Lymphadenopathy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Maria Fernanda Villarreal, M.D. [2] Raviteja Guddeti, M.B.B.S. [3]

Synonyms and keywords: Lymph nodes enlarged; Enlarged lymph nodes; Lymphadenitis; Swollen lymph nodes; Swollen/enlarged lymph nodes

Overview

Lymphadenopathy (also known as "enlarged lymph nodes) refers to lymph nodes which are abnormal in size, number or consistency. Common causes of lymphadenopathy are infection, autoimmune disease, or malignancy. Lymphadenopathy may be classified according to distribution into 2 groups: generalized lymphadenopathy and localized lymphadenopathy. The pathogenesis of lymphadenopathy is characterized by the inflammation of lymph nodes. This process is primarily due to an elevated rate of trafficking of lymphocytes into the node from the blood, exceeding the rate of outflow from the node. Lymph nodes may also be enlarged secondarily as a result of the activation and proliferation of antigen-specific T and B cells (clonal expansion). Lymphadenopathy is very common, the estimated incidence of lymphadenopathy among children in the United States ranges from 35%- 45%. Patients of all age groups may develop lymphadenopathy. Lymphadenopathy is more commonly observed among children. Common complications of lymphadenopathy, may include: abscess formation, superior vena cava syndrome, and intestinal obstruction. Diagnostic criteria for malignant lymphadenopathy, may include: node > 2 cm, node that is draining, hard, or fixed to underlying tissue, atypical location (e.g. supraclavicular node), associated risk factors (e.g. HIV or TB), fever and/or weight loss, and splenomegaly. On the other hand, diagnostic criteria for benign lymphadenopathy, may include: node < 1 cm, node that is mobile, soft-or tender, and is not fixed to underlying tissue, typical location (e.g. supraclavicular node), no associated risk factors, and palpable and painful enlargement. Laboratory findings consistent with the diagnosis of lymphadenopathy, may include: elevated lactate dehydrogenase (LDH), mild neutropenia, and leukocytosis. There is no treatment for lymphadenopathy; the mainstay of therapy is treating the underlying condition.

Classification

• Lymphadenopathy may be classified according to distribution into 2 groups:

• Generalized lymphadenopathy
• Localized lymphadenopathy

Pathophysiology

• The pathogenesis of lymphadenopathy is characterized by the inflammation of lymph nodes. This process is primarily due to an elevated rate of trafficking of lymphocytes into the node from the blood, exceeding the rate of outflow from the node.
• The inmune response between the antigen and lymphocyte that leads to cellular proliferation and enlargement of the lymph nodes.
• Lymph nodes may also be enlarged secondarily as a result of the activation and proliferation of antigen-specific T and B cells (clonal expansion).
• On gross pathology, characteristic findings of lymphadenopathy, include:

• Enlarged lymph node
• Soft greasy yellow areas within capsule

• On microscopic histopathological analysis, characteristic findings of lymphadenopathy will depend on the aetiology.
• Common findings, include:

Non-specific reactive follicular hyperplasia (NSRFH)

• Large spaced cortical follicles
• Tingible body macrophages, normal dark/light GC pattern

Lymph node metastasis

• Foreign cell population (usually in subcapsular sinuses)
• +/-nuclear atypia
• +/-malignant architecture

Toxoplasmosis

• Large follicles
• Epithelioid cells perifollicular & intrafollicular
• Reactive GCs
• Monocytoid cell clusters

Cat-scratch disease

• PMNs in necrotic area
• "Stellate" (or serpentine) shaped micro-abscesses
• Presence of granulomas

Dermatopathic lymphadenopathy

• Melanin-laden histiocytes
• Histiocytosis

Systemic lupus erythematosus lymphadenopathy

• Blue hematoxylin bodies
• Necrosis
• No PMNs

Causes

Causes by Organ System

Cardiovascular	Apo a-i deficiency
Chemical/Poisoning	Anthrax, Black widow spider venom, Zinc
Dental	Lip cancer
Dermatologic	Aphthous stomatitis, Asymmetric periflexural exanthem , Dermatomyositis, Erysipelas, Erythroderma, Gingivostomatitis, Infantile papular acrodermatitis, Leprosy, Mastitis, Measles, Melanoma, Mumps, Sarcoidosis, Spotted fevers, Yaws
Drug Side Effect	Allopurinol, Atenolol, Bcg vaccine, Captopril, Carbamazepine, Cephalosporins, Certolizumab pegol, Hydralazine, Infliximab, Oxaprozin, Penicillin, Penicillium marneffei, Phenytoin, Pinta, Pneumococcal vaccine 13-valent , Primidone, Pyrimethamine, Quinidine, Sulfonamides, Sulindac, Tiagabine, Typhoid vaccination
Ear Nose Throat	Aphthous stomatitis, Kikuchi's disease, Lymphangioma, Lymphangitis, Lymphatic filariasis, Lymphoma, Malignant lymphoma, Mesenteric adenitis, Sinus histiocytosis, Streptococcal pharyngitis, Vincent's angina
Endocrine	Castleman's disease, Chediak-higashi syndrome, Hyperthyroidism
Environmental	No underlying causes
Gastroenterologic	Brucellosis, Colorectal cancer, Hemophagocytic lymphohistiocytosis, Stomach cancer, Whipple's disease
Genetic	Chediak-higashi syndrome, Churg-strauss syndrome, Faisalabad histiocytosis, Familial alphalipoprotein deficiency, Familial hemophagocytic lymphohistiocytosis, Familial histiocytic reticulosis, Griscelli disease, Lipogranulomatosis, Rosai-dorfman disease, Siccardi syndrome, Sphingomyelinase deficiency, Wt limb blood syndrome, X-linked agammaglobulinaemia, X-linked lymphoproliferative syndrome
Hematologic	Acute lymphatic leukemia, Acute lymphoblastic leukemia, Acute lymphocytic leukemia, Addison's disease, Adult t cell leukemia, Apo a-i deficiency, Autoimmune haemolytic anaemia, Autoimmune lymphoproliferative syndrome type 1, Caspase-8 deficiency, Chancroid, Chronic lymphatic leukemia, Chronic lymphocytic leukemia, Churg-strauss syndrome, Cutaneous t cell lymphoma, Familial alphalipoprotein deficiency, Familial hemophagocytic lymphohistiocytosis, Familial histiocytic reticulosis, Hairy cell leukaemia, Hemoblastosis, Histiocytosis x, Hodgkin's lymphoma, Hyperimmunoglobulinemia d , Kawasaki disease, Large granular lymphocyte leukemia, Lassa fever, Leukemia, Macroglobulinemia, Myeloproliferative disorder, Non-hodgkin's lymphoma, Plasma cell leukemia, Primary autoimmune haemolytic anaemia, Pseudolymphoma, Septicaemia, Siccardi syndrome, Sinus histiocytosis, Waldenström macroglobulinemia, Yersinia pestis
Iatrogenic	Bcg vaccine, Pneumococcal vaccine 13-valent , Radiotherapy, Typhoid vaccination
Infectious Disease	African sleeping sickness, Aids, Bartonella, Bejel, Borrelia burgdorferi, Boutonneuse fever, Brucellosis, Cat scratch disease, Chagas' disease, Coccidioidomycosis, Congenital toxoplasmosis, Cowpox, Coxsackie virus infections, Cryptococcosis, Cutaneous leishmaniasis , Cytomegalovirus infection, Dengue, Diphtheria, Epstein-barr virus, Erysipelas, Erythroderma, Ethotoin, Filaria, Fungal blastomycosis, German measles, Hepatitis a, Hepatitis b, Herpes simplex, Herpes virus 2, Histoplasmosis, Hiv-1 disease, Human immunodeficiency virus, Infectious mononucleosis, Inflammatory pseudotumor, Influenza, Lassa fever, Leptospirosis, Listeriosis, Lyme disease, Lymphangitis, Lymphatic filariasis, Lymphogranuloma venereum, Measles, Mesenteric adenitis, Moraxella catarrhalis, Mucocutaneous leishmaniasis, Mumps, Mycobacterium avium-intracellulare, Mycobacterium chelonae, Mycosis fungoides, Onchocerciasis, Opisthorchiasis, Paracoccidioidomycosis, Plague, Pneumoconiosis, Protozoa, Rat-bite fever, Rhabditida infections, Rickettsiae, Rubella, Sarcoidosis, Scrub typhus, Secondary syphilis, Sennetsu fever, Septicaemia, Serum sickness, Sexually transmitted diseases, Smallpox, Sporotrichosis, Spotted fevers, Streptococcal pharyngitis, Streptococcal tonsillitis, Syphilis, Systemic infection, Three-day fever, Toxoplasma, Toxoplasmosis, Trypanosomiasis, Tuberculosis, Tularemia, Typhus fever, Varicella, Visceral leishmaniasis, Western equine encephalitis, Whipple's disease, Wuchereria bancrofti, Yaws, Yersinia pestis
Musculoskeletal/Orthopedic	Dermatomyositis, Rhabdomyosarcoma, Rheumatoid arthritis
Neurologic	African sleeping sickness, Western equine encephalitis
Nutritional/Metabolic	Lipogranulomatosis
Obstetric/Gynecologic	Breast cancer, Lymphogranuloma venereum
Oncologic	Acute lymphatic leukemia, Acute lymphoblastic leukemia, Acute lