Kelompok 19

Angrety S. B. Stefanie K. Claudia I. Felix Hansen Juni Ray B. Charisa Lazarus Jason A. S. 1010030 1010095 1010003 1010101 1010070 1010140 1010093 1010074

LIMFOPOIESIS & HISTOLOGI NODULUS LIMFATIKUS

Pluripoten stem sel

Limfoid stem sel

Pro sel T Sel limfosit T Sel NK
Sel Tk Sel Tc

Pro sel NK

Pro sel B Sel limfosit B Sel plasma antibodi

makrofag

Lsg hancurkan antigen

fagositosis

Cortex Cortex luar : nodulus limfatikus (sel B, sel retikular, sel dendritik, serat retikular) Cortex dalam (zona paracortex): jaringan limfoid padat (sel T) Medulla Terdapat Medullary cord yaitu jaringan limfoid yang tersusun di sekitar pembuluh darah. Hillus : arteri, vena, saraf, p.limfe P.L. aferen sinus subkapsularis sinus trabekularis sinus medularis P.L. eferen

Imunogenitas Tumor

Komponen Sistem Imun

Mekanisme efektor sistem imun

Immunologi tumor
Pertumbuhan sel kanker ditentukan oleh kemampuan sel kanker berproliferasi dan kemampuannya menghindari respon imun (immune surveillance) Sel kanker akan mengekspresikan antigen permukaan yg khas dan seringkali memicu respon imun.

Imunogenitas tumor
Imunogenitas tumor sangat tergantung pada bagaimana tumor itu terbentuk. Tumor akibat karsinogen dan infeksi virus bersifat imunogenik. Tumor akibat mutasi (delesi,translokasi,insersi gen virus) sifat imunogenitasnya rendah.

Respon imun terhadap tumor

Sel NK dapat mengenali sel terinfeksi dan sel yg mengalami stress dan meresponnya dengan langsung membunuh sel tersebut, mensekresi sitokin unflamasi dan juga merupakan sumber INF-a yg utama, yg dapat mengaktivasi makrofag untuk membunuh mikroba yg difagositosisnya Aktivasinya tergantung keseimbangan reseptor aktivasi dan inhibisi

 Sel NK mempunyai 2 reseptor: KARs dan KIRs dimana aktivasi KARs dihambat o/ KIRs Pada sel kanker, ekspresi MHC1 seringkali menurun bahkan tidak diekspresikan, maka tidak ada yg menghambat aktivasi KARs dan terjadilah lisis sel target Salah satu kompleks reseptor aktivasi pada sel NK adalah reseptor NKG2D (sbg reseptor aktivasi primer, dpt mengatasi inhibisi o/ ikatan KIRs dg MHC1)

ONKOGENESIS

Tumor
Pertumbuhan tumor terjadi karena mutasi dari 4 jenis gen: Gen yang memperngaruhi pertumbuhan sel ( proto-oncogenes dan tumor suppressor genes) Gen yang mengatur apoptosis Gen yang mengatur perbaikan DNA

 Memenuhi kebutuhan growth factor Penurunan sensitivitas terhadap growth inhibitory signal Menghindar dari apoptosis Kapasitas untuk membelah terus Membentuk vaskularisasi baru Kemampuan metastasis

Perubahan fundamental pd sel yg menyebabkan timbulnya fenotip malignan

Memenuhi kebutuhan growth factor

Oncogene ada lah gen yang berasal dari mutasi proto-oncogene yang menyebabkan terjadinya cell growth. Growth factor Growth factor receptor
Perubahan genetik pd reseptor menyebabkan terjadinya proliferasi sel tanpa adanya perangsangan dari growth factor Cth: ekpresi berlebihan dari gen ERBB terdapat pada 80% kasus squamous cell CA pd Paru

Signaling Transduction Proteins

Siklus sel

Penurunan sensitivitas terhadap growth inhibitory signal

Menghindar dari apoptosis

Kapasitas untuk membelah terus

Membentuk vaskularisasi baru

Definition Non-Hodgkins Lymphoma (NHL)

