TUMS050509 1

Lymphoid Neoplasm

IRIANIWATIDepartment of Pathology GMUSM

TUMS050509 2

TUMS050509 3

Neoplastic proliferations of white cells

• Lymphoid Neoplasms• Myeloid Neoplasms

- Acute myelogenous leukemia- Myelodysplastic syndromes- Chronic myeloproliferative disorders

• Histiocytosis Langerhans cell hitiocytosis

TUMS050509 4

Lymphoid Neoplasmsclose to immune regulatory system

• Lymphoid neoplasm are tumors of the immune system disrupt normal immune regulatory mechanisms

• Evidences: susceptibility to infection, autoimmune diseases

TUMS050509 5

Lymphoid Neoplasmsclose to immune regulatory system

• Patients with inherited or acquired immunodeficiency are at high risk of developing certain lymphoid neoplasm, particularly these associated with EBV infection

TUMS050509 6

Lymphoid Neoplasms

• All lymphoid neoplasms are derived from single transformed cell monoclonal

• Divided into 2 big groups: - Non Hodgkins Lymphoma (NHL)- Hodgkins Lymphoma (HL)

TUMS050509 7

Lymphoid Neoplasms

• NHLs often present as involvement of a particular tissue site

• Sensitive molecular assay usually show that the tumor is widely disseminated at the time of diagnosis only systemic therapy are curative

TUMS050509 8

Lymphoid Neoplasms

• HLs are often presents at a single site spreads methodically to contiguous lymph nodes group

• Early course tumors may be cured with local therapy alone

TUMS050509 9

Lymphoid Neoplasms• HL spreads in orderly fashion, and as a result

STAGING is of importance in determining therapy

• The spread of NHL is less predictable most patients are assumed to have systemic disease at the time of diagnosis staging in particular NHL provides useful prognosis information, but generally not important in guiding therapy

TUMS050509 10

E T I O L O G Y• Chromosomal translocation: Chronic Meylocytic Lymphoma

(CML), Burkitt lymphoma• Inherited genetic factors: Bloom syndrome, Fanconi anemia,

ataxia telangiectasia, Down syndrome• Viruses: HTLV-1, EBV, KSHV, HHV-8 • Environmental agents: Helicobacter pylorii (gastric B-cell

lymphoma), gluten-sensitive enteropathy (T-cell lymphoma), HIV (B-cell lymphoma)

• Iatrogenic factors: radiotherapy & chemotherapy mutagenic effect

TUMS050509 11

Lymphoid NeoplasmsCertain relevant principles must be

emphasized

• Can be suspected from the clinical features, but histological examination of lymph nodes and other involved tissue is required for diagnosis

• The vast majority of lymphoid neoplasm (80% - 85%) are of B-cell origin; most of the remainder being T-cell tumors; only rarely are tumors of NK origin encountered

• Two basic forms of B-cell lymphoma: follicular & diffuse type

TUMS050509 12

The WHO Classification of the

Lymphoid NeoplasmsI. Precursor B-cell Neoplasms: neoplasms

of immature B-cellsII. Peripheral B-cell Neoplasms: neoplasms

of mature B-cellsIII. Precursor T-cell Neoplasms: neoplasms

of immature T-cellsIV. Peripheral T-cell and NK-cell

Neoplasms: neoplasms of mature T-cell and NK-cell

V. Hodgkin Lymphoma: neoplasms of Reed-Sternberg cells and variants

TUMS050509 13

Origin of Lymphoid Neoplasms

CLP: common lymphoid precursor; BLB: pre-B lymphoblast; NBC: naive B-cell; MC: mantle B-cell; GC: germinal center B-cell;

MZ: marginal zone B-cell; DN: CD4/CD8 double negative pre-T cell; DP: CD4/CD8 double positive pre-T cell; PTC: peripheral T-cell

TUMS050509 14

TUMS050509 15

Precursor B & T cell neoplasms

• Acute lymphoblastic Leukemia (ALL): contain of immature cells, precursor B / T cells (lymphoblast)

• 85% arising from precursor B cell childhood acute leukemia

• The less common, from precursor T cell adolescent males lymphoma

TUMS050509 16

Precursor B & T cells neoplasms

• There is overlap in the clinical behaviour of B & T- ALL.

