Primary Mediastinal Bcell Lymphoma

1
Primary Mediastinal B-cell Lymphoma

• Grand
  Rounds 9/24/2004
• 
  Caron Rigden, M.D.

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

• 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

• 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

• 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

• 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
Ddx

• Lymphoblastic lymphoma
• Primary mediastinal b-cell lymphoma
• Hodgkins disease
• Anaplastic large-cell lymphoma
• Germ cell tumor
• Thymoma

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
Background

• First described in 1980 by Lichtenstein et al
• 1980s 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
Clinical Features

• Median age 30
• Femalegtmale 21
• 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

• 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
Histopathology

• 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

13

• 
  Pileri et al, Histopathology 2002,
  41 482-509

14

• 
  
  B Barth et al, The Lancet
  Oncology 2002, 3 229-234

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

• 
  Barth et al, Lancet Oncology 2002, 3 229-234

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
Reported Studies on Management and Outcome of
Patients with PMBCL

• 
  van Besien et al, JCO 2001, 19 1855-1864

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

• 
  
  Todeschini et al, BJC 2004, 90 372-376

21

• 
  
  Todeschini et al, BJC 2004, 90 372-376

22

• 
  
  Tedeschini et al, BJC 2004, 90 372-376
  
  

23

• 
  
  van Besien et al, JCO 2001 1855-1864

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

• 
  
  
  Sehn et al, Blood 91 717-723

26

• 
  Sehn et al, Blood 91
  717-723

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

• 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

• 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