NHL is a cancer that starts in cells called lymphocytes, which are part of the bodys immune system. Lymphocytes are in the lymph nodes and other lymphoid tissues (spleen & bone marrow). Cells in the lymphatic system either grow without control or do not die as cells normally do.
www.cancer.org ; www.emedicinehealth.com

Epidemiology & Incidence

-US: 66,000 cases of NHL / year, about 19,500 die. -The median age at presentation for most subtypes of NHL is older than 50 years. - In general, the incidence of NHL is slightly higher in men than in women, with a male-to-female ratio of approximately 1,4:1 -It is estimated to be the sixth most common cancer in the United States -NHL is more common in : immunodef, autoimmun disease, immunosupresant, >> White males. -Higesht rates US, Europe, Australia. Lowest Asia
www.cancer.org ; www.emedicinehealth.com

Etiology
- Unknown, the abnormal cell may be triggered by an infection or expossure to something in the environment. - NHLs may result from chromosomal translocations, environmental factors, immunodeficiency states, and chronic inflammation.

www.cancer.org ; www.emedicinehealth.com

Ann Arbor Staging System

Stage I The lymphoma is in only 1 lymph node area or lymphoid organ. Stage II The lymphoma is in 2 or more groups of lymph nodes on the same side of (above or below) the diaphragm. Stage III The lymphoma is found in lymph node areas on both sides of (above and below) the diaphragm. Stage IV The lymphoma has spread outside of the lymph system into an organ that is not right next to an involved node.
www.cancer.org ; www.emedicinehealth.com

Risk Factors
Older age Gender (men>women) Rase,ethnicity,geography Exposure to certain chemicals Radiation Exposure Immune system deficiency Autoimmune diseases Infection (viruses, bacteria)
www.cancer.org ; www.emedicinehealth.com

KLASIFIKASI & PROGNOSIS

Rappaport Classification (berdasarkan sitologi dan pola pertumbuhan)

Lukes-Collins Classification (berdasarkan asal sel & gambaran imunologik)

Working Formulation
Low Grade Small lymphocytic Intermediate Grade Follicular large cell High Grade Large cell immunoblastic Lymphoblastic Small non-cleaved cell (Burkitt and non-Burkitt type)

Follicular small-cleaved cell Diffuse small cleaved cell

Follicular mixed smallcleaved and large cell

Diffuse mixed small and large cell

Diffuse large cell

The Revised European American Lymphoma Classification (REAL)/WHO

I. Precursor B-cell neoplasm: Precursor B-lymphoblastic leukemia/lymphoma II. Mature (peripheral) B-cell neoplasms A. B-cell chronic lymphocytic leukemia / small lymphocytic lymphoma B. B-cell prolymphocytic leukemia C. Lymphoplasmacytic lymphoma D. Splenic marginal zone B-cell lymphoma (+/- villous lymphocytes) E. Hairy cell leuekmia F. Plasma cell myeloma/plasmacytoma G. Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue type H. Nodal marginal zone lymphoma (+/- monocytoid B-cells) I. Follicle center lymphoma, follicular, J. Mantle cell lymphoma K. Diffuse large cell B-cell lymphoma L. Burkitt's lymphoma/Burkitt's cell leukemia

T-Cell and Natural Killer Cell Neoplasms I. Precursor T cell neoplasm: Precursor T-lymphoblastic lymphoma/leukemia II. Mature (peripheral) T cell and NK-cell neoplasms A. T cell prolymphocytic leukemia B. T-cell granular lymphocytic leukemia C. Aggressive NK-Cell leukemia D. Adult T cell lymphoma/leukemia (HTLV1+) E. Extranodal NK/T-cell lymphoma, nasal type F. Enteropathy-type T-cell lymphoma G. Hepatosplenic gamma-delta T-cell lymphoma H. Subcutaneous panniculitis-like T-cell lymphoma I. Mycosis fungoides/Szary's syndrome J. Anaplastic large cell lymphoma, T/null cell, primary cutaneous type K. Peripheral T cell lymphoma, not otherwise characterized L. Angioimmunoblastic T cell lymphoma M. Anaplastic large cell lymphoma, T/null cell, primary systemic type

