A 19-YO Woman with Huge Mediastinal Mass

She had history of chronic cough and night sweat for 1 month. She had no swelling of face nor upper extremities.

Left axillary and left lower cervival lymph node were palpated afterward.

Chest film showed large mediastinal mass. CT chest and abdomen

A large lobulated anterior mediastinal mass (4.5x10x6.5 cm) involving prevascular space of superior mediastinum and surrounding SVC, brachiocephalic vessels, ascending aorta, aortic arch MPA, left main pulmonary artery without obstruction. Multiple small paraaortic LN above IMA origin

Atelectasis and obstructive pneumonia at lingular segment of LUL and bronchopneumonia at aterior segment of LUL

CT Image of Neck and Chest

Pretreatment FDG-PET/CT Image

Echocardiography Good LV contraction, LVEF 65.1%, no LA

dilatation, no significant valvular dysfunction No abnormal wall motion. No intracardiac

shunt, no intracardiac mass, normal pericardium, no pericardial effusion

Lymph Node Tissue Diagnosis

Lymph node biopsy, left cervical group Diffuse large B-cell lymphoma, anaplastic

variant Some resembling Hodgkin or Reed-Sternberg

cells Lymphoma cells mark distinctly with CD20, not

CD3 or EMA. Some mark with CD30 Bone marrow biopsy

Negative for lymphoma cells High LDH 1037 U/L (N 225-450), ECOG 2

Diffuse Large B-cell Lymphoma: At Least Three Disease

ActivatedB Cell-like

(ABC DLBCL)

Germinal CenterB Cell-like

(GCB DLBCL)

Primary MediastinalB Cell

Lymphoma (PMBL)

Cell of origin

Germinal center

B cell

? Post-germinal

Center B cell

? Thymic B cell

• BCL-2Translocation

• C-relamplification

Oncogenic Mechanisms

ConstitutiveactivationOf NF-kB

Chr. 9q24Amplification

PDL2

Clinical

outcome

Favorable

59% 5-yr survival

Poor

30% 5-yr survival

Favorable

64% 5-yr survival

Primary Mediastinal B-Cell Lymphoma (PMBL)

Large cells with polymorphic nuclei that have an abundant rim of clear cytoplasm. Fibrosis commonly results in compartmentalization of the neoplastic cellsImmunophenotyping demonstrates the presence of B-cell antigens in all cases (CD19, CD20, CD22 and CD79a). Bcl-2 is expressed in 80% of cases, CD10 is infrequently expressed and CD21 is negative. Surface immunoglobulin (sIg) expression is absent, CD30 staining is common, but weak. In contrast to HL, the transcription factors PAX5, BOB.1, Oct-2 and PU.1 are always expressed and CD15 is negative.

Comparison of DLBCL and PMLBCL

DLBCL PMLBCL

Median age (years) 55 35

Nodal/extranodal presentation 65%/35% 0%/100%

Sex distribution (M:F) 1:1 1:4

Stage I-II/III-IV 40%/60% 80%/20%

Bulky disease 30% 60%-70%

Haematologica 2008;93:1364-71.

PMBL vs HL vs MGZL

Dunleavy K, et al. Gray zone lymphoma; better treated like Hodgkin lymphoma or mediastinal large B-cell lymphoma. Curr Hematol Malig Rep 2012;7:241-7.

Diagnosis and Treatment

Diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma stage IIIBX

IPI = 3 (LDH, stage, ECOG); Bulky

Treatment R-CHOP-21 x 8 cycles After CR, autologous stem cell transplantation

was done without prior radiotherapy

Interim PET after 2nd R-CHOP

A soft tissue density mass at left anterosuperior mediastinum, 4.5x6.0 cm at prevascular, paraaortic, AP window, lower paratracheal to left hilar region; no cervical lymphadenopathy

No FDG avidity at soft tissue density mass. Mild FDG avidity at left hilar node (residual tumor)

CT whole body after 4th R-CHOP

Decreased size of soft tissue mass at anterior mediastinum, 3.7x1.9x3 cm. No pericardial effusion

Decreased size of multiple lymph nodes at left gastric, EG junction, paraaortic, aortocaval, celiac region

PET/CT after 8th R-CHOP

No pathological size of lymph nodes in head and neck regions, normal orbits and paranasal sinuses

No pulmonary mass or nodule. An ill-defined isodensity mass in anterosuperior mediastinum (5x2.8 cm) occupying in prevascular space, paraaortic and AP window

No demonstrable mass or cyst or fluid in abdominal and pelvic cavity

No demonstrable bony destruction IMP: complete response, no active lymphoma

Haematologica 2008;93:1364-71.

