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Enlargement of Lymph Nodes and Spleen¶

Chapter 70 | Part 2: Cardinal Manifestations and Presentation of Diseases · Part 2 – Cardinal Manifestations & Presentation · Chapter 70

Key Clinical Points¶

Lymphadenopathy in primary care: >66% have nonspecific causes (viral/bacterial), <1% are malignancies.
Referral data: 84% of patients referred for lymphadenopathy have benign diagnoses; 16% have malignancy (lymphoma or metastatic adenocarcinoma).
Supraclavicular and scalene node enlargement is always abnormal and requires investigation due to drainage of lung and retroperitoneal regions.
Virchow's node (enlarged left supraclavicular node) specifically suggests a gastrointestinal primary.
Size criteria: Nodes <1.0 cm² are usually benign; >2.25 cm² (1.5 cm × 1.5 cm) is the best threshold for distinguishing malignant/granulomatous from other causes.
Texture clues: Hard, non-tender, and nonmovable nodes suggest metastatic cancer or lymphoma; tender nodes suggest inflammatory processes or capsule stretching.
Splenomegaly symptoms include LUQ pain, heavy sensation, and early satiety.
Spleen size: Normal weight <250 g, max diameter 13 cm (ultrasound), or 12 cm (radionuclide scan).
Splenomegaly mechanisms: Reticuloendothelial system hyperplasia (e.g., malaria, thalassemia) vs. infiltration/abnormal flow (e.g., lymphoma, Gaucher's).
Massive splenomegaly is highly suggestive of specific hematologic conditions like CML, Hairy cell leukemia, or Myelofibrosis.
Avoid glucocorticoids for lymphadenopathy unless there is life-threatening pharyngeal obstruction.
Splenectomy indications: Symptom control in massive splenomegaly, traumatic rupture, correction of cytopenias in hypersplenism, and rarely for staging Hodgkin's lymphoma.

1. DEFINITION & OVERVIEW¶

• Lymphadenopathy: Definition: Enlargement of lymph nodes. ◦ May be an incidental finding or a presenting sign/symptom of illness. ◦ Requires clinical determination if it is a normal finding or requires further study, up to and including biopsy. • Splenomegaly: Definition: Enlargement of the spleen. ◦ The spleen is a reticuloendothelial organ with embryologic origin in the dorsal mesogastrium (approx. 5 weeks' gestation). ◦ Located in the left upper quadrant (LUQ), attached to the stomach via the gastrolienal ligament and to the kidney via the lienorenal ligament. ◦ Normal size: Weight <250 g; maximum cephalocaudad diameter of 13 cm by ultrasonography or 12 cm by radionuclide scan. It is usually not palpable in most adults.

2. EPIDEMIOLOGY¶

• Primary Care Context: ◦ >66% of patients with lymphadenopathy have nonspecific causes or upper respiratory illnesses (viral/bacterial). ◦ <1% of cases in primary care are malignancies. ◦ Referral Data: 84% of referred patients have a 'benign' diagnosis; 16% have malignancy (lymphoma or metastatic adenocarcinoma). ◦ Of the benign cases, 63% had a nonspecific or reactive etiology (no causative agent found); others were specifically identified as infectious mononucleosis, toxoplasmosis, or tuberculosis. • Age and Malignancy Risk: ◦ Children/Young Adults: Typically have benign disorders (viral/bacterial infections, mononucleosis, toxoplasmosis, and in some countries, tuberculosis). ◦ Age >50: Incidence of malignant disorders increases; incidence of benign disorders decreases. • Prevalence of Palpable Spleen: ◦ Not always indicative of disease; found in 3% of asymptomatic, male, freshman college students (some remained palpable after 10 years without malignancy). ◦ In some tropical countries (e.g., New Guinea), the incidence of splenomegaly may reach 60%.

3. ETIOLOGY & PATHOPHYISIOLOGY¶

• Spleen Physiology: ◦ Red Pulp: Contains pulp sinuses and reticuloendothelial cell-lined cords; responsible for filtering blood. ◦ White Pulp: Lymphoid follicles within the red pulp matrix; involved in immune response. ◦ 'Pitting' Process: Mechanism where old/damaged RBCs (e.g., with parasites, Howell-Jolly bodies, or Heinz bodies) are trapped in the cords because they cannot pass through slit openings in the sinusoids. ◦ Adaptation: The spleen provides extra-medullary hematopoiesis and stores platelets and marginated neutrophils for response to bleeding or infection. • Lymphadenopathy Etiologies (Table 70-1): ◦ Infectious: ◦ Viral: EBV, CMV, infectious hepatitis, HSV, HV-6, VZV, rubella, measles, adenovirus, HIV, etc. ◦ Bacterial: Streptococci, staphylococci, cat-scratch disease, brucellosis, tularemia, plague, chancroid, melioidosis, glanders, TB, syphilis, diphtheria, leprosy, bartonella. ◦ Fungal/Chlamydial/Parasitic: Histoplasmosis, toxoplasmosis, leishmaniasis, etc. ◦ Immunologic: RA, SLE, Dermatomyositis, Sjögren's syndrome, Serum sickness, Drug hypersensitivity (phenytoin, hydralazine, allopurinol, etc.), Graft-versus-host disease. ◦ Malignant: Hodgkin's disease, non-Hodgkin's lymphomas, leukemias, metastatic cancers from various sites. ◦ Other: Lipid storage diseases (Gaucher’s, Niemann-Pick, Faburberg, Tangier), Hyperthyroidism, Sarcoidosis, Castleman's disease.

4. CLINICAL FEATURES¶

• General Presentation: ◦ Symptoms: Sore throat, cough, fever, night sweats, fatigue, weight loss, or pain. ◦ History factors: Age, sex, occupation, pet exposure, sexual behavior, drug use (e.g., phenytoin). • Physical Exam Findings: ◦ Localized vs. Generalized: Generalized (3+ noncontiguous areas) often associated with mononucleosis, toxoplasmosis, AIDS, SLE, or leukemias. ◦ Site-Specific Clues: ◦ Occipital: Scalp infection. ◦ Preauricular: Conjunctival infections, cat-scratch disease. ◦ Supraclavicular/Scalene: Always abnormal; reflect lung/retroperitoneal issues (lymphoma, cancer, or infections). ◦ Virchow's Node: Enlarged left supraclavicular node → metastatic GI primary. ◦ Axillary: Localized infection of upper extremity or melanoma/lymphoma. ◦ Inguinal: Lower extremity trauma/infection, STDs (syphilis, herpes), or rectal/genital malignancies. • Splenomegaly Features: ◦ Symptoms: LUQ pain, heavy sensation, early satiety. ◦ Pain mechanisms: Acute swelling (capsule stretch), infarction, or inflammation. • Lymph Node Morphology: ◦ Size Criteria: ◦ ≤ 1.0 cm² → usually benign/nonspecific; observe after excluding mononucleosis/toxoplasmosis. ◦ >2.0 cm → predictor for malignant or granulomatous disease (in specific cohorts). ◦ >2.25 cm² (1.5 cm × 1.5 cm) → best limit for distinguishing malignant/granulomatous from other causes. ◦ Texture Criteria: ◦ Tender: Indicates capsule stretch during rapid expansion or inflammatory process. ◦ Lymphoma: Large, discrete, symmetric, rubbery, firm, mobile, and nontender. ◦ Metastatic Cancer: Hard, nontender, and nonmovable (due to tissue fixation). • Nonsuperficial Adenopathy: ◦ Mediastinal/Hilar: Young patients → mononucleosis, sarcoidosis; Older patients → lung cancer, lymphoma, TB. ◦ Intra-abdominal/Retroperitoneal: Usually malignant (lymphoma or germ cell tumors in young men).

5. DIFFERENTIAL DIAGNOSIS¶

• Splenomegaly Mechanisms (Table 70-2): ◦ Reticuloendothelial system hyperplasia (Increased demand for splenic function): ◦ Hematologic: Malaria, Spherocytosis, Sickle cell anemia, Thalassemia, Myelofibrosis. ◦ Immune/Infection: Infectious mononucleosis, AIDS, Sarcoidosis, Thyrotoxicosis (benign lymphoid hypertrophy). ◦ Other: Serum sickness, immune hemolytic anemias, drug reactions, etc. ◦ Infiltration or Abnormal Flow: ◦ Infiltration: Hodgkin's lymphoma, Gaucher’s disease, Niemann-Pick disease, Myeloproliferative syndromes (polycythemia vera, essential thrombocytosis), Angiosarcomas. ◦ Other: Hemangiomas, fibromas, lymphangiomas, splenic cysts. • Massive Splenomegaly (Table 70-3): High suspicion for specific hematologic conditions: ◦ Chronic myeloid leukemia ◦ Hairy cell leukemia ◦ Myelofibrosis with myeloid metaplasia ◦ Polycythemia vera ◦ Gaucher’s disease ◦ Sarcoidosis

6. INVESTIGATIONS & DIAGNOSIS¶

Initial Assessment:
Evaluate site, size, and texture of lymph nodes.
Assess for systemic symptoms (fever, weight loss) and splenomegaly.
Size-Based Triage:
Node ≤ 1.0 cm² → exclude mononucleosis/toxoplasmosis → observe if no systemic illness.
Node >2.25 cm² (1.5 cm × 1.5 cm) → high suspicion for malignant or granulomatous disease → proceed to biopsy/imaging.
Location-Specific Workup:
Supraclavicular/Scalene → always investigate for malignancy or infection.
Mediastinal/Hilar → evaluate for lung cancer (older), mononucleous, or sarcoidosis (younger).
Splenomegaly Evaluation:
Determine if 'massive' (based on clinical presentation) → prioritize workup for CML, Hairy cell leukemia, or Myelofibrosis.

7. MANAGEMENT & TREATMENT¶

General Lymphadenopathy Management:
Avoid glucocorticoids unless there is life-threatening pharyngeal obstruction (e.g., infectious mononucleosis).
Splenectomy Indications:
Symptom control in massive splenomegaly.
Traumatic rupture of the spleen.
Correction of cytopenias in hypersplenism.
Staging Hodgkin's lymphoma (rarely).

8. KEY PEARLS & CLINICAL TRAPS¶

• Rule of Thumb: Supraclavicular and scalene nodes are always abnormal; they require investigation regardless of size. • Size Thresholds: 2.25 cm² (1.5 cm × 1.5 cm) is the critical threshold for distinguishing malignancy/granuloma from other causes. • Texture Clues: Hard, non-tender, and fixed nodes suggest metastatic cancer; tender nodes suggest inflammation or rapid growth (e.g., leukemia). • Massive Splenomegaly: If clinical features suggest massive splenomegaly, suspect CML, Hairy cell leukemia, or Myelofibrosis.

Reference Tables¶

TABLE 70-1 Diseases Associated with Lymphadenopathy 1. Infectious diseases¶

Harrison's 22e, p.477

1. Infectious diseases
  a. Viral—infectious mononucleosis syndromes (EBV, CMV), infectious
  hepatitis, herpes simplex, herpesvirus-6, varicella-zoster virus, rubella,
  measles, adenovirus, HIV, epidemic keratoconjunctivitis, vaccinia,
  herpesvirus-8
  b. Bacterial—streptococci, staphylococci, cat-scratch disease, brucellosis,
  tularemia, plague, chancroid, melioidosis, glanders, tuberculosis, atypical
  mycobacterial infection, primary and secondary syphilis, diphtheria,
  leprosy, bartonella
  c. Fungal—histoplasmosis, coccidioidomycosis, paracoccidioidomycosis
  d. Chlamydial—lymphogranuloma venereum, trachoma
  e. Parasitic—toxoplasmosis, leishmaniasis, trypanosomiasis, filariasis
  f. Rickettsial—scrub typhus, rickettsialpox, Q fever
  2. Immunologic diseases
  a. Rheumatoid arthritis
  b. Juvenile rheumatoid arthritis
  c. Mixed connective tissue disease
  d. Systemic lupus erythematosus
  e. Dermatomyositis
  f. Sjögren’s syndrome
  g. Serum sickness
  h. Drug hypersensitivity—diphenylhydantoin, hydralazine, allopurinol,
  primidone, gold, carbamazepine, etc.
  i. Angioimmunoblastic lymphadenopathy
  j. Primary biliary cirrhosis
  k. Graft-versus-host disease
  l. Silicone-associated
  m. Autoimmune lymphoproliferative syndrome
  n. IgG4-related disease
  o. Immune reconstitution inflammatory syndrome (IRIS)
  3. Malignant diseases
  a. Hematologic—Hodgkin’s disease, non-Hodgkin’s lymphomas, acute or
  chronic lymphocytic leukemia, hairy cell leukemia, malignant histiocytosis,
  amyloidosis
  b. Metastatic—from numerous primary sites
  4. Lipid storage diseases—Gaucher’s, Niemann-Pick, Fabry, Tangier
  5. Endocrine diseases—hyperthyroidism
  6. Passive congestion
  7. Other disorders
  a. Castleman’s disease (giant lymph node hyperplasia)
  b. Sarcoidosis
  c. Dermatopathic lymphadenitis
  d. Lymphomatoid granulomatosis
  e. Histiocytic necrotizing lymphadenitis (Kikuchi’s disease)
  f. Sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman
  disease)
  g. Mucocutaneous lymph node syndrome (Kawasaki’s disease)
  h. Histiocytosis X
  i. Familial Mediterranean fever
  j. Severe hypertriglyceridemia
  k. Vascular transformation of sinuses
  l. Inflammatory pseudotumor of lymph node
  m. Congestive heart failure

TABLE 70-2 Diseases Associated with Splenomegaly Grouped by Pathogenic Mechanism Enlargement Due to Increased Demand…¶

Harrison's 22e, p.481

Enlargement Due to Increased Demand for Splenic Function
Reticuloendothelial system hyperplasia (for removal of defective erythrocytes)	Malaria
Spherocytosis	Leishmaniasis
Early sickle cell anemia	Trypanosomiasis
Ovalocytosis	Ehrlichiosis
Thalassemia major	Disordered immunoregulation
Hemoglobinopathies	Rheumatoid arthritis (Felty’s syndrome)
Paroxysmal nocturnal hemoglobinuria	Systemic lupus erythematosus
Pernicious anemia	Collagen vascular diseases
Immune hyperplasia	Serum sickness
Response to infection (viral, bacterial, fungal, parasitic)	Immune hemolytic anemias
Infectious mononucleosis	Immune thrombocytopenias
AIDS	Immune neutropenias
Viral hepatitis	Drug reactions
Cytomegalovirus	Angioimmunoblastic lymphadenopathy
Subacute bacterial endocarditis	Sarcoidosis
Bacterial septicemia	Thyrotoxicosis (benign lymphoid hypertrophy)
Congenital syphilis	Interleukin 2 therapy
Splenic abscess	Extramedullary hematopoiesis
Tuberculosis	Myelofibrosis
Histoplasmosis	Marrow damage by toxins, radiation, strontium
	Marrow infiltration by tumors, leukemias, Gaucher’s disease
Enlargement Due to Abnormal Splenic or Portal Blood Flow
Infiltration of the Spleen
Intracellular or extracellular depositions	Hodgkin’s lymphoma
Amyloidosis	Myeloproliferative syndromes (e.g., polycythemia vera, essential thrombocytosis)
Gaucher’s disease	Angiosarcomas
Niemann-Pick disease	Metastatic tumors (melanoma is most common)
Tangier disease	Eosinophilic granuloma
Hurler’s syndrome and other mucopolysaccharidoses	Histiocytosis X
Hyperlipidemias	Hamartomas
Benign and malignant cellular infiltrations	Hemangiomas, fibromas, lymphangiomas
Leukemias (acute, chronic, lymphoid, myeloid, monocytic)	Splenic cysts
Lymphomas	Hemophagocytic lymphohistiocytosis
Unknown Etiology

TABLE 70-3 Diseases Associated with Massive Splenomegaly a Chronic myeloid leukemia Lymphomas Hairy cell leukemia…¶

Harrison's 22e, p.481

Chronic myeloid leukemia	Gaucher’s disease
Hairy cell leukemia	Sarcoidosis
Polycythemia vera	Diffuse splenic hemangiomatosis