Hodgkin lymphoma Nodular lymphocyte predominance Hodgkin's lymphoma Classical Hodgkin's lymphoma
Nodular sclerosis Hodgkin's lymphoma Lymphocyte-rich classical Hodgkin's lymphoma Mixed cellularity Hodgkin's lymphoma Lymphocyte depletion Hodgkin's lymphoma

Stadium Berdasarkan Ann Arbor

Stadium I II Keterangan Pembesaran KGB hanya 1 regio IE : jika hanya terkena 1 organ extralimfatik tidak difuse / batas tegas Pembesaran 2 regio KGB / lebih, tetapi masih 1 sisi diafragma. II2 : pembesaran 2 regio KGB dlm 1 sisi diafragma II3 : pembesaran 3 regio KGB dlm 1 sisi diafragma IIE : pembesaran 1 regio / lbh KGB dlm 1 sisi diafragma & 1 organ extralimfatik tidak difuse / batas tegas Pembesaran KGB di 2 sisi diafragma

III

IV

Jika mengenai 1 organ extralimfatik / lebih tetapi secara difus dengan atau tanpa melibatkan limfatik

Semua stadium dibagi berdasarkan ada atau tidaknya gejala sistemik : demam, keringat malam, hilangya berat badan lebih dari 10% berat normal (jika terdapat gejala sistemik tersebut beri huruf B, jika tidak ada beri huruf A)

Patogenesis

White Blood Cells Neoplasm

Non-random chromosomal abnormalities Most common : translocation Genes that mutated or altered : development, growth, or survival of the malignant cell Oncoproteins genomic aberrations block normal maturation BCL-6 Proto-oncogenes are activated in lymphoid cells by errors that occur during antigen receptor gene rearrangement and diversification

Genetic Virus : HTLV-1, EBV, KSHV/HHV-8 Chronic Immune Stimulation Iatrogenic : radiation, chemotherapy Smoking : benzene AML

Non Hodgkin Lymphoma

(Diffuse Large B-Cell Lymphoma) Disregulation of BCL 6 overexpression holds cells in undifferentiated, proliferative state ; repress p53 c-MYC : proliferative Chromosome 14 and 18 overexpression BCL 2 disregulation BCL 6

Patofisiologi + GK

 Mass (DLCBL) : rapidly enlarging mass at nodal or extranodal Cancer Cachexia (weakness, anorexia, anemia, weight loss) BMR cytokine: tumor and host (TNF, IL-1, interferon-) soluble factors produced by tumors proteolysis, lipid mobilizing, catabolism homeostatic change

 Erosive, Infiltrative hematochezia, constipation, abdominal pain Febris : cytokine Sweating : febris compensation

Komplikasi
GIT
Perdarahan Infeksi Peritonitis

Terapi
Gagal ginjal Kerusakan hepar Keganasan

Leher
Thyroid, parathyroid Jalan nafas

Diagnosis Dasar
Bpk L, 54thn (FR60Y) KU: benjolan RLQ 2bln yll, makin membesar (sus. neoplasia, lymphadenopathy, lymphadenitis) Sjk 1 bln: benjolan di leher, febris hilang timbul (febris recurrens), srg berkeringat mlm hr (night sweat) (sus. Lymphadenitis TB, lymphoma) 1 mgg terakhir: nyeri terus menerus (continua) seluruh (difus) bag.perut, benjolan leher x nyeri

 X bertani krn malaise, anorexia, nausea, kad vomitus (GK sistemik) Sejak 6bln: BB menurun ~10kg (sus. Lymphadenitis TB, lymphoma) BAB agak sulit & lbh jarang (konstipasi), kad.hematochezia R.Kebiasaan: merokok sjk muda & pekerjaan srg pakai pestisida (FR u/ NHL) Respirasi: 24x/min (batas atas) Suhu: 380C (febris)

Pemeriksaan Fisik
KU: CM , tampak kesakitan Kepala : conjunctiva anemis +/+ (krn hematochezia, mgkn kronis) Leher: teraba masa a/r coli dextra, 2X1,5cm, oval, soliter, batas tegas, permukaan licin, nyeri tekan(-), terfiksasi, tidak ikut bergerak ketika menelan, tdk tampak tanda2 radang. (sus. Neoplasia) Abdomen: Perkusi: dull(+) RUQ & LUQ (krn ada masa) Palpasi: nyeri tekan slrh Q, defance muscular(+), benjolan di RUQ x jls teraba

