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  1. 1. Primary Mediastinal B-cell Lymphoma Grand Rounds 9/24/2004 Caron Rigden, M.D.
  2. 2. Case Presentation • 34 y/o male presented with a 3 week history of sob, chest pain, and increased facial swelling • He also reported intermittent fevers, no chills, increased fatigue, decreased appetite, and a 10 pound weight loss over the previous month
  3. 3. • PMH- none • NKDA • Medications- none • Social- single, lives alone, 1 ppd tobacco, 6 beers/week, +marijauna • FHx- father MI at 40, mother “thyroid problems”, brother surgery for “aortic problems”, sister Graves disease
  4. 4. Exam: 96.4 77 147/95 18 100% r.a. Gen: sitting comfortably, well-nourished Heent: sclera anicteric, mmm, no LAD, neck supple, no thyromegally, trachea midline, + R supraclavicular fullness Lungs: cta b Cvs: RRR with distant heart sounds Abd: +bs, soft, nt/nd, no HSM appreciated Ext: no c/c/e Skin: no rashes Neuro: non-focal
  5. 5. Laboratory Data: • BMP wnl • Wbc 8 with normal differential • Hgb 14 • Plt 368 • Ca 8.5 • Alb 4.1 • Alk phos 73 • Ast/Alt 20/14 • U/A wnl • LDH 321 • Uric acid 4.2
  6. 6. Imaging: • CXR: widened mediastinum • CT thorax: anterior mediastinal mass 10x8x8 cm extending up to the thoracic inlet. Marked encasement and extrinsic compression of the adjacent great vessels. Distal narrowing of the trachea. No pulmonary masses. • CT abd/pelvis: mild hepatomegally, no lad
  7. 7. Ddx: • Lymphoblastic lymphoma • Primary mediastinal b-cell lymphoma • Hodgkin’s disease • Anaplastic large-cell lymphoma • Germ cell tumor • Thymoma
  8. 8. Tissue dx: Primary Mediastinal B- Cell Lymphoma +CD 20, vimentin - CD 30, keratin, cea, and S-100 • BMbx: normocellular, negative for lymphoma involvement
  9. 9. Background • First described in 1980 by Lichtenstein et al • 1980’s cell of origin (resident B-cells of the thymus) was determined • 1994 REAL classification described PMBCL as a distinct subtype of DLBCL • 2.4 % of all NHL
  10. 10. Clinical Features • Median age 30 • Female>male 2:1 • Symptoms are related to the rapidly growing mediastinal mass: SVC most common complication at dx 30% phrenic nerve palsy hoarseness chest pain sob breast swelling 1/6 have fever/weight loss pruritis is rare
  11. 11. • Staging: Ann Arbor CXR, CT C/A/P, B BMbx, serum LDH, B-2 microglobulin • 5/6 of patients are stage IE or IIE at the time of dx • Extranodal disease • At dx 70% are locally advanced usually involving the lungs, pleura, pericardium, and chest wall • Involvement of the bone marrow or extrathoracic structures is rare at dx • With recurrence, 90% of cases involve the CNS, kidneys, ovaries, adrenals, and pancreas
  12. 12. • Diffuse proliferation of medium-large cells of heterogeneous morphology • Strands of fibers and/or sclerosis present in varying degrees in 50% of cases • Clear cells • No pathognomonic morphologic feature that reliably distinguishes PMBCL from DLBCL Histopathology
  13. 13. Pileri et al, Histopathology 2002, 41: 482-509
  14. 14. B Barth et al, The Lancet Oncology 2002, 3: 229-234
  15. 15. Immunophenotype: • B-cell origin with positivity for: CD45, CD20, CD19, CD22 • Surface IG negative • CD 21 negative • MHC I negative • CD 30 may be positive, but stain with less intensity than Hodgkin/Anaplastic Large Cell • CD 3 and other T-cell markers negative Cytogenetics: • Gains in segments of 9q, 12,q, and Xq have been observed
  16. 16. Barth et al, Lancet Oncology 2002, 3: 229-234