The recommended first-line therapy is chemotherapy and radiotherapy (grade B). An anthracycline-based chemotherapy with CHOP, MACOP-B or VACOP-B is recommended (grade B)

Patients with an inadequate early response should be candidates for early intensification with high-dose chemotherapy (grade C)

Patients with refractory or relapsed disease should undergo rescue programs including intensive, non-cross-resistant debulking treatment followed, in chemosensitive patients, by high-dose chemotherapy and ABMT (grade B).

HDS/ABMT, n = 44

3rd generation regimens, n = 277

CHOP, n = 105

P < .0001 426 pts

100%

80

60

40

20

0 2 4 6 8 10 12 14 16 18 years

Haematologica 2002;87:1258-126

Overall survival by chemotherapy subtype in the IELSG study of 426

patients with primary mediastinal large B-cell lymphoma (PMBL)

The Therapeutic Outcome with the Inclusion of Radiation Therapy

Chemotherapy subgroup

Patients who achieved CR

after CHT

Conversions to CR among patients who received RT while in PR

Global CR after

chemotherapy and RT

First-generation 50/105 (49%) 14/21 (67%) 64/105 (61%)

Third-generation

142/277 (51%) 76/90 (84%) 218/277 (79%)

High-dose 23/44 (53%) 10/13 (77%) 33/44 (75%)

Overall 215/426 (51%) 100/124 (81%) 315/426 (74%)

Haematologica 2002;87:1258-64.

Multivariate analysis of poor prognostic factors influence OS

P-value Exp (B) 95% Cl

Increasing age 0.0002 1.02 1.01-1.03

Male sex 0.02 1.49 1.05-2.12

Poor performance status 0.001 0.51 0.34-0.77

Advanced stage 0.004 0.57 0.39-0.83

Induction chemotherapy 0.0002 0.49 0.34-0.71

R-CHOP RT vs CHOP RT

Vassilakopoulos TP, et al. Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone with or without radiotherapy in primary mediastinal large B-cell lymphoma: the emerging standard of care. The Oncologist 2012;17:139-49.

R-CHOP RT vs CHOP RT

Vassilakopoulos TP, et al. Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone with or without radiotherapy in primary mediastinal large B-cell lymphoma: the emerging standard of care.

The Oncologist 2012;17:139-49.

Comparative Outcome of 76 PMBL with R-CHOP RT and 45 Historical Control with CHOP RT

Vassilakopoulos TP, et al. Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone with or without radiotherapy in primary mediastinal large B-cell lymphoma: the emerging standard of care. The Oncologist 2012;17:139-49.

Leuk Lymphoma 2012; early online:1-7,

All Patients Early Stage Patients

Leuk Lymphoma 2012; early online:1-7,

Front-line ASCT in PMBL

OS PFS DFS

Rodriguez J, et al. Primary mediastinal large cell lymphoma (PMBL): frontline treatment with autologous stem cell transplantation (ASCT). The GEL-TAMO experience. Hematol Oncol 2008;26:171-8.

A 30-YR Female with Bilateral Cervical Lymphadenopathy

She had chronic intermittent fever with night sweats for 3 months. Bilateral enlarged cervical lymph nodes were palpated.

Physical examination revealed moderate anemia without jaundice, bilateral cervical and supraclavicular lymphadenopathy, and palpable splenomegaly.

Cervical lymph node biopsy revealed classical Hodgkin lymphoma, nodular sclerosis type.

CT whole body Multiple matted LN at

bilateral supraclavicular regions, right upper paratracheal, paraesophageal, subcarina, intraabdominal cavity, bilateral iliac regions

Hepatomegaly and splenomegaly with multiple splenic lymphoma nodules

Initial Laboratory Results

CBC : Hb 8.6 g/dl, WBC 4880/mm3 (N 75, band 15, L 6, M 2), platelet 295,000/mm3

ESR 75 mm/h LDH 964 U/L (N 225-450 U/L) Albumin 3.2 g/dl, Ca 8.5 mg/dl Bone marrow study

Multifocal marrow necrosis with diffuse myelofibrosis with abnormal medium to large mononuclear cells marked with CD30+, CD20-, CD3-, ALK-, CD15-

Diagnosis

Classical Hodgkin’s lymphoma, nodular sclerosis

Stage IVBS

Advanced Stage with 4 risk factors Hb < 10.5 g/dl Stage IV Albumin < 4 g/dl Lymphocyte < 8%

Treatment group

EORTC/GELA GHSG

Limited stage CS I-II without risk factors

(supradiaphragmatic)

CS I-II without risk factors

Intermediate stage

CS I-II with ≥1 risk factors (supradiaphragmatic)

CS I, IIA with ≥1 risk factors

CS IIB with risk factors C/D, but not A/B

Advanced stage CS III-IV CS IIB with risk factors A/B, CS III/IV

Risk factors A large mediastinal mass

B age ≥50 years

C elevated ESR

>50 mm/h without B

symptoms;