 Pem Lab:

SGOT & SGPT (): fx hepar BUN & Creatinine (): fx hepar

LDH: dbn Hb():Anemia As.urat (): Hyperuricemia Ht(): Anemia B2M (): WBC(): Leukositosis MM/leukemia/lymphoma LED(): inflamasi CEA (): mgkn krn perokok Diff count Limfositosis berat SADT: mgkn infeksi berat CA 19-9: N

 CT scan abd: Tampak dinding ileum yg menebal di slrh bag yg memberikan gbrn hipodens yg berbatasan dgn cairan kontras dgn ketebalan s/ 5,2cm hingga 7,45cm yg menimbulkan penyempitan lumen ileum serta tampak mukosa iregular. Tampak adanya masa nodular di kanan yg memberikan enhancement post pemberian kontras dgn ukuran 6,5 x 5 x 4,4 cm

 Biopsi kgb coli dextra: Diffuse Non Hodgkins Lymphoma Lymphocytic Type (Low Grade Lymphoma)

DK: Diffuse Non Hodgkins Lymphoma Lymphocytic Type (Low Grade Lymphoma) + Anemia ringan + Hyperuricemia

Pem. Penunjang
Pem. hematologi rutin Hb, Ht Leukosit, trombosit hitung jenis LED SADT Pem. fungsi hepar: SGOT, SGPT Pem.fungsi ginjal: BUN, Creatinine Pem.elektrolit: Na, K, Mg, Ca Asam urat Tumor marker: CEA, CA 19-9, B2M LDH Beta-2 microglobulin

CT Scan (thorax, abdomen, pelvis) PET Scan MRI Chest Xray Biopsy Immunophenotyping Lymphangiogram Gallium scan

TREATMENT

Depends on : The type of non-Hodgkin's lymphoma Its stage How quickly the cancer is growing The patient's age Whether the patient has other health problems If there are symptoms present (fever and night sweats)

Slow-growing non-Hodgkin's lymphoma without symptom

Might not require treatment for years Close follow-up is necessary

Indolent lymphoma produces symptoms

Therapy will usually consist of chemotherapy and biological therapy Stage I and II often require radiation therapy

Aggressive type of lymphoma

A combination of chemotherapy and biological therapy is usually indicated Sometimes radiation therapy will be added

1. Chemotherapy
A drug treatment either as an injection or oral form that kills cancer cells Can involve one medication or multiple medications and be given alone or in conjunction with other therapies

2. Radiation therapy
High doses of radiation are used to kill cancer cells and shrink tumors This modality can be used alone or in conjunction with other therapies

3. Stem cell transplant

Allows to receive large doses of chemotherapy or radiation therapy to kill the lymphoma cells, that might not be killed with standard levels of therapy This therapy is used if lymphoma returns after treatment !

4. Biological drugs
Medications that enhance immune system's ability to fight cancers In NHL, monoclonal antibodies are used for treatment Rituximab (Rituxan) is such a drug used in the treatment of B cell lymphoma

5. Radio immunotherapy medications

Made of monoclonal antibodies that transport radioactive materials directly to cancer cells Ibritumomab (Zevalin) and Tositumomab (Bexxar) are two drugs approved for this use in lymphomas

Additional aspects of cancer treatments

Supportive care Moderate physical activity Eating the appropriate amounts of foods Vitamin (especially vitamin D) Acupuncture

PROGNOSIS

International Prognostik Index

Good Poor

Umur
Stage Lokasi Performans stat.

< 60 thn
I/ II No outside Aktivitas (N)

> 60 thn
III/ IV > 1 limfoma di luar Lymph node Tdk bisa / susah beraktivitas

LDH

LDH (N)

LDH meningkat

1 risk factor : low risk, 5 years lymphoma survival rate 70 % 2-3 risk factor: Intermediate risk , 5 years lymphoma survival rate 48-50 % 4-5 risk factor: High risk, 5 years lymphoma survival rate 26 %

Quo ad vitam Quo ad functionam Quo ad sanationam

: dubia ad malam : dubia ad malam : dubia ad malam