  17. 17. Proportion of Cases That Overexpress or Have Mutations in Certain Oncogenes in PMBCL vs DLBCL PMBCL DLBCL Bcl-2 rearrangement none 20% Bcl-2 overexpression 20-30% 20-30% Bcl-6 mutation none 50% Mal overexpression yes no van Besien et al, JCO 2001, 19: 1855-1864
  18. 18. Reported Studies on Management and Outcome of Patients with PMBCL van Besien et al, JCO 2001, 19: 1855-1864
  19. 19. Multicenter Italian retrospective study of 138 patients from 1982-1999 treated with CHOP vs. M MACOP-B/VACOP-B + IF-RT as consolidation. • 70% stage I-II • IPI 59.4% low-intermediate, 16.6 % high-intermediate, 5.7% high risk • Median f/u 66 months • Overall CR was 70% and EFS 64.4% • IF-RT given only to patients in CR
  20. 20. Todeschini et al, BJC 2004, 90: 372-376
  21. 21. Todeschini et al, BJC 2004, 90: 372-376
  22. 22. Tedeschini et al, BJC 2004, 90: 372-376
  23. 23. van Besien et al, JCO 2001: 1855-1864
  24. 24. Retrospective analysis of 35 patients with PMBCL treated with high-dose CBV plus autologous transplant to determine outcome and prognostic features for progression-free survival. • Estimated survival varied significantly depending upon disease status at transplantation: -first response had an estimated 5-yr. PFS of 83%. -refractory had an estimated 5-yr PFS of 58% -relapsed had an estimated 5-yr PFS of 27% • Strongest predictor of PFS was chemotherapy responsiveness immediately before transplantation. • Even chemotherapy non-responsive had an estimated 5-yr PFS of 33% Sehn et al, Blood 1998, 91: 717-723
  25. 25. Sehn et al, Blood 91: 717-723
  26. 26. Sehn et al, Blood 91: 717-723
  27. 27. • Overall standard of care is anthracycline based regimen +/- IF-RT. • Upon re-imaging if residual mass about 20% of original volume then risk of recurrence is high requiring consolidation with radiation or high dose chemotherapy and transplant • No prospective trials comparing transplantation and conventional chemotherapy • Patients receiving a response lasting longer than 18 months are likely to be cured • Treatment failure usually occurs during initial treatment or within 6-12 months of completion of therapy
  28. 28. So where is our patient? Completed 12 weeks of VACOP-B with a good partial response. Subsequently completed 20 days of radiation. Currently awaiting restaging.
  29. 29. References: Aisenberg A, Primary Large Cell Lymphoma of the Mediastinum. Seminars in Oncology 26: 251-258, 1999 Barth T, Leithauser F, Joos S, Bentz M, Moller P: Mediastinal (Thymic) Large B-Cell Lymphoma: Where Do We Stand? Lancet Oncology 3: 229-234, 2002 Sehn H. L, Antin J, Shulman L, Mauch P, Elias A, Kadin M, Wheeler C: Primary Diffuse Large B-Cell Lymphoma of the Mediastinum: Outcome Following High-Dose Chemotherapy and Autologous Hematopoietic Cell Transplantion. Blood 91: 717-723, 1998 Piler SA, Dirnhofer S, Went P, Ascani S, Sabattini E, Marafioti T, Tzankov A, Leoncini L, Falini B, Zinzani PL: Diffuse Large B-Cell Lymphoma: One or More Entities? Presents Controversies and Possible Tools for its Subclassification. Histopathology 41: 482-509, 2002 Todeschini g, Secchi S, Morra E, Vitolo U, Orland E, Pasini F, Gallo E, Ambrosetti A, Tecchio C, Tarella C, Gabbas A, Gallamini A, Gargantini L Pizzuti M, Fioritoni G, Gottin L, Rossi G, Lazzarino M, Menestrina F, Paulli M Palestro M, Cabras M, Di Vito F, Pizzolo G: Primary Mediastinal Large B- Cell Lymphoma: Long-term Results from a Retrospective Multicentre Italian Experience in 138 Patients Treated With CHOP or MACOP-B/VACOP-B. BJC 90: 372-376, 2004 Van Besien K, Kelta M, Bahagunu P: Primary Mediastinal B-Cell Lymphoma: A Review of Pathology and Management. JCO 19: 1855-1864, 2001

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