• B-ALL uncommonly presents as a mass in the skin/ bone and T-ALL presents with leukemic picture

• ALL must be distinguished from CML due to differing response to chemotherapy

TUMS050509 17

The Classification of the Lymphoid Neoplasms WHO

Precursor B-cell NeoplasmsDiagnosis: precursor B lymphoblastic leukemia/lymphoma

•Asal: sel B prekursor sumsum tulang mengekspresikan TdT

tidak mengandung Ig permukaan•Genotipa:

translokasi kromosom t(12;21), CBFα dan ETV6 rearrangement•Klinis:agresif

predominan pada anak-anak, gejala : pansitopeni

TUMS050509 18

The WHO Classification of the Lymphoid Neoplasms

III. Precursor T-cell NeoplasmsDiagnosis: precursor T lymphoblastic leukemia/lymphoma

-Asal: prekursor sel T, sering dari timusMengekspresikan TdT

- Genotipa:Translokasi kromosom, lokus reseptor sel TPaling sering rearrangement TAL1

TUMS050509 19

Acute lymphoblastic leukemia / lymphoma

-Originate from B-cell or T-cell, mostly from T-cell-Can be differed by B-cell marker CD22-The nuclear chromatin is delicate and finely stippled, and nucleoli are either absent or inconspicuous

TUMS050509 20

The WHO Classification of the Lymphoid Neoplasms

II. Peripheral B-cell Neoplasms• CLL / small lymphocytic lymphoma• B-cell prolymphocytic leukemia• Lymphoplasmacytic lymphoma• Splenic and nodal marginal zone lymphoma• Extranodal marginal zone lymphoma• Mantel cell lymphoma• Follicular lymphoma• Marginal zone lymphoma• Hairy cell leukemia• Plasmacytoma / plasma cell myeloma • Diffuse large B-cell lymphoma• Burkitt lymphoma

TUMS050509 21

II. Peripheral B-cell Neoplasms Small Lymphocytic LeukemiaSmall Lymphocytic Lymphoma

• The two indistinguishable disorders:- morphologically, phenotypically - genotypically differing in the degree of peripheral blood lymphocytosis

• Proliferation center: loose aggregates of pro-lymphocyte pathognomonic

• Tumor cells usually infiltrate the splenic white and red pulp, and the hepatic portal tract, although the extent of involvement varies widely.

TUMS050509 22

II. Peripheral B-cell Neoplasms Small Lymphocytic LeukemiaSmall Lymphocytic Lymphoma

Diffuse effacement of nodal architecture The majority of the tumor cells are small round lymphocytes.Arrow: pro-lymphocyte

TUMS050509 23

II. Peripheral B-cell Neoplasms Follicular Lymphoma

• The most common form of NHL in the USA (45% of adult lymphomas)

• Usually present in the middle age and afflicts males and females equally

• Less common in Europe, and rare in Asian population

• The tumor cells closely resemble normal germinal center B-cells

TUMS050509 24

II. Peripheral B-cell Neoplasms Follicular Lymphoma

• In most cases, at low magnification, a predominantly nodular or nodular and diffuse growth pattern is observed

• Involvement: bone marrow (85%), spleen, liver

• Te overall median survival is 7 to 9 years, is not improved by aggressive therapy

TUMS050509 25

II. Peripheral B-cell Neoplasms Follicular Lymphoma

• Two principle cells are observed in varying proportion:(1) small cell with irregular or cleaved nuclear contour and scant cytoplasm centrocyte(2) larger cells with open nuclear chromatin, several nucleoli, and modest amount of cytoplasm centroblast

TUMS050509 26

Follicular Lymphoma (spleen)

Prominent nodules represent white pulp follicles expanded by follicular lymphoma cells

TUMS050509 27

Follicular Lymphoma

Malignant lymph follicles are marked by Bcl-2 positive

TUMS050509 28

Follicular Lymphoma

Small lymphoid cells with condensed chromatin and irregular or cleaved nuclear outline (centrocyte), mixed with a population of

larger cells with nucleoli (centroblast)

TUMS050509 29

Mantle cell lymphoma

Neoplastic lymphoid cells surround a small, atrophic germinal center exhibiting mantle zone pattern of growth

Homogenous population of small lymphoid cells with somewhat irregular nuclear outlines, condensed chromatin, and scant cytoplasm.

