Lymphoproliferative Disorders I

Dilip K. Das, MBBS, MD, PhD, DSc, FRCPath.

Department of Pathology, Faculty of Medicine,
Kuwait University
 The Lymphatic System

• Lymphatic tissue is widely distributed in the body, either as

lymphatic organs or as diffuse, dense, or nodular collections of
lymphocytes, and it collectively constitutes the lymphatic system.
• A lymphatic organ is a mass of lymphatic tissue that is surrounded
by a connective tissue capsule or covered by an epithelium.
Lymphatic organs include (1) lymph nodes, (2) thymus (3) spleen,
and (4) tonsils.
• Much lymphatic tissue of the body is not part of lymphatic organs
and is found in many locations, including the wall of the
gastrointestinal tract, and the wall of the air passages of the
respiratory system. The abbreviations GALT and BALT stand for
gut associated lymphoid tissue and bronchial associated lymphoid
tissue, respectively.
Structural Organization of the Immune System

• All lymphoid cells originate in the

bone marrow.
• Lymphoid cell precursors destined
to become T-lymphocytes mature in
the thymus (hence T-cells).
• Development of B-lymphocytes
occurs entirely in the bone marrow
(hence B-cells).
• The thymus and bone marrow are
primary lymphoid organs.
• Lymph nodes, spleen, and mucosa-
associated lymphoid tissue are
secondary lymphoid organs. From General and Systemic Pathology by JEC Underwood

• Peripheral blood T- and B-

lymphocytes circulate in a defined
pattern through secondary
lymphoid organs.
 Lymph Nodes
• A lymph node is an organized
collections of lymphoreticular
tissue in the form of pink-gray,
round to oval, or bean-shaped
encapsulated organ. It varies in
size from less than 1 mm to 2-3
cm. These are the filters along the
lymphatic system. Their job is to
(1) produce lymphocytes and
antibodies, (2) filter the lymph
(remove dead bacteria and other
foreign bodies), (3) serve as a
defense mechanism to prevent the
spread of malignant cells, and (4)
represent potential hemopoietic
organs.
• There are 500-600 lymph nodes
(lymph glands) in the body. They
are located at anatomically
constant points along the course
of lymphatic vessels.
• The common site of distribution
for clinical consideration are the
cervical, axillary, mediastinal,
retroperitoneal, iliac, and inguinal
regions.
 Histology of Lymph Nodes
• Anatomically, a lymph node is divided
into an outer cortex and an inner
medulla. The area between cortex and
medulla is called paracortex.
• The cortex is predominantly a B-
dependent area and contains primary
and secondary lymphoid follicles. The
primary follicles are compact
collections of inactive or resting
lymphocytes. The secondary follicle,
which develop from an antigenic
stimulus, show a pale central area of
lymphocytes at various stages of
differentiation. The pale central area
is surrounded by a mantle or corona
of small, dark-staining lymphocytes.
• The paracortex is a T-dependent area.
• The medulla contains medullary
cords with string-like arrays of both
B- ad T-cells, plasma cells, and
macrophages that converge on to the
hilus.
Histology of Lymph Nodes: B- and T-Cell
Distribution

CD20 for B-Cells

H&E CD3 for T-Cells

 The mantle zone contains the mantle
cells. The pale central area of a
secondary follicle contains lymphoid
cells at various stages of differentiation,
viz., cleaved cells (centrocytes), non-
cleaved cells (centroblasts), and
immunoblast. In between these cells can
be seen scattered phagocytic histiocytes
(Starry-sky macrophages). The
immunoblast leaves the germinal center
for the interfollicular area and forms
plasma cells.
The development of resting T-cells in to
T-immunoblasts and activated T-cells
appear to occur in the paracortex in a Hypothetical scheme of lymphocyte
manner similar to that of B-cells. differentiation (Harris).
Cells from a Reactive Cervical Lymph Node: FNA
Smear
 Lymphoproliferative Disorders:
Definition
• Lymphoproliferative disorders: Diseases in which
cells of the lymphatic system grow (proliferate) excessively.
• Cells of the lymphatic system (Immune system): T-
lymphocytes, B-lymphocytes, plasma cells, macrophages,
dendritic cells, and natural killer cells (together called
lymphoreticular cells).
• Proliferation of lymphoreticular cells: Benign (reactive)
or malignant (lymphoma).
• Lymphoproliferative disorders I: Reactive lesions of the
lymph nodes.
• Lymphoproliferative disorders II: Malignant diseases of
the lymphoreticular cells, a group of malignant neoplasms that
includes Hodgkin's lymphoma, and non-Hodgkin lymphoma
(lymphocytic leukemias and lymphomas, histiocytic
lymphomas, multiple myeloma and plasmacytoma, and all
immunosecretory disorders associated with monoclonal
gammopathy).
 Lymphoproliferative Disorders I:
Reactive Changes in Lymph Nodes
1. Acute non-specific lymphadenitis.
2. Chronic non-specific lymphadenitis.
3. Specific reactive changes.
D. Infectious lymphadenitis:
• Infectious mononucleosis.
• Toxoplasmosis.
• Lymphadenitis in immunodeficiency states.
• Catscratch disease.
I. Lymphadenitis of autoimmune origin or of unknown
etiopathogenesis:
• Rheumatoid arthritis.
• Castleman's Disease.
• Kikuchi-Fujimoto Disease.
• Rosai-Dorfman Disease.
 Acute Non-Specific Lymphadenitis
• Clinical: Enlarged tender lymph
nodes (fluctuant when undergo
suppurative necrosis; overlying skin
is red and sinus formation may
follow).
• Cause: Direct challenge of
microbial agents (most commonly),
or foreign material introduced into
wounds in the catchment area.
• Gross: Lymph nodes are swollen,
gray-red, and engorged.
• Histology:
• Prominence of lymphoid follicles
• Large germinal centers
• Numerous mitotic figures
• Debris of cellular or bacterial origin
in histiocytes
• Necrosis or suppuration with
neutrophilic infiltration, when acute
A. A 10 year old boy with right axillary swelling. B.
lymphadenitis is due to bacterial Organizing inflammation(MGG X 100). C. Smear shows
origin. lymphocytes, plasma cells, histiocytes and neutrophils
(MGG X 400). D. Gram staining of the smear shows
clusters of gram positive cocci (x 1000).
Chronic Non-Specific Lymphadenitis
• Clinical: enlarged but non-tender lymph nodes.
• Morphology: Three common patterns are recognized.
• Follicular hyperplasia:
• Paracortical lymphoid hyperplasia:
• Sinus histiocytosis:
Chronic non-specific lymphadenitis: Follicular
hyperplasia