>30 mm/h with B

symptoms

D ≥4 nodal areas

A large mediastinal mass

(>1/3 maximum horizontal chest

diameter)

B extranodal disease

C elevated ESR

D ≥3 nodal areas

GHSG, German Hodgkin Study Group

EORTC, European Organisation for Research and Treatment of Cancer

GELA, Groupe d’Etude des Lymphomes de l’adulte

Advanced Stage HL

Associated with failure rate 30-40% with anthracycline polychemotherapy

Treatment Evaluation of regimens comprising multi-agent

chemotherapy Multiple consolidative strategies Improved disease control

Higher Intensive regimens to increase efficacy

BEACOPP-based regimen (GHSG) standard BEACOPP Escalated BEACOPP BEACOPP-14

> 2000 patients treated: esc BEACOPP CR: >90% (RT: 15-65%) FFTF: 82-88%, 4-10 yr follow up OS: 86-90%, 4-10 yr follow up MDS/AML: 0.9%

Significant more hematological and infectious toxicity, secondary leukemia/MDS, infertility

BEACOPP escalated

Hodgkin Lymphoma Advanced Stages

Overall Survival (y)

Pro

bab

ilit

y

109876543210

1.0

0.8

0.6

0.4

0.2

0.0

Only alkylating agents (1965)

No treatment (1940)

C/ABVD

BEACOPP base

Other intensive regimen Standford V regimen and RT to any bulky

disease Consolidation treatment

Consolidation RT Patient with poor risk or residual lesions Less toxic than ASCT Supported by EORTC (MOPP/ABV IFRT) in

PR cases Not recommended in PET-CR patients (GELA

H89, GHSG H15)

Autologous stem cell transplant (ASCT) Only in very high risk patient Not recommended in 1st CR patient

Risk Adapted Treatment

Assessing chemosensitivity by interim PET Prognostic value of PET after 2 cycles of chemotherapy

(PET2) PET2 – negative better FFS High negative predictive value for disease progression Low positive predictive value

Ongoing trial 2xABVD PET2+ BEACOPP-14 or EB; PET2-

ABVD or ABV (UK RATHL) 2xEB PET2+ 6xEB rituximab; PET2- 2x vs

6xEB (GHSG HD18)

Gallamini A, et al. Early interim 2-[18F] Fluoro-2-deoxy-D-glucose positron emission tomography is prognostically superior to international prognostic score in advanced-stage Hodgkin’s lymphoma: a report from a joint Italian-Danish study. JCO 2007;25(24):3746-52.

BEACOPPesc vs ABVD in advanced HL

3 Italian cooperative group Michelangelo Foundation The Gruppo Italiano di Terapie Innovative nei Linfomi

(GITIL) The Intergruppo Italiano Linfomi (IIL)

Unfavorable and advanced HL patients (331 patients) 6x ABVD 4x BEACOPPesc/ 4x BEACOPPstd For CR and VGPR pt 30 G IFRT For <CR, relapse salvage with ifosfamide-based

and HDT/ASCT with BEAM

Viviani S, et al. NEJM 2011;365(3):203-12.

Viviani S, et al. NEJM 2011;365(3):203-12.

Better initial control in BEACOPP

No difference in long-term clinical outcome

esc BEACOPP vs ABVD in early unfavorable and advanced stage HL

4 published trials (2868 adult patients) GHSG HD9 and HD14 from Germany HD2000 and GSM-HD from Italy

PFS significantly longer for escBEACOPP OS, not statistically significant More toxicity in escBEACOPP than ABVD

Hematological, infection, AML/MDS No differences in 2nd cancer, TRM or infertility

16-60 adult patients with unfavorable/ advanced HL benefited from escBEACOPP for PFS, no difference in OS

Bauer K, et al. Cochrane Database of Systematic Reviews 2011, Issue 8.

Bauer K, et al. Cochrane Database of Systematic Reviews 2011, Issue 8.

Case continued

The patient was treated with ABVD x4 CT whole body after 4x ABVD

Much improvement of multiple lymph nodes and masses

Small cervical, surpraclavicular nodes < 1 cm No mediastinal mass Multiple paraaortic node 1-1.7 cm Normal live and spleen No pelvic mass, no ascites

Before After ABVDx4

Case continued

Much improvement after 4 cycles of ABVD Another 2 cycles of ABVD was added PET/CT after completion of 6th ABVD was

done No hypermetabolic or enlarged lymph node in

neck, chest and intraabdominal regions and no abnormal uptake in the bony structure that indicated no evidence of active lymphoma

Suggestive of hypermetabolic intramural myoma at posterior fundus

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