TUMS050509 30

TUMS050509 31

II. Peripheral B-cell Neoplasms Diffuse large B-cell lymphoma

(DLBCL)• Slight male predominance• Average age about 60 years• 5% of childhood lymphoma• Clinically present with a rapidly

enlarging, often asymptomatic mass, at a single nodal or extranodal site

TUMS050509 32

Diffuse large B-cell lymphoma

Spleen: typical isolated large mass

TUMS050509 33

Diffuse large B-cell Lymphoma

Tumor cells show prominent nucleoli

TUMS050509 34

Diffuse large B-cell lymphoma

Tumor cells with large nuclei, open chromatin, and prominent nucleoli

TUMS050509 35

II. Peripheral B-cell Neoplasms Burkitt lymphoma

• Categories: (1) African (endemic) Burkitt lymphoma, (2) sporadic (non-endemic), (3) a subset of aggressive lymphoma occuring in individual with HIV infection

• Responds well to short-term, high dose chemotherapy (children & young adults)

• Clinical featureBoth endemic & non-endemic are found largely in children and young adults (30%)

• Most tumor manifests at extra-nodal sites

TUMS050509 36

Burkitt lymphoma

Low power: many tingible body macrophages Starry sky appearance

Monotonous appearance, tumor cells with multiple small nucleoli and high mitotic index (typical)

TUMS050509 37

Burkitt Lymphoma

Several starry sky macrophages was shown (arrows)

TUMS050509 38

II. Peripheral B-cell Neoplasms Multiple myeloma of the skull

The sharply punched-out bone lesions are most obvious in the calvarium

TUMS050509 39

Multiple myeloma (bone aspirate)

Normal marrow cells are replaced by plasma cells

TUMS050509 40

Lymphoplasmacytic lymphoma

Bone marrow biopsy: various degrees of plasma cell differentiationMast cell

TUMS050509 41

The WHO Classification of the Lymphoid Neoplasms

IV. Peripheral T&NK-cell Neoplasms• T-cell prolymhocytic leukemia • Large granular lymhocytic leukemia• Mycosis fungoides / Sezary syndrome• Peripheral T-cell lymphoma, unspecified• Anaplastic large cell lymphoma • Angioimmunoblastic T-cell lymphoma• Enteropathy-associated T-cell lymphoma• Panniculitis-like T-cell lymphoma• Hepatosplenic γδ T-cell lymphoma• Adult T-cell leukemia/Lymphoma• NK/T-cell lymphoma, nasal type• NK-cell leukemia

TUMS050509 42

IV. Peripheral T&NK-cell Lymphoma

Peripheral T-cell lymphoma

• T-cell lymphoma without specific defining features fall collectively into the category of “unspecified”

• Account for approximately half of all T-cell lymphoma in the western world

• As a group they are aggressive malignant with low 5-yrs• They may be nodal or extra nodal• Variable expression most nodal expressing CD4+• They may be associated with eosinophilia

TUMS050509 43

IV. Peripheral T&NK-cell Lymphoma

Peripheral T-cell lymphoma

A spectrum of small, intermediate, and large lymphoid cells, many with irregular nuclear contours.

TUMS050509 44

IV. Peripheral T&NK-cell Lymphoma

Anaplastic large cell lymphoma

mitosis

TUMS050509 45

Anaplastic large cell lymphoma

“Hallmark” cells with horseshoe-like or “embryo –like” nuclei and abundant cytoplasma lie near the center of the field.

