Patho - 4th Asessment - Lymphoproliferative Disorders I - 31 Jan 2007

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 mucosaassociated lymphoid tissue are secondary lymphoid organs. • Peripheral blood T- and Blymphocytes circulate in a defined pattern through secondary lymphoid organs.

From General and Systemic Pathology by JEC Underwood

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 •

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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 Bdependent 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), noncleaved 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 manner similar to that of B-cells.

Hypothetical scheme of lymphocyte differentiation (Harris).

Cells from a Reactive Cervical Lymph Node: FNA Smear

Lymphoproliferative Disorders: Definition

• Lymphoproliferative disorders: Diseases in which

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cells of the lymphatic system grow (proliferate) excessively. • Cells of the lymphatic system (Immune system): Tlymphocytes, 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. 2. 3.

Acute non-specific lymphadenitis. Chronic non-specific lymphadenitis. Specific reactive changes.

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Infectious lymphadenitis:

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Infectious mononucleosis. Toxoplasmosis. Lymphadenitis in immunodeficiency states. Catscratch disease.

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Lymphadenitis of autoimmune origin or of unknown etiopathogenesis:

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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).

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Cause: Direct challenge of

microbial agents (most commonly), or foreign material introduced into wounds in the catchment area.

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Gross: Lymph nodes are swollen, gray-red, and engorged.

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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 lymphadenitis is due to bacterial origin.

A. A 10 year old boy with right axillary swelling. B. Organizing inflammation(MGG X 100). C. Smear shows 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. •

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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 • •

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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.

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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.

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Dilatation of subcapsular and medullary sinuses due to infiltration by nonneoplastic histiocytes , containing phagocytosed intact lymphocytes (emperipolesis). This ultimately leads to effacement of nodal architecture.

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Histiocytes are S-100 positive (dendritic cell family)