linfoma radiology

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Radiological Manifestations of

Skeletal Lymphoma

John O’Neill, MB, BAO, BCh, MRCPI, MSc, FRCR (UK),

a,b

Karen Finlay, MD, FRCPC,a,b Eric Jurriaans, MD, FRCPC,a,b

and Lawrence Friedman, MBBCh, FRCPC, FACRa,b

Lymphoreticular neoplasms primarily arise in extraskeletallocations with skeletal involvement usually secondary tohematogenous spread or by direct invasion from surround-ing involved lymph nodes or soft tissues. Primary lym-phoma of bone is relatively rare in comparison. Lymphomaencompasses Hodgkin’s and non-Hodgkin’s disease, Bur-

kitt’s lymphoma, and mycosis fungoides. Skeletal diseasemay present with symptoms localized to the site of boneinvolvement, as an incidental finding on imaging for otherreasons, or as part of the staging of the disease. It isimportant that the radiologist is cognizant of the many presentations of skeletal lymphoma. We present a review of the radiological imaging of skeletal lymphoma withconventional radiographs, computed tomography, scinti-graphic studies, and magnetic resonance imaging.

Primary lymphoma of bone is rare and skeletal changes

are more commonly encountered either as hematogenous

dissemination to bone from a primary extraskeletal site orby direct invasion. These changes usually occur duringthe course of the disease rather than a presenting feature.

Skeletal disease may present with symptoms localized to

the site of bone involvement, as an incidental finding on

imaging for other reasons, or as part of the staging of thedisease.

The classification of lymphoma is continuously

undergoing modification with the ultimate goal of providing clinicians with a universal diagnostic basis

for therapeutic decisions. In 1994 the Revised Euro-

pean American Lymphoma classification was pro-

posed by the International Lymphomas Study Group

and has recently been incorporated into the World

Health Organization classification of tumors of hemo-poietic and lymphoid tissues.1 It is predominantly

based on cell lineage and cell differentiation utilizing

genetic, immunophenotypic, biologic, and clinical fea-tures (Table 1). Cell type and degree of differentiation

may change during the course of the disease altering

treatment and prognosis.2 In basic broad categories,lymphomas are divided into malignant lymphomas

and Hodgkin’s lymphoma, the former occurring three

times more frequently than the latter.

Skeletal involvement varies considerably depend-ing on the cell type and method of detection.3 Exam-

ples include histiocytic and lymphocytic lymphomas,

which have a 21 and 12% rate of bone involvement,

respectively.

4

Postmortem examination demonstratesskeletal changes in 50% of Hodgkin’s lymphoma

cases with significantly less detected on radiographicstudies.3 The latter, however, varies considerably with

the method of imaging. The detection and recognition of

skeletal disease is essential in both the primary diagnosis

and the staging of the disease process and thus it isimportant that the radiologist is cognizant of the many

presentations of skeletal lymphoma. We present a review

of the radiological imaging of skeletal lymphoma withconventional radiographs, computed tomography (CT),

scintigraphic studies, and magnetic resonance imaging

(MRI) and have concentrated on the following catego-ries: primary bone lymphoma, Hodgkin’s lymphoma,non-Hodgkin’s lymphoma (NHL), Burkitt’s lymphoma,

and mycosis fungoides.

Primary Lymphoma of Bone

Oberling first described this entity in 1928 and sug-gested the diagnosis of reticulum cell sarcoma but it

From the aDepartment of Radiology, St. Josephs Healthcare Hamilton,

Ontario, Canada; and bMcMaster Health Sciences, Hamilton, Ontario, Canada.

Reprint requests: John O’Neill, MB, BAO, BCh, MRCPI, MSc, FRCR(UK), Radiology Department, St. Josephs Hospital, 50 Charlton AvenueEast, Hamilton, Ontario L8N 4A6, Canada. E-mail: [email protected].

Curr Probl Diagn Radiol 2009;38:228-236.

© 2009 Published by Mosby, Inc.

0363-0188/2009/$36.00 0

doi:10.1067/j.cpradiol.2008.07.001

228 Curr Probl Diagn Radiol, September/October 2009

mailto:[email protected]





was not until 1939 that it was separated from Ewingsarcoma by Parker and Jackson. In the same year it

was included in the Bone Sarcoma Registry by Ewing

under the heading of reticulum cell lymphosarcoma.5

Ivins and Dahlin introduced the term primary bone

lymphoma (PBL) in 1963.6 Diagnosis requires a pri-

mary focus in a single bone, histological confirmation,

and no evidence of distant lymph node or metastasis ator within 6 months of presentation.7 Regional lymph

node disease is acceptable as is multifocal bone

involvement. PBL is responsible for less than 5% of malignant bone tumors and less than 1% of NHL.8 The

majority of PBL are from NHL, usually a diffuse

B-cell subtype, with 6% arising from Hodgkin’s lym-

phoma.Patients usually present with a long history of pain

localized to the site of involvement, or pathological

fracture (22%). In a large retrospective detailed imag-ing review of 237 patients with PBL, the following

features were recognized.7 The age ranged from 2 to

88 years with the majority evenly distributed betweenthe second and eighth decades at a mean of 42 years.

