A. Normal Lymph Node (LN)

1. Subcapsular Space: capsular sinuses, lined by Macrophages (histiocytes)
2. Trabecular Sinuses
3. Lymphoid Follicles (B cell rich) in cortical region
   1. Central zone, different cell types include B lymphocytes and Macrophages
   2. Mantle Zone (cuff): B lymphocytes, more monotonous than central zone
4. Paracortical zone (T cell rich): histiocytes, small B and T cells, immunoblasts
5. Medulla with efferent lymphatic duct - lymphocytes, macrophages, dendritic cells
6. Lymphocytes home to LN by specific binding to Post Capillary, High-Endothelial Venules
7. Major site of immune responses to lymph-borne protein angens

B. Spleen

1. Normal Anatomy
   1. Fed by single splenic artery
   2. Artery pierces capsule at hilum and divides into smaller branches
   3. Early arterioles are surrounded by PALS (see below) in the White Pulp
   4. Distally, the arterioles end in vascular sinusoids in the Red Pulp
   5. Normal weight ~150gm in adults
2. Red Pulp
   1. Sinusoids with most RBCs (erythrocytes) within a reticular network
   2. Filtration region for dying RBCs
   3. Macrophages and dendritic cells in large amounts; lesser lymphocytes, plasma cells
3. White Pulp
   1. Germinal Center - lymphoid follicle (B cells) with surrounding Marginal Zone
   2. The marginal zone contains mainly B cells and C4+ T cells
   3. Periarteriolar Lymphatic sheath (PALS): arterioles surrounded by T lymphocytes
   4. The PALS T cells are ~65% CD4+, 35% CD8+
4. Major site of immune responses to blood-borne antigens

C. Definition of Reactive LN Hyperplasia

1. Enlargement of any lymphoreticular organ due to antigenic stimulation
2. Normal Lymphoid follicle and LN morphology remain intact

D. Types of LN Enlargement

1. Reactive Follicular Hyperplasia
2. Paracortical Hyperplasia
3. Sinus Histiocytosis
4. Reactive (Generalized) Hyperplasia
5. Atypical Hyperplasia
   1. Does not fit in to classification scheme above
   2. Insufficient evidence for diagnosis of lymphoma, but may progress to neoplasia
   3. May be exaggerated reactive hyperplasia with rapid resolution
   4. May include Castleman Disease

E. LN Changes Which Mimic Lymphoma

1. Follicular
   1. Marked increase in germinal centers (lymphoid follicles)
   2. Secondary Syphilis: possibly with granuloma formation
   3. Rheumatoid arthritis: some patients have marked follicular hyperplasia
   4. Lymphadenopathy Syndrome (HIV)
   5. Castleman Disease (Giant Lymph Node Hyperplasia)
   6. SLE - follicular hyperplasia, necrosis [6]
   7. Kimura Disease (see below)
2. Sinus Pattern
   1. Dilatation of lymphoid structures with cell infiltration
   2. Histiocytosis X (Langerhan's Cell Histiocytosis)
   3. Lymphangiogram effect
   4. Sinus histiocytosis with massive lymphadenopathy
   5. Metastatic Carcinoma and Melanoma
3. Diffuse Pattern
   1. Post-vaccine and viral lymphadenitis
   2. Dermatopathic lymphadenitis: melanin pigment deposition in LN
   3. Drug hypersensitivity: including dilantin (phenytoin)
   4. Angioimmunoblastic Lymphadenopathy (AILD; see below)
   5. Metastatic Carcinoma
   6. Metastatic Melanoma
   7. Kikuchi-Fujimoto Disease (see below)
4. Mixed Pattern
   1. Infectious Mononucleosis (Epstein-Barr Virus)
   2. Toxoplasmosis
   3. Cat scratch disease
   4. Lymphogranuloma inguinale
   5. Metastatic Carcinoma and Melanoma
5. Toxoplasmosis
   1. many germinal centers
   2. paracortical and sinus areas expanded
   3. often seen with isolated cervical lymph node involvement
6. Autoimmune Lymphoproliferative Syndrome (APLS) [1]
   1. Rare childhood disease with autoimmune phenomena and marked lymphadenopathy
   2. Defect in cell surface protein Fas (CD95) mediated cell death induction
   3. Failure to delete T lymphocytes
   4. Massive expansion of CD3+4-8- T lymphocytes
7. Monoclonal gammopathies can occur with any of these syndromes

F. Angioimmunoblastic Lymphadenopathy (AILD)

1. Usually with "dysproteinemia," that is, hypergammaglobulinemia (75%)
2. Anemia (71%), majority of which is Coombs' Positive (53%)
3. LN shows architectural effacement
4. Angiography shows small vessel proliferation in LN
5. Atypical Hyperplasia: including immunoblasts, histiocytes, plasma cells

