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Non-Hodgkin Lymphoma of Bone

DEFINITION AND PATHOGENESIS

  • (formerly reticulum cell sarcomalymphosarcoma, or follicular lymphoma)
  • Ann Arbor Staging System
    • Stage I: primary lesion only (node, bone, other)
    • Stage II: nodes involved in more than two anatomic regions on the same side of the diaphragm
    • Stage III: nodes involved on both sides of the diaphragm
    • Stage IV: bony mets
  • Non-Hodgkin's lymphomas are classified under the general headings:
    • Low grade
    • Intermediate grade
    • High grade
    • Miscellaneous
  • Primary NHL of bone may represent tumors of post-germinal center B-cells (bone marrow is the normal site of homing of plasma cells which are terminally-differentiated, immunoglobulin-secreting post-germinal center B-cells (NHL may represent tumors of post-germinal center B-cells)

IMPORTANCE

  • About 4-5X as common as Hodgkin's disease of bone
  • 3-7% of all primary osseous malignancies

CLINICAL FEATURES

  • ± diffuse or dull, aching bone pain, fatigue
  • ± fever, ? wt, night sweats
  • Accounts for approximately 4-5% of all primary bone tumors (most non-Hodgkin's, usually diffuse histiocytic lymphoma)
  • May present with pathologic fracture and soft tissue mass
  • Compression fx/vertebral plana in axial locations
  • Sxs may be present for up to several years
  • Neurologic deficits in spinal lesions
  • Secondary involvement of bone is about 25% in children
  • (most frequent areas are spine, pelvis, skull)
  • M:F = 1.5-1.8:1 (also whites:blacks)
  • Wide age range (2-88 yrs, mean 42-51 reported)
  • ???? alk?
  • Joint effusion may occur from local extension from bone
  • Epidural extension may occur in spinal locations and cause neurologic sxs
  • Neurolymphomatosis
    • direct lymphomatous involvement of peripheral nerves
    • reported rare association with Guillain-Barre syndrome
  • Has been reported arising in chronic osteomyelitis

RADIOLOGIC FEATURES

  • Most common sites: distal femur, proximal tibia, proximal femur, proximal humerus, mid-shaft femur
  • Femur (29%), pelvis (19%), humerus (13%), tibia (10%)
  • Osteolytic lesions (70%) with permeative bone destruction to mixed lytic/blastic (28%) or blastic (2%) lesions
  • Cortical destruction often associated with adjacent muscle and soft tissue involvement
  • Sequestra (also seen in EG, osteomyelitis, fibrosarcoma, MFH, desmoplastic fibroma) may be seen (16%)
  • Periosteal reactions are often (47%) present (esp long bones)
  • Soft tissue mass (48%) is best visualized with MRI
  • Isointense to hypointense signal (compared to muscle) on T1-weighted MRI, 2/3 with heterogeneity on T2-weighted images
  • Pathologic fx may be the presenting finding (~20%)
  • Compression fx in spinal lesions (vertebra plana)
  • Bone scan may reveal "silent" bony lesions, usually (98%) shows uptake
    • Failure to show uptake may hinder the dx
  • MRI
    • Isointense to hyperintense to muscle on T1-weighted images
    • Hyperintense to fat on T2-weighted images
  • FDG-PET
    • More sensitive than gallium scan (which has low spatial resolution and lack of specificity)
    • PET fused with CT increases sensitivity because of physiological uptake in the abdomen
    • Sensitivity reported 85-95% and 8-59% of pts will have a change of stage using PET
    • Uptake varies with grade of disease
    • 18F-FDG is not tumor specific (eg, inflammatory cells, hyperplastic bone marrow, infection)
    • Should not be performed until 2-3 months following XRT; 1 month following chemotx
    • Sensitivity (79-84%) and specificity (90-92%) for detection of residual disease (accuracy of 85%)
    • Used during and at the end of therapy to provide a more accurate response classification than assessment by CT
    • Can identify refractory disease early

GROSS PATHOLOGY

  • Grossly soft, less likely to show pus-like necrosis

HISTOLOGIC FEATURES

  • Larger round cells, moderate cytoplasm, clear borders, hyperchromatic nuclei (pleomorphic)
  • ~92% are diffuse large B cell lymphomas
  • Special stains:
  • + PAS, ??diastase
  • ± reticulin
  • Immunohistochemistries:
  • + common leukocyte antigen
  • B or T cell positivity
  • + CD19, CD20 immunoperoxidase (B cell marker)
  • HLA-DR
  • Kappa light chain markers
  • + UCHL-1 for T-cell origin

DIFFERENTIAL CLINICOPATHOLOGIC DIAGNOSIS

  • Metastatic or secondary lymphoma
  • Ewing sarcoma
  • Metastatic neuroblastoma
  • Metastatic embryonal rhabdomyosarcoma
  • Osteomyelitis
  • Eosinophilic granuloma (ddx in vertebra plana)
  • Hodgkin's disease
  • Mastocytosis