The male:female ratio was 1.8:1. Long bone involve-

ment is more common than flat bone, 71% versus

22%, and is commonly metadiaphyseal (69%) with thefemur, tibia, and humerus the commonest bones in-

volved. Lesions can be epiphyseal, metaphyseal, or

diaphyseal and may cross a joint space to involve the

opposing bone (4%) (Fig 1). Synovitis of adjacent joint may occur and usually affects the knee. Con-

ventional radiographic features include lytic (70%),mixed (28%), and rarely, blastic (2%) patterns. Thecommonest lytic pattern is permeative or moth-eaten.

Sequestra may occasionally be seen. Initial radio-

graphs may be normal (5%), but abnormalities can be

demonstrated on bone scan or MRI before conven-tional radiographic changes. On average, conventional

radiographs become abnormal in this subgroup within

10 months. Periosteal reaction ranges from an inter-

rupted single or multiple layers to a single continuous

layer and is present in almost 50% of patients. Very

rarely disease may be confined to the periosteum.Radionuclide bone scans are abnormal in the vast

majority of patients, 98%, demonstrating mild to

marked increased uptake. CT is excellent in delineat-

ing cortical destruction, whereas MRI is more sensi-tive than CT for assessing degree of soft tissue

involvement, 48%, which indicates a more aggressive

lesion with a poorer long-term outcome.MRI signal characteristics were inhomogeneous

and variable with the majority of lesions isointense or

hypointense to muscle on T1 and hypo/iso/hyperin-

tense to subcutaneous fat on T2. Low signal intensityon both T1 and T2 is speculated to be related to a high

content of fibrous tissue.9 A recent MRI study of 29

patients with PBL marrow signal intensity were non-

specific intermediate on T1 and high signal on T2.10

Enhancement patterns were heterogeneous in 59%.Soft-tissue extension was present in 76% and demon-

strated a more homogenous appearance on T1, 90%

iso-intense to muscle, T2, 91% high signal intensity(SI), and diffuse enhancement in 82%. Interestingly

cortical bone was abnormal in the majority, 93%, with

permeative cortical destruction with linear foci 52%.

Intramedullary extension is best assessed on MRI andin this series a clear line of demarcation with normal

marrow was present in 55%.10 Rarely PBL may be

confined to the periosteum or cortex with diffusecortical thickening without medullary involvement.10

The differential diagnosis is dependent on the age at

presentation. In children, Ewing’s sarcoma, osteomy-elitis, metastatic neuroblastoma, and Langerhans’ cell

histiocytosis should be considered, whereas in the

second decade lytic osteosarcoma should be included.

Adult differential includes metastatic disease and my-eloma. Overall survival is 91% at 5 years and 87% at

10 years with combined modality of chemotherapy

and radiotherapy.11,12

Primary Multifocal Bone LymphomaPrimary multifocal bone lymphoma is a subtype of

primary bone lymphoma and comprises between 11

and 33% of PBL.13,14 Diagnosis requires the involve-

ment of multiple bone sites without distant lymphnode or visceral involvement for 6 months post pre-

sentation. Patient presentation and imaging character-

istics are similar to those in PBL, allowing for multiplebone involvement, although there are no large

TABLE 1. Basic WHO classification of lymphomas

B-cell neoplasms

● Precursor B-cell neoplasm

● Mature B-cell neoplasms (incl. Burkitt lymphoma)

● B-cell proliferations of uncertain malignant potential

T-cell and NK-cell neoplasms

● Precursor T-cell neoplasms

● Mature T-cell and NK-cell neoplasms (incl. Mycosis

fungoides)● T-cell proliferations of uncertain malignant potential

Hodgkin lymphoma

Curr Probl Diagn Radiol, September/October 2009 229



than children. Presentation is usually with local pain and

tenderness. The dorsolumbar spine, pelvis, ribs, femora,

and sternum are the commonest sites in order of frequen-

cy.19 Osteolytic lesions are commonest but lesions may

be mixed or sclerotic. The latter occur between 15 and

45%. An ivory vertebra represents diffuse sclerosis,

homogenous or heterogenous, of a vertebral body. Ver-tebra plana, a flattened vertebral body, is a less common

finding but both may occur and are not limited to

lymphoma. Localized sclerosis of a vertebra, sternum, orpelvis secondary to adjacent to lymph node disease iscommon. Anterior erosion may occur from involvement

of paravertebral lymphadenopathy. Diffuse skeletal os-

teosclerosis may occur in response to extensive marrowdisease or diffuse bone marrow fibrosis. Ill-defined os-

tiolytic lesions, which may have a sclerotic rim, are often

associated with a periosteal reaction, lamellated or with a

“sunburst” pattern.19 Rarely, hypertrophic osteoarthrop-

athy occurs, usually in patients with mediastinal involve-

ment.

