Lymphoid System

T. Utoro Department of Pathology GMUSM

neoplasms of the

Neoplastic proliferations of white cells

Lymphoid Neoplasms Myeloid Neoplasms - Acute myelogenous leukemia - Myelodysplastic syndromes - Chronic myeloproliferative disorders Histiocytosis Langerhans cell hitiocytosis

Structure of Normal Lymphnode

Lymphoid Neoplasms
Certain 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

Lymphoid Neoplasms
close to immune regulatory system

Lymphoid neoplasm are tumors of the immune system disrupt normal immune regulatory mechanisms (evidences: susceptibility to infection, autoimmune diseases) Patients with inherited or acquired immunodeficiency are at high risk of developing certain lymphoid neoplasm, particularly these associated with EBV infection

Lymphoid Neoplasms
All lymphoid neoplasms are derived from single transformed cell monoclonal Divided into 2 big groups: NHLs and HLs

NHLs often present as involvement of a particular tissue site, but sensitive molecular assay usually show that the tumor is widely disseminated at the time of diagnosis only systemic therapy are curative
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

Lymphoid Neoplasms
HL spreads in orderly fashion, and as a result staging is of importance in determining therapy In contrast, 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

ETIOLOGY
Chromosomal translocation: 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

Lymphoid Neoplasms
I. Precursor B-cell Neoplasms: neoplasms of immature B-cells II. Peripheral B-cell Neoplasms: neoplasms of mature B-cells III. Precursor T-cell Neoplasms: neoplasms of immature T-cells IV. Peripheral T-cell and NK-cell Neoplasms: neoplasms of mature T-cell and NK-cell V. Hodgkin Lymphoma: neoplasms of ReedSternberg cells and variants

The WHO Classification of the

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

Neoplasma prekursor sel B & T

ALL: mewakili sekaligus tumor yang terdiri dari sel-sel imatur, prekursor sel B / T (limfoblas) 85% berasal dari prekursor sel B childhood acute leukemia Sisanya dari prekursor sel T adolescent males lymphoma

Neoplasma prekursor sel B & T

Ada overlap antara B & T dalam hal sifat klinis, kadang B memberikan gejala limfoma, dan T memberikan perubahan gambaran hematologik Harus bisa membedakan ALL dari CML karena respon terhadap kemoterapi yang berbeda

Precursor B-cell Neoplasms

Diagnosis: precursor B lymphoblastic leukemia/lymphoma

The Classification of the Lymphoid Neoplasms WHO

Berasal dari sel B prekursor sumsum tulang yang mengekspresikan TdT dan tidak mengandung Ig permukaan Genotipa: translokasi kromosom t(12;21), melibatkan CBF dan ETV6 rearrangement Klinis: agresif, predominan pada anak-anak, dengan simtom yang berhubungan dengan pansitopeni akibat gangguan sumsum tulang

III. Precursor T-cell Neoplasms

Diagnosis: precursor T lymphoblastic leukemia/lymphoma

The WHO Classification of the Lymphoid Neoplasms

-Berasal dari prekursor sel T, sering dari timus -Mengekspresikan TdT -Translokasi kromosom, lokus reseptor sel T -Paling sering rearrangement TAL1

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

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

II. Peripheral B-cell Neoplasms

Small Lymphocytic Leukemia Small Lymphocytic Lymphoma

The two indistinguishable disorders: morphologically, phenotypically, and genotypically; differing only 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.

II. Peripheral B-cell Neoplasms

Small Lymphocytic Leukemia Small Lymphocytic Lymphoma

Diffuse effacement of nodal architecture

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

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

II. Peripheral B-cell Neoplasms

Follicular Lymphoma
In most cases, at low magnification, a predominantly nodular or nodular and diffuse growth pattern is observed 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 Involvement: bone marrow (85%), spleen, liver Te overall median survival is 7 to 9 years, is not improved by aggressive therapy

II. Peripheral B-cell Neoplasms

Follicular Lymphoma (spleen)

Prominent nodules represent white pulp follicles expanded by follicular lymphoma cells

Follicular Lymphoma

Malignant lymph follicles are marked by Bcl-2 positive

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)

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.

Diffuse large B-cell lymphoma (DLBCL)

Slight male predominance Age about 60 years 5% of childhood lymphoma Clinically present with a rapidly enlarging, often symptomatic mass, at a single nodal or extranodal site

II. Peripheral B-cell Neoplasms

Diffuse large B-cell lymphoma

Spleen: typical isolated large mass

Diffuse large B-cell Lymphoma

Tumor cells show prominent nucleoli

Diffuse large B-cell lymphoma

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

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 feature Both endemic & non-endemic are found largely in children and young adults (30%) Most tumor manifests at extra-nodal sites

Burkitt lymphoma

Low power: many tingible body macrophages Starry sky appearance

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

Burkitt Lymphoma

Several starry sky macrophages was shown (arrows)

Multiple myeloma of the skull

II. Peripheral B-cell Neoplasms

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

Multiple myeloma (bone aspirate)

Normal marrow cells are replaced by plasma cells

Lymphoplasmacytic lymphoma

Mast cell

Bone marrow biopsy: various degrees of plasma cell differentiation

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 T-cell lymphoma Adult T-cell leukemia/Lymphoma NK/T-cell lymphoma, nasal type NK-cell leukemia

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

IV. Peripheral T&NK-cell Lymphoma

Peripheral T-cell lymphoma

IV. Peripheral T&NK-cell Lymphoma

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

Anaplastic large cell lymphoma

IV. Peripheral T&NK-cell Lymphoma

mitosis

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

IV. The WHO Classification of the Lymphoid Neoplasms

V. Hodgkin Lymphoma
Classical subtype Nodular sclerosis Mixed cellularity Lymphocyte-rich Lymphocyte depletion Lymphocyte pre-dominance

V. Hodgkin Lymphoma

Lymphocyte predominant.

Mixed cellularity

Lymphocyte rich

Lymphocyte depleted

Nodular sclerosis

V. Hodgkin Lymphoma

Reed-Sternberg cell, positive for CD30

V. Hodgkin Lymphoma

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

Reed-Sternberg cells and variants

A. Diagnostic RS-cells with 2 nuclear lobes, large inclusionlike nucleoli, and abundant cytoplasm B. 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.

(Reed-Sternberg cells and variants)

Hodgkin lymphoma

Hodgkin lymphoma:
nodular sclerosis type

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

Hodgkin lymphoma:
mixed cellularity type

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

Hodgkin lymphoma
lymphocytic predominance type

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

Ann Arbor Staging System

Stage I A/B Stage II A/B I IE II IIE Stage III A/B III IIIE IIIS IIIES Stage IV A/B IV Involvement of a single lymph node region or A single extra lymphatic organ or site Involvement of 2 or more lymph node regions on the same side of the diaphragm, or With localized contiguous involvement of an extra lymphatic organ or site Involvement of lymph node regions of both sites of the diaphragm Or, with localized contiguous involvement of an extra lymphatic organ or site, or With involvement of spleen, or both extra lymphatic organ or site and spleen involvement Diffuse or disseminated involvement of one or more extra lymphatic organs with or without associated lymph node involvement

References
Rubins Pathology. Clinical Foundations of Medicine, 2005. Emanuel Rubin cs; Lippincott Williams & Wilkins. Robbins Pathologic Bases of Medicine, 2005. Cotran, Kumar, Collins. Saunders Pathology, 2nd ed. 2002. Arthur S. Schneider, Philip A. Szanto; Lippinctt Williams & Wilkins