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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

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