8In our series all patients had diffuse large B-cell NHL.0][11][12][13] The low incidence of PBL underpins the controversies associated with definition, management strategies and prediction of outcome. 11The common sites of bone involvement include the ribs, pelvis, sternum, clavicle, femur, humerus and vertebrae. 1,7It is therefore unusual to find lymphoma involving the small bones of the hands and feet. 1 NHL is present in about 1% to 3% of HIV-seropositive patients at the time of initial diagnosis of HIV infection. 2he HIV is not involved in the malignant transformation of B cells since no HIV sequences have been detected in the lymphoma cells. 14However, the HIV infection induces the production of a variety of cytokines and growth factors that play an important role in the activation and differentiation of B cells. 14,15In AIDS-associated Burkitt lymphoma (BL), which accounts for 30 per cent of all cases of AIDSassociated lymphomas, the molecular lesions involve activation of myelocytomatosis cancer oncogene (cMYC) and inactivation of tumour suppressor protein (P53). 10,14,16

In our series all patients had diffuse large B-cell NHL
With AIDS-associated large B-cell lymphoma (LBL) the molecular alterations involve deregulation of the BCL-6 proto-oncogene. 14][18] Radiological features are quite variable and somewhat non-specific. 1,4The lytic destructive pattern (Figure 2) is the most common radiological presentation. 5,17This pattern may be described as 'permeative', 'moth-eaten' or 'geographic' with well-defined margins. 2,7The blastic sclerotic pattern is more common in secondary bone lymphoma. 4Often the lesion is a mixture of sclerotic and lytic patterns. 1Subtle or 'near-normal' radiographic pattern may need magnetic resonance imaging (MRI) or bone scintigraphy to assess the pathology. 4The process is often poorly demarcated with a large area of transition from normal bone. 1 In long bones the diaphysis tends to be preferentially involved; however, the metaphysis may also be involved (Figures 3 and 5).Cortical break may be accompanied by a large soft tissue mass.Periosteal reaction is unusual and non-specific.Lesions can be solitary or polyostotic. 1In the spine, bone lymphoma is characterised by involvement of both vertebral bodies and posterior elements. 17There is usually a large extradural mass with canal stenosis and cord compression (Figure 6).All the above radiological patterns were observed in this study.CT scan may be more sensitive than conventional radiography for cortical breakthrough, but its main role is ruling out the presence of nodal disease or other soft tissue involvement in the chest and abdomen. 4MRI is useful to assess the extent of bone marrow and soft tissue involvement as well as the status of the spinal cord.Bone marrow shows low signal intensity on T1-weighted sequences and high signal intensity on T2-weighted images. 4,19Bone scintigraphy always shows an increased uptake and is useful for demonstrating multifocal bone involvement. 4,7one lymphoma can resemble various conditions which can make the diagnosis difficult and delayed. 1 Some of these conditions include bone infections (chronic pyogenic osteomyelitis, tuberculosis, fungal), systemic conditions like Paget's disease, primary bone malignancies (e.g.osteosarcoma, Ewing sarcoma, leukaemias) and metastatic deposits like in prostatic cancer.Definitive diagnosis is established on biopsy. 3,4,8ymphoma in HIV is more widespread and presents with extensive organ involvement than in the HIVnegative population. 7Traditional treatment modalities include chemotherapy alone or in combination with irradiation therapy. 13The CHOP regimen is considered the minimum standard of care. 20The patient receives six to eight cycles every three weeks as an outpatient.Antiretroviral therapy is an important part of management.Response is assessed by plain radiographs (Figure 4) and PET scan.

NHL is present in about 1% to 3% of HIV-seropositive patients at the time of initial diagnosis of HIV infection
The outcome for NHL in the setting of HIV continues to improve as insights into the pathology and treatment advance. 21,22Awareness of clinical manifestations and the various patterns of bone involvement in HIV/AIDS is important in making the diagnosis.

Conclusion
Bone lymphoma should be considered in any HIVpositive patient presenting with unexplained swelling and pain.Despite the concerted drive to control HIV disease, lymphoma is still one of the most common HIV-related malignancies. 3,21The mortality rate in our study was 62.2% (n = 28), probably owing to patients being referred late from peripheral hospitals and bone lesions are not suspected early.Some of the poor prognostic factors observed in this study included low absolute CD4 count and number of extra-nodal sites involved.
The authors did not receive payments directly or indirectly from a third party in support of any aspect of this work.Conflict of interest: none.

Figure 1 .
Figure 1.Piegraph shows the age distribution in years of 45 patients with HIV-associated bone lymphoma

Figure 4 .
Figure 3a and b.Conventional radiographs of an 11year-old girl who presented with severe pain in the left arm and leg and inability to mobilise for 1 month.She was diagnosed with secondary NHL with multiple skeletal involvement and deposits on both sides of the diaphragm.a b

Figure 5 Figure 6 .
Figure 5. AP radiograph showing a pathological fracture (arrow) of the humeral diaphysis in a 38year-old male patient with primary bone NHL