• Caused by inflammatory processes that stimulate B-cells.

• Prominence of secondary follicles (large, round or oblong germinal
centers with centrocytes, centroblasts, immunoblasts and tingible body
macrophages).
• Plasma cells and histiocytes in parafollicular areas.
• Striking hyperplasia of mononuclear phagocytic cells in lymphatic
sinuses.
• Can be confused with follicular lymphomas.
 Paracortical Hyperplasia in Lymph Node

A B

Reactive changes in T-cell region, which encroach upon B-cell follicles.

A mixed cellular infiltrate including T-immunoblasts in interfollicular area.
Hypertrophy of sinusoidal and vascular endothelial cells.
 Sinus Histiocytosis in Lymph Node

Distention of lymphatic sinusoids by histiocytes.

Lining endothelial cells are markedly hypertrophied.
Commonly seen in lymph nodes draining a cancer and represent an
immune response of the host against the tumor or its product.
 Infectious Mononucleosis
• Caused by Epstein-Barr virus
(EBV).
• Paracortical lymphoid
hyperplasia is prominent
feature.
• Immunoblasts in lymph node
sinuses.
• Partial or complete obliteration
of lymph node architecture by
proliferating immunoblasts.
• Binucleated or multinucleated
immunoblasts resembling
Reed-Sternberg cells of
Hodgkin’s lymphoma.
 Toxoplasmic Lymphadenitis and Meningitis

Toxoplasma lymphadenitis:
• Caused by a parasite called Toxoplasma gondii.
• Prominent follicular hyperplasia.
• Small collections of epitheliod macrophages in inter-follicular region.
• Perisinusoidal monocytoid B-cell hyperplasia.
 AIDS Associated Lymphadenopathy

• Caused by Human immunodeficiency virus (HIV).

• Marked follicular hyperplasia, with a distinctive loss of Mantle
zones.
• Foci of interfollicular hemorrhage (follicle lysis).
• Variable degree of vascular proliferation.
• Depletion of lymphocytes in both follicles and interfollicular
areas.
• High incidence of superimposed neoplasms, e.g., Kaposi
sarcoma, Hodgkin lymphoma, and diffuse B-cell lymphoma.
 Cat Scratch Disease
• History of close contact with Cat.
• A delicate gram-negative
pleomorphic bacillus called
Bartonella henslae, which is
harbored by young cat and
kittens is implicated.
• Axillary and cervical
lymphadenitis.
• Follicular hyperplasia.
• Suppurative granulomatous foci:
consist of elongated or stellate
abscess, with central necrosis,
containing polymorphonuclear
leukocytes and surrounded by
palisaded macrophages and
fibroblasts.
• Monocytoid B-cell hyperplasia. Catscratch disease: Stellate abscess showing
suppurative granulomatous foci and confimed by
Warthin-Starry silver stain and immunohistochemical
technique (Barr and Qiu, 2005).
 Rheumatoid Arthritis

• Reactive follicular hyperplasia.

• Prominence of plasma cells in interfollicular area.
• Focal PAS positive eosinophilic hyaline material ± calcification.
• Sarcoid-like granulomas.
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 Castleman's Disease (SYN: Angiofollicular
Hyperplasia, Giant lymph node hyperplasia)
• Rare lymphoproliferative disease,
characterized by massive lymph node
hyperplasia.
• Mediastinum (60%), neck,
retroperitoneal, and axillary lymph
nodes are commonly affected.
• Types: Hyaline vascular (90%), plasma
cell type (<10%), and mixed.
• Hyaline vascular type: Poorly
developed germinal center surrounded
by expanded mantle zone, consisting
of small CD20+ lymphocytes arranged
in an onion skin manner. Increased
interfollicular vascularity with
endothelial hyperplasia.
• Plasma cell type: More numerous and
larger hyperplastic follicles with
germinal centers and more expanded
mantle zone. Vascular proliferation in
follicles. Plasma cell proliferation in
interfollicular area.
Kikuchi-Fujimoto Disease (Histiocytic
Necrotizing Lymphadenitis)
Young patients (female predominate) with acute tender cervical
lymphadenopathy and low-grade fever. Paracortical areas of
coagulative necrosis with abundant karryorrhective debris.
Karyorrhective foci contain various types of histiocytes,
plasmacytoid monocytes, immunoblasts, and small and large
lymphocytes. Abundance of T-cells with predominance of CD8+ over
CD4+ cells.
 Rosai-Dorfman Disease (Sinus
Histiocytosis with Massive Lymphadenopathy)
• Prominent enlargement of
lymph nodes.
• Dilatation of subcapsular
and medullary sinuses due
to infiltration by non-
neoplastic histiocytes ,
containing phagocytosed
intact lymphocytes
(emperipolesis). This
ultimately leads to
effacement of nodal
architecture.
• Histiocytes are S-100
positive (dendritic cell
family)