Bone marrow disease is often focal in nature and

thus may not be identified on bilateral iliac crestmarrow sampling. MRI is beneficial in these cases as

it is sensitive in demonstrating marrow infiltration and

in addition may help in guiding biopsy.17,18 In a studyassessing the value of MRI versus bone marrow

biopsy involving 26 patients, MRI identified seven

cases of spinal disease, only three of which werepositive on crest biopsy. MRI-positive patients had a

higher relapse rate in the 24-month follow-up period

than the MRI-negative patients.17

Lymphocytic-predominant and nodular sclerosis are

less aggressive histological subtypes than mixed cellu-

larity and depleted lymphocytes and carries a better

prognosis. The latter has a greater incidence of boneinvolvement and aggressive osteolytic lesions. The dif-

FIG 2. Multifocal primary bone lymphoma–HD. 40-year-old male with 3-month history of multifocal back pain. (A) Lateral lower thoracic spinedemonstrating wedge compression fracture with increased AP diameter of a 10th thoracic vertebra. Corresponding sagittal T2 (B) thoracic spinewith diffuse increase signal intensity and collapse of T10, T4, and L1 with secondary spinal stenosis at T4. Signal intensity was of uniform low signalon T1 (not shown).




ferential diagnosis for new bone lesions occurring in

treated HD includes recurrent disease, development of

NHL, and osteomyelitis due to immunosuppression. The

overall 5-year survival for all stages of Hodgkin’s disease

is 91% with higher stage disease survival as low as 70%.

Non-Hodgkin’s Lymphoma

NHL is the most prevalent hematopoietic neoplasm and

includes many clinicopathologic subtypes, the majority

of which are of B-cell origin. Each subtype has its own

FIG 3. Secondary Hodgkin’s lymphoma: 25-year-old male with known history. Hodgkin’s lymphoma presented with left scapular pain. (A) APscapula demonstrates a well-defined lucent lesion with a nonsclerotic border of the body of the scapula extending to the glenohumeral joint and

acromion. Localized increased uptake on bone scan (B), with decreased signal on T1 (C), and increased signal on T2 (D) in the correspondingarea seen on conventional radiograph.




FIG 4. Secondary NHL: 68-year-old male with known NHL. AP right hip baseline (A), 6 weeks (B), and 3 months later (C). Initial radiograph is normal,progresses to diffuse permeative subtle changes, and finally to diffuse osteolysis, superolateral femoral neck cortical destruction, and pathologicalinter-trochanteric fracture. Bone scan (D) at 6 weeks with diffuse radiotracer uptake right proximal femur, bilateral distal femurs, and left clavicle.Remaining area’s increased uptake was confirmed as degenerative in nature. Coronal bilateral (E) and unilateral (F) coronal T1 and bilateral coronalshort tau inversion recovery (STIR) hips (G), performed at 2 months. Diffuse heterogeneous low signal intensity within the femoral neck and proximal rightfemoral shaft on T1 with mixed low and high signal on STIR bilaterally with right diaphyseal periosteal reaction.




distinct epidemiology, etiology, morphology, immuno-

phenotype, genetics, clinical features, and response to

therapy.20 In general, those of a large cell type withdiffuse rather than nodular type growth have a more

aggressive pattern of growth. It is more common in

males, 1.4:1, and affects all ages with a median age of 55

years. Patients predisposed to developing NHL includethose with congenital immunosuppression, those with

FIG 5. Primary bone lymphoma: 60-year-old male with left ankle tenderness post trauma. (A) AP ankle demonstrating a subtle permeativedestruction distal tibial diametaphysis initially thought normal. Repeat radiograph (B) at 10 weeks shows rapid progression with diffuse osteolysisextending into diaphysis with exuberant periosteal reaction. Coronal T1 (C) and sagittal STIR (D) MRI sequences correlate with above findings withdiffuse low signal intensity on T1 and high signal on STIR with cortical destruction on medial and lateral borders. Extensive soft-tissue infiltration,low on T1, and high signal on STIR, not appreciated on radiographs. This example stresses the initial subtle changes that may progress rapidly.




ous T-cell lymphoma (CTCL). MF is the most com-

mon type of CTCL. Sezary syndrome is a variant of MF occurring in 5% of cases. The skin is the primary

site of involvement. Stage IVB disease is character-

ized by visceral, including skeletal, involvement. The

disease occurs more frequently in men, 2:1, and mayoccur in all age groups, but patients are commonly in

the sixth decade with a mean age at presentation of 50

years.Three separate types of bone lesion occur and

predominantly affect the appendicular skeleton: osteo-

lytic, osteoblastic, and diffuse osteoporosis.25-27 Cor-tical bone destruction with associated soft-tissue mass

and periostitis may occur. Sezary syndrome is the

leukemic phase of MF with generalized erythroder-

ma.28 It is associated with a symmetrical seronegative

polyarthritis secondary to malignant synovial infiltra-

tion.29 Marrow involvement occurs in up to 20% of

patients with CTCL and is often present at the time of diagnosis and may be nodular localized or infiltrative.

When the latter is present, it is associated with diffuse

dissemination and a shortened survival time.29 StageIVB disease has a mean survival of 18 months.

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