IHC: ALK protein

TUMS050509 46

IV. The WHO Classification of the Lymphoid Neoplasms

V. Hodgkin Lymphoma

• Classical subtypeNodular sclerosisMixed cellularityLymphocyte-richLymphocyte depletion

• Lymphocyte pre-dominance

TUMS050509 47

V. Hodgkin Lymphoma: KLINIS• Manifes sebagai benjolan periferal, tidak sakit,

mengenai satu atau lebih limfonodi• Penyebaran dapat diperkirakan (lewat saluran

limfe aferen dan eferen)• Pada penyebaran lanjut makin sulit diprediksi

karena mulai ada penyebaran hematogen• Simtom konstitusional (40%): demam ringan

(kadang siklik), berkeringat malam, penurunan berat badan (10% dari bb), pruritus, sakit pada daerah tumor sesudah minum alkohol

TUMS050509 48

V. Hodgkin Lymphoma: KLINIS• Karakteristik: defisiensi fungsi sel T• Disfungsi imunitas ini dapat diperberat

dengan pemberian obat-obat imunosupresan

• Pada 50% kasus ditemukan limfositopeni absolut

• Imunitas humoral masih ada sampai akhir

TUMS050509 49

Urut-urutan frekwensi lokasi

1. Cervical & mediastinal (anterior – nodular sclerosis type)

2. Axillar, inguinal, retroperitoneal3. Antecubital, Popliteal, mesenterik

TUMS050509 50

V. Hodgkin Lymphoma

Lymphocyte predomi-Nant, (paling lembut). Umur <35th. L:P=4:1

Mixed cellularity, dekade 4-5.Cure rate 75%

Lymphocyte rich

Lymphocyte depleted. Paling agresif.

Nodular sclerosis. Paling banyak, dengan prognosis baik. Cure rate 80-85%

TUMS050509 51

V. Hodgkin Lymphoma

Reed-Sternberg cell, positive for CD30

TUMS050509 52

V. Hodgkin Lymphoma

Reed-Sternberg cell (HE stained)Mirror-image nuclei contain large eosinophilic nucleoli

TUMS050509 53

Reed-Sternberg cells and variantsA. Diagnostic RS-cells with 2 nuclear lobes, large inclusion-

like nucleoli, and abundant cytoplasmB. Mononuclear variant. C. Lacunar variant, characteristic of the nodular sclerosis

subtype. It has a folded or multilobated nucleus lying within a clear space created by disruption of its cytoplasm during processing

D. Lymphohistiocytic (L&H) variant, complex nuclear irregularities, small nucleoli, fine chromatin, and abundant pale cytoplasm.

TUMS050509 54

Hodgkin lymphoma (Reed-Sternberg cells and variants)

A B

C D

TUMS050509 55

TUMS050509 56

TUMS050509 57

Hodgkin lymphoma:nodular sclerosis type

Well-defined bands of pink, acellular collagen that subdivided the tumor cells and associated reactive infiltrate into nodules

TUMS050509 58

Hodgkin lymphoma:mixed cellularity type

Numerous mature-looking lymphocytes surround scattered, large pale-staining L&H variants (“popcorn” cells)

TUMS050509 59

Hodgkin lymphomalymphocytic predominance type

Reed-Sternberg cells is surrounded by reactive cells, including eosinophils

TUMS050509 60

Ann Arbor Staging SystemStage I

A/BI

IE

Involvement of a single lymph node regionorA single extra lymphatic organ or site

Stage IIA/B

II

IIE

Involvement of 2 or more lymph node regions on the same side of the diaphragm, orWith localized contiguous involvement of an extra lymphatic organ or site

Stage IIIA/B

III

IIIE

IIISIIIES

Involvement of lymph node regions of both sites of the diaphragmOr, with localized contiguous involvement of an extra lymphatic organ or site, orWith involvement of spleen, or both extra lymphatic organ or site and spleen involvement

Stage IVA/B

IV Diffuse or disseminated involvement of one or more extra lymphatic organs with or without associated lymph node involvement

TUMS050509 61

TUMS050509 62

TUMS050509 63

References • Rubin’s Pathology. Clinical Foundations of

Medicine, 2005. Emanuel Rubin cs; Lippincott Williams & Wilkins.

• Robbin’s Pathologic Bases of Medicine, 2005. Cotran, Kumar, Collins. Saunders

• Pathology, 2nd ed. 2002. Arthur S. Schneider, Philip A. Szanto; Lippinctt Williams & Wilkins