DISEASE COURSE AND TREATMENT

  • International Harmonization Project criteria for response assessment in lymphoma
    • Complete response (CR): complete disappearance of all detectable disease with (a) FDG-avid prior to tx; mass of any size permitted if PET negative, or (b) varibly FDG-avid or PET negative; regression to normal size LNs on CT; spleen/liver not palpable, nodules disappear; normal bone marrow bx on repeat bx, immunochemistry negative
    • [Complete response unconfirmed (Cru): as in CR but with residual mass >1.5cm that has regressed by >75% has been removed because of the advent of PET]
    • Partial response (PR): at least 50% reduction in the sum of the product of the greatest diameters of the 6 largest nodes with no increase in the size of the other nodes and no new sites of disease; Hepatic and splenic nodules should also decrease by at least 50%; bone marrow irrelevant if + previously; (a) FDG-avid or PET + prior to tx: one or more PET + at previously involved site; (b) variably FDG-avid or PET negative: regression on CT
    • Stable disease (SD): response is less than PR but not progressive; (a) FDG-avid or PET positive prior to tx: PET positive at prior sites of disease and no new sites on CT or PET; (b) variably FDG-avid or PET negative: no change in size of previous CT lesions
    • Progressive disease (PD) or Relapsed disease (RD): appearance of new lesion(s) >1.5cm in any axis, >50% increase in sum product of the diameters in >1 node, or >50% increase in longest diameter of a previously identified node >1cm in short axis; lesions PET + if FDG-avid lymphoma or PET + prior to tx; >50% increase from nadir in the sum product of the diameters of any previous lesions; new or recurrent bone marrow involvement
  • Lymph node bx (if enlarged nodes present) at the time of bone bx is indicated to establish dx and proper stage
  • Isolated bony lesion: neoadjuvant chemotherapy (± XRT), ± wide resection, reconstruction and adjuvant chemotx
  • Large cleaved cell lymphomas with a better prognosis than large noncleaved cell lymphomas
  • Pathologic fractures: may do best with resection (± XRT) since XRT alone will lead to delay in fx healing
  • An indicator of poor prognosis for freedom from relapse
  • Surgery indicated for bx, prophylactic fixation of impending fxs, fixation of fxs
  • > 60 yrs of age at time of diagnosis is an indicator of poor prognosis for survival
  • CNS involvement has worse outcome
  • Diffuse bony lesions: XRT ± IM fixation devices using fixation criteria as in metastatic disease
  • 5-yr DFS 30-50%, 10-yr survival 48%
  • Intercurrent disease with no LR must be monitored
  • 5-yr overall survival in pelvic locations 38%
    • An indicator of poor prognosis for freedom from relapse
  • Development of multiple myeloma with primary T-cell lymphoma of bone has been reported

REFERENCES

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Figures
Figure 1a. An elderly man complained of left hip pain. An AP radiograph shows minimal degenerative changes to the joint. On close inspection, perhaps a lucent supra-acetabular lesion can be appreciated.
Figure 1b. An axial CT image reveals the mixed lucent and scerotic nature of the intraosseous lesion with extraosseous extension both anteriorly and posteriorly, characteristic of lymphoma of bone.
Figure 1c. A coronal CT image reveals the posterolateral soft tissue extension in this cut.
Figure 1d. A coronal T1-weighted MR image reveals the infiltrative hypointense lesion within the supra-acetabular region with extra-osseous extension medially.
Figure 1e. A T1-weighted fat suppression image reveals the hyperintense lesion in the supra-acetabular region as well as the medial intrapelvic soft tissue extension of the tumor.
Figure 1f. A high power view reveals mostly large cells, consistent with a large B-cell lymphoma.
Figure 1g. On further inspection, the cells are not cleaved.
Figure 1h. Here, a nest of tumor cells are crowding out the adjacent marrow.
Figure 2a. A 20 year old woman complained of left knee pain for 6 years. She had no constitutional symptoms. Here, an AP radiograph of the left knee reveals a densely scerotic proximal tibial lesion without definite soft tissue extension.
Figure 2a. A lateral radiograph of the knee reveals the extension to the subchondral bone and to the metadiaphyseal junction of the proximal tibia.
Figure 2c. A whole body bone scan reveals the solitary nature of the lesion in the proximal left tibia.
Figure 2d. A close up view of the bilateral knees reveals the intense uptake in the proximal left tibia.
Figure 2e. A coronal T1-weighted image reveals the hypointense intramedullary changes of the proximal tibia without soft tissue extension.
Figure 2f. An axial T1-weighted MR image reveals the infiltrative nature of the lesion with little fat signal remaining within the bone.
Figure 2g. A sagittal T1-weighted MR image reveals the well-demarcated and geographic nature of the lesion. The differential diagnosis includes chronic osteomyelitis, low-grade intramedullary osteosarcoma and lymphoma of bone.
Figure 2h. A T-2 weighted sagittal MR image reveals the hyperintense nature of the neoplasm.
Figure 2i. A low power 40X view reveals the intramedullary hematopoiesis has been completely replaced with fibrotic marrow.
Figure 2k. The patient was found to have a Diffuse large B-cell lymphoma of non-germinal center (activated B-cell) phenotype. Here, a 400X view reveals cords of large cells.
Figure 2l. CD20 is diffusely positive. Other positive stains included CD45. The cells were negative for keratin, S100, CD3, CD10, BCL-6, MUM-1, BCL-2, CD30, and CD15.
Figure 2m. Ki67 was positive in roughly 30-40% of tumor cell nuclei.
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