LIMFOMA MALIGNUMNON HODGKIN

IRZA WAHIDSUBAGIAN HEMATOLOGI & ONKOLOGI FK UNAND - RS DR M DJAMIL PADANG

 

DEFINISISekelompok keganasan primer limfosit yang dapat berasal dari limfosit B, limfosit T dan kadang ( amat jarang ) berasal dari sel NK ( natural killer ) yang berada dalam sistim limfe, sangat heterogen baik tipe histologis, gejala, perjalanan klinis, respon terapi maupun prognosis

Non-Hodgkin’s Lymphoma

• Non-Hodgkin’s lymphomas (NHL) are a heterogeneous group of malignant lymphomas. There are many different subtypes, every few years the classification is updated. Today, morphology, immunophenotype, molecular, cytogenetics, and other techniques are used for diagnosis.

• Treatment generally depends on the aggressiveness of the disease (indolent, aggressive, or very aggressive)

• Current ICD-9-CM diagnosis code range 200.0_ – 200.8_ and 202.0_ – 202.9_

Lymphoma and Multiple Myeloma2004 U.S.

Malignancy New Cases Deaths

All Cancer s 1,368,030 563,700Non-Hodgkin’s

Lymphoma 54,370 19,410Hodgkin’s Disease 7,880 1,320

CA Cancer J Clin 2004; 54:8-29

Former First Lady

Jacqueline Kennedy Onassis

King Hussein of Jordan

Television star, The A-Team. Sylvester Stallone's adversary in "Rocky III.”

“Mr. T”(Lawrence Tureaud)

ETIOLOGI DAN FAKTOR RISIKO

Etiologi pasti tidak diketahui beberapa faktor risiko :

•Paparan lingkungan dan pekerjaan seperti peternak pekerja hutan / pertanian yang disebabkan paparan herbisida dan pelarut organic serta paparan ultraviolet

* Diet tinggi lemak hewani dan merokok

Etiology of NHL

• Immune suppression– congenital (Wiskott-Aldrich)– organ transplant (cyclosporine)– AIDS– increasing age

• DNA repair defects– ataxia telangiectasia– xeroderma pigmentosum

Etiology of NHL• Chronic inflammation and antigenic stimulation

– Helicobacter pylori inflammation, stomach– Chlamydia psittaci inflammation, ocular adnexal

tissues– Sjögren’s syndrome

• Viral causes– EBV and Burkitt’s lymphoma– HTLV-I and T cell leukemia-lymphoma– HTLV-V and cutaneous T cell lymphoma– Hepatitis C

KLASIFIKASI

* Penggolongan histologi LNH merupakan masalah yang rumit dan sukar •Perkembangan terakhir klasifikasi yang banyak dipakai adalah formulasi praktis •( working formulation = WF 1982 ) dan Revised Europe – American Classification of Lymphoid Neoplasms / World Health Organization ( REAL / WHO 1997)

WHO/REAL Classification of Lymphoid NeoplasmsB-Cell Neoplasms

Precursor B-cell neoplasmPrecursor B-lymphoblastic leukemia/lymphoma

(precursor B-acute lymphoblastic leukemia)Mature (peripheral) B-neoplasmsB-cell chronic lymphocytic leukemia / small lymphocytic

lymphomaB-cell prolymphocytic leukemiaLymphoplasmacytic lymphoma‡

Splenic marginal zone B-cell lymphoma (+ villous lymphocytes)*

Hairy cell leukemiaPlasma cell myeloma/plasmacytomaExtranodal marginal zone B-cell lymphoma of MALT typeNodal marginal zone B-cell lymphoma

(+ monocytoid B cells)*Follicular lymphomaMantle cell lymphomaDiffuse large B-cell lymphoma

Mediastinal large B-cell lymphomaPrimary effusion lymphoma†

Burkitt’s lymphoma/Burkitt cell leukemia§

T and NK-Cell NeoplasmsPrecursor T-cell neoplasm

Precursor T-lymphoblastic leukemia/lymphoma(precursor T-acute lymphoblastic leukemia

‡ Formerly known as lymphoplasmacytoid lymphoma or immunocytoma II Entities formally grouped under the heading large granular lymphocyte leukemia of T- and NK-cell types* Provisional entities in the REAL classification

Mature (peripheral) T neoplasmsT-cell chronic lymphocytic leukemia / small

lymphocytic lymphomaT-cell prolymphocytic leukemiaT-cell granular lymphocytic leukemiaII Aggressive NK leukemiaAdult T-cell lymphoma/leukemia (HTLV-1+)Extranodal NK/T-cell lymphoma, nasal type#

Enteropathy-like T-cell lymphoma**Hepatosplenic γδ T-cell lymphoma*Subcutaneous panniculitis-like T-cell lymphoma*Mycosis fungoides/Sézary syndromeAnaplastic large cell lymphoma, T/null cell,

primary cutaneous typePeripheral T-cell lymphoma, not otherwise characterized Angioimmunoblastic T-cell lymphomaAnaplastic large cell lymphoma, T/null cell,

primary systemic typeHodgkin’s Lymphoma (Hodgkin’s Disease)

Nodular lymphocyte predominance Hodgkin’s lymphomaClassic Hodgkin’s lymphoma

Nodular sclerosis Hodgkin’s lymphoma (grades 1 and 2)Lymphocyte-rich classic Hodgkin’s lymphomaMixed cellularity Hodgkin’s lymphomaLymphocyte depletion Hodgkin’s lymphoma

† Not described in REAL classification § Includes the so-called Burkitt-like lymphomas** Formerly known as intestinal T-cell lymphoma # Formerly know as angiocentric lymphoma

Klasifikasi WF ( 1982 )

Low grade malignancySmall lymphocytic / plasmacytoid

Follicular, predominantly small cleaved cellFollicular, mixed small cleaved and large cell

Intermediete grade malignancyFollicular, predominantly large cell

Difuse, small cleaved cellDiffuse, mixed small and large cell

High grade malignancy Large cell, immunoblastic

Lymphoblastic Small, non cleaved cell

PENDEKATAN DIAGNOSTIK

1. Anamnesis

Umum Pembesaran KGB atau organ

BB menurun ≥ 10 % dalam waktu 3 bulanDemam tinggi ≥ 38 C ≥ 1 minggu tanpa sebab

Keringat malamKeluhan anemia

Keluhan organ ( seperti lambung, nasofaring )Penggunaan obat ( Diphantoine )

KhususPenyakit autoimun ( SLE, syogren, reuma )

Kelainan darahInfeksi ( Toxoplasmosis, mononucleosis, tuberculosis, lues, cakar kucing

2. Pemeriksaan fisik

* Pembesaran KGB

•Kelainan / pembesaran organ

•* Performance status : WHO, Karnofsky

3. Pemeriksaan penunjang

Laboratorium* Rutin Darah perifer lengkap ( DPL ), Gambaran darah tepi ( GDT )

Urine lengkap* Kimia Klinik

* Imunophenotyping parafin panel CD 20, CD 3

Radiologi* Foto torak CT Scan torak

* USG Abdomen CT Scan abdomen* Limfografi

Biopsi KGB

BMP & biopsi SST

Diagnosis of NHL• Excisional biopsy is preferred to show nodal

architecture (follicular vs diffuse).• Immunohistochemistry to confirm cells are

lymphoid– LCA (leukocyte common antigen)– Monoclonal staining with Ig or Ig

• Flow cytometry:– CD 19, CD20 for B cell lymphomas– CD 3, CD 4, CD8 for T cell lymphomas

Diagnosis of NHL

• Chromosome changes– 14;18 translocation in follicular lymphoma

• bcl-2 oncogene

– t(8;14), t(2;8), t(8;22) in Burkitt’s lymphoma

• c-myc oncogene

– t(11;14) in mantle cell lymphoma• cyclin D1 gene

STADIUM ( Ann Arbor Modifikasi Cotswald )* Stadium I Pembesaran 1 KGB regional I E 1 organ extra limfatik tetapi tidak difus

* Stadium II Pembesaran min.2 KGB regional tapi masih 1 sisi diafragma II.2 Pembesaran 2 regio KGB, II.3 Pembesaran 3 regio KGB II E Pembesaran 1 regio KGB + 1 extralimfatik tidak difus

* Stadium III Pembesaran KGB regional 2 sisi diafragma

* Stadium IV Jika mengenai minimal 1 organ extralimfatik, difusA : bila tanpa gejala sistemik, B : dg gejala sistemikX : bila ada bulky mass ( > 1/3 torak, > 10 cm untuk KGB

PENATALAKSANAAN1. Radioterapi

2. Radioterapi + Kemoterapi3. Kemoterapi

Generasi Pertama

Cyclophosphamide 750 mg IV hari 1Oncovin 1,4 mg IV hari 1

Adriamisin 50 mg IV hari 1Prednison oral

4X20mg hari 1– 5, 3 X 20 mg hr ke 6, 2 X 20 mg hr ke 7, 1 X 20 mg hr ke 8 siklus diulangi setiap 21 hari selama 6 siklus

Generasi dua* M-Bacod, MOPP, COPBLAM, CAP-BOP

Generasi tiga* MACOP B, COPBLAM III, COPBLAM IV, CHOP-Bleo/CMED

relaps : salvage terapi

Treatment Options:Indolent lymphomas

FOLLICULAR LYMPHOMA• 10-15% in Stage I or II

– potentially curable– local radiotherapy

• 85-90% Stage III or IV– incurable– treatment does not prolong survival

Reasons to Treat in Advanced Indolent Lymphomas

• Constitutional symptoms• Anatomic obstruction• Organ dysfunction• Cosmetic considerations• Painful lymph nodes• Cytopenias

Treatment Options inAdvanced Indolent Lymphomas

• Observation only.• Radiotherapy to site of problem.• Systemic chemotherapy

– oral agents: chlorambucil and prednisone– IV agents: CHOP, COP, fludarabine, 2-CDA.

• Antibody against CD20: Rituxan, Bexxar, Zevalin.

• Stem cell or bone marrow transplant.

CHOP Chemotherapy

• Cyclophosphamide (Cytoxan)• Hydroxydaunorubicin

(Adriamycin)• Oncovin (vincristine)• Prednisone

Treatment Options:Aggressive Lymphomas

Aggressive• Diffuse large cell lymphoma, large cell

anaplastic lymphoma, peripheral T cell lymphoma.

Very Aggressive• Burkitt’s lymphoma and lymphoblastic

lymphoma.

Treatment Options for Early Stage Aggressive Lymphomas

• Often in Stage I or II– potentially curable– disseminates through bloodstream early– must use systemic chemotherapy

• CHOP x 6 cycles• CHOP x 3 cycles followed by radiotherapy

Treatment Options for Advanced Stage Aggressive Lymphomas

• Systemic chemotherapy– CHOP (± Rituxan for over 70 age group)

• ± Intrathecal chemotherapy – AIDS patients and CNS involvement

• ± Radiotherapy– Spinal cord compression, bulky disease

PROGNOSIS

LOW GRADE : 6 – 7 YRS (MED SURVIVAL)

AGGRESSIVE : 3 – 4 YRS (MED SURVIVAL)

RAPIDLY PROGRESSIVE60 % (5-YRS SURVIVAL)

T E R I M A K A S I H