Lymph Nodes

Normal Anatomy of the Lymph Nodes

Lymph node has arteries that feed it and veins that drain it as well as circulation from the lymphatics that drain into the subcapsular sinus. This is important because:

(1) in malignancies the neoplastic cells can drain through lymphatics therefore metastases are seen in the capsule.

(2) lymphocytes are targeted to the lymph node through their interaction with high endothelial venules Þ T and B cell will home to the interfollicular (aka paracortical) region = any region in lymph node not confined to the follicle.

Follicles are divided into:

primary nodules of non Ag stimulated cells (generally not seen in adults)
secondary areas: cells that recognize Ag undergo blastic transformation to form the germinal center surrounded by darker staining region known as the mantle.

Medulla of node: lymphocytes migrate here after stimulation then reenter the blood stream to go to target tissue.

If a B lymphocyte differentiates into a plasma cell it will either stay in the medulla or go back to the bone marrow.

Draining sinuses are home to histiocytes. Conditions in which they proliferate cause distention of lymphoid sinuses.

B cell Development

Ag independent phase of B cell development occurs in the bone marrow.

Most of the B cells in the marrow are considered pre B cells until they rearrange their Ig chains

The heavy chain rearranges first, followed by k , then l .

successful rearrangement of the heavy chain and either k or l Þ cell can emigrate from bone marrow into the blood.

B cell is then targeted to the lymph node where it will encounter Ag, usually in non-follicle area of paracortical area.

Then, with the help of T-cells, these B cells will begin to proliferate in the germinal center where the B-cell selection takes place for high affinity for Ag. Low affinity B cells die.

So germinal center has a lot of cell death and proliferation. Those that are selected will go onto to differentiate into a plasma B cell or a memory B cell.

The mantle zone is made up of B cells that are being pushed out by the proliferating germinal center. Every germinal center is a clone of B cells.

Germinal Centers: are the dark zones that correspond to proliferating B cells.

The light zones correspond to B cells that that are being selected for their ability to recognize Ag; this requires the help of follicle dendritic cells which hold Ag in immune complexes that the B cells can either recognize or not.

So any condition in which one is exposed to Ag, infection or autoimmune process Þ the lymph nodes will become enlarged and pathologic.

Causes of Lymphadenopathy – Primarily infection.

Bacterial: e.g. cut along arm Þ draining of bacteria into local lymph node Þ recognition of Ag Þ proliferation of germinal centers Þ expansion. Biopsy would not be indicated.

Viral: e.g. infectious mononucleosis due to infection with EBV virus. Diagnosis can be made by serology in most instances. Sometimes it may not be clear when a patient presents with lymph adenopathy and biopsy is then indicated.

Parasitic: rare: e.g. Toxoplasmosis can lead to an acute infectious phase with adenopathy which can be misinterpreted as a lymphoma but is discovered to be a reactive node due to toxoplasma after resection.

Fungal: mostly in the immuno-deficient: cryptococus or histoplasmosis.

Lympho-hematopoetic neoplasm: can definitely involve the lymph node. Discussed in later lecture.

lymph nodes are evaluated in all mastectomies or colectomies.

Autoimmune Disease: cause activation of B cell compartment associated with expansion and follicular hyperplasia.

Patterns of Lymphadenopathy – The area of the lymph node that is affected depends on what cells are predominantly excited in the response.

FOLLICULAR HYPERPLASIA MORPHOLOGY: B Cells: Increase in # and size of morphologically normal follicles in medulla. Retain mantle zones and over all architecture, bi/poly lobed germinal centers.

Associated Conditions: - Non-specific - Rheumatoid arthritis - Syphilis - HIV infection - Castleman’s changes (off center nucleus with clock face appearance perinuclear hallo and basophilic rim) Þ HHV-8 infection.

(2) Plasma Cell HYPERPLASIA MORPHOLOGY: Interfollicular plasmacytosis due to early differentiation of some B cells during response to antigen with help of interdigitated dendritic cells and T cells in the interfollicular zone.Þ early IgM spike or an autoimmune state. Can see larger transformed (aka activated) lymphoid cells with prominent nucleolus and cleared out nucleus.

Associated Conditions: - RA - Syphilis - Castleman’s "changes" associated with HHV-8 infection – SLE

(3) PARACORTICAL HYPERPLASIA MORPHOLOGY: T cells (and early B cell immune response): Expansion of interfollicular regions of lymph node. Multiple cell types create a mottled look (light/dark/light)

Associated Conditions: - infection: CMV (acute phase), EBV(spleenomegally) - Post-vaccination - Dilantin hypersensitivity - CAs: T cell lymphomas - Hodgkin’s disease

(4) MIXED FOLLICULAR AND INTERFOLLICULAR HYPERPLASIA

Associated Conditions: - Toxoplasma lymphadenitis; Autoimmune: SLE; Granulomatous lymphadenitis: Sarcoidosis , Cat-scratch disease, TB or atypical mycobacterial infection

(5) SINUS PATTERN MORPHOLOGY Histiocytes: Expansion of nodal sinuses. Streaky pink appearance on low power. Can see the histiocytes with abundant cytoplasm at high power.

Associated Conditions: - Sinus Histiocytosis; Malignancies: Histiocytic malignancies Marginal zone B cell lymphoma or hyperplasia Anaplastic large T cell lymphoma

(6) SUPERIMPOSED LESIONS: metastases, abscesses, granulomas which appear as plunked down gross lesions within node

Associated Condition: Tuberculous Lymphadenitis (highly infectious yellowish granulomas), tumors of breast, head CA

Histological Description of Particular Conditions:

EBV INFECTION MORPHOLOGY: - Interfollicular hyperplasia very pink looking node with few germinal centers.

Scattered large activated B and T cells (immunoblasts) COMMENTS: - Morphologically can be easily confused with lymphoma. - Lymph node biopsy is not recommended in individuals with infectious mononucleosis because you can’t distinguish it from a reactive lymphoma on this basis. Peripheral blood should show Ý reactive lymphocytes.

TOXOPLASMA LYMPHADENITIS MORPHOLOGY: - Mixed follicular and Interfollicular hyperplasia - Marginal zone B cell hyperplasia (light staining area of post follicular B cells which have gone through the germinal center, differentiated and are on the way to becoming plasma cells) – Many small granulomas that encroach upon germinal center. COMMENTS: - Parasitic cysts rarely seen. - Diagnosis is usually confirmed by serology. Patient needs to be at risk for exposure.

HIV INFECTION MORPHOLOGY DEPENDS ON STAGE OF INFECTION:

EARLY - Florid follicular hyperplasia (explosive lymphadenopathy), dumbbell shaped germinal centers, less prominent marginal zone hyperplasia, monocytoid B cell hyperplasia, Multinucleated giant cells (occasionally)
MID-STAGE "burnt" out hypo trophic germinal centers +/- follicular hyperplasia, slight plasmacytocis
END-STAGE - Lymphocyte depletion

CAT-SCRATCH DISEASE MORPHOLOGY: - Mixed follicular and Interfollicular hyperplasia - Granulomatous inflammation with necrosis - "stellate" abscesses (central necrosis of abscess) COMMENTS: - Axillary or cervical lymphadenitis usual presentation. – Organism: Bartonella hensilae hard to stain. PCR and serology available to diagnose.

RHEUMATOID LYMPHADENITIS MORPHOLOGY: - due to Follicular hyperplasia with associated Interfollicular plasmacytosis. Plasma cells tend to encroach on the germinal centers. COMMENTS: - 30-75% of rheumatoid arthritis patients.

SYSTEMIC LUPUS ERYTHEMATOSUS MORPHOLOGY: Mixed follicular and interfollicualr hyperplasia - Interfollicular plasmacytosis – nonspecific Necrosis - Hematoxylin bodies (pathoneumonic for SLE) which are extracellular nuclear material bound by auto-antinuclear Ab COMMENTS: - 30-60% of patients