G. Kikuchi Fujimoto Disease [2,3,10]

1. Fever and night sweats with tender unilateral or bilateral cervical LAD
2. Mediastinal, inguinal, peritoneal or retroperitoneal LAD can occur
3. Parotid swelling may also occur (intraparotid LN enlargement)
4. Female to Male 4:1
5. ESR is only slightly increased
6. Pathology shows necrotizing lymphadenitis with histiocytes
7. May appear to mimic lymphoma
8. Disease is benign and self-limited

H. Rosai-Dorfman Disease [10]

1. Rare disease of massive, nontender cervical LAD, age <20
2. Proliferation of sinusoidal histiocytes
3. Pyrexia
4. Parotid gland enlargement
5. Leukocytosis often present
6. Generally benign course

I. Kimura Disease [4]

1. Chronic, self-limited inflammatory condition of unknown etiology
2. Endemic in Asia (not reported in Europeans or Americans)
3. Male to Female 3:1, mean age ~35 years
4. Components of Disease
   1. Lymphadenopathy - insidious onset, follicular hyperplasia
   2. Tumor-like skin nodules
   3. Major salivary glands may become enlarged
   4. Hypereosinophilia and IgE increases are common
   5. IgE reticular networks in lymph nodes
5. No treatment required
6. Slow regression of symptoms usually over 6-12 months

J. Lymphedema [7,8]

1. Obstruction or obliteration of lymphatic ducts
   1. Leads to accumulation of extracellular fluid
   2. Fluid is protein-rich and very difficult to remove
2. Secondary causes more common than primary (idiopathic) causes [8]
3. Secondary Lymphedema
   1. Most commonly complication of local and regional therapy for cancer
   2. Usually in women following lymphadenectomy for breast cancer
   3. Infection due to filiarisis causing obstruction
   4. Idiopathic primary lymphedema (may be congenital deformity)
   5. Yellow Nail Syndrome
4. Primary Lymphedema
   1. Usually classified by age when lymphedema first appeared
   2. Congenital lymphedema occurs at birth or within first 2 years of life
   3. Hereditary primary lymphedema is also called Milroy's Disease
   4. Lymphedema praecox (most common primary form) occurs 10:1 in women to men
   5. Lymphedema praecox is usually unilateral and localized to foot and calf
   6. Lymphedema tarda is less common with delayed onset
5. Symptoms
   1. Swelling of affected limb or area
   2. Massive swelling / obstruction can lead to elephantiasis
   3. Pain - nerve constriction
   4. Vascular compromise and ischemia (compartment syndromes may occur)
6. Differential Diagnosis [8]
   1. Chronic venous insufficiency
   2. Myxedema
   3. Lipedema
   4. Malignant lymphedema
7. Treatment
   1. Careful attention to edema management essential for long term success
   2. Aggressive decongestive lymphatic therapy - specialized physical therapy
   3. Specific compressive garments are critical part of this therapy
   4. Multilayer bandaging + compression hosiery if preferred for compression [9]
   5. Low level laser therapy has shown some efficacy in poastmastectomy lymphedema
   6. Pharmcotherapy of limited benefit
   7. Surgical therapy: excisional procedures, microsurgical interventions
   8. Suction techniques to remove excess subcutaneous tissue
8. Physical Therapy [7,8]
   1. Also called decongestive lymphatic therapy
   2. Pysiotherapy with skin massage combined with compression stockings, exercise
   3. Initiate and maintain reduction in lymphedema
   4. Reduction in fluid ~40% or more
9. Coumarins
   1. Coumarin therapy may have some efficacy in primary and infective lymphedema
   2. Topical coumarin therapy under development
   3. Warfarin is not effective in patients with lymphedema after breast cancer evaluation [5]

References

1. Fisher GH, Rosenberg FJ, Straus SE, et al. 1995. Cell. 81:935
2. Norris AH, Krasinskas AM, Salhany KE, Gluckman SJ. 1996. Am J Med. 101(4):401
3. Snow RL and Ferry JA. 1997. NEJM. 336(7):492
4. Weiden PL, Bauermeister DE, Fatta EA. 1998. Lancet. 351(9109):1098 (Case Report)
5. Loprinzi CL, Kugler JW, Sloan JA, et al. 1999. NEJM. 340(5):346
6. Bloom BJ and Zukerberg LR. 1999. NEJM. 340(19):1491 (Case Record)
7. Szuba A, Cooke JP, Yousuf S, Rockson SG. 2000. Am J Med. 109(4):296
8. Rockson SG. 2001. Am J Med. 110(4):288
9. Badger CM, Peacock JL, Mortimer PS. 2000. Cancer. 88:2832
10. McGill TJI and Wu CL. 2002. NEJM. 346(25):1989 (Case Record)