Primary Mediastinal B-cell Lymphoma

Grand Rounds 9/24/2004

Caron Rigden, M.D.

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

• 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

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

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

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

Ddx:

• Lymphoblastic lymphoma

• Primary mediastinal b-cell lymphoma

• Hodgkin’s disease

• Anaplastic large-cell lymphoma

• Germ cell tumor

• Thymoma

Tissue dx: Primary Mediastinal B- Cell Lymphoma

+CD 20, vimentin

- CD 30, keratin, cea, and S-100

• BMbx: normocellular, negative for lymphoma involvement

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

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

• 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

• 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

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

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

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

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

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

Reported Studies on Management and Outcome of Patients with PMBCL

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

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

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

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

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

van Besien et al, JCO 2001: 1855-1864

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

Sehn et al, Blood 91: 717-723

Sehn et al, Blood 91: 717-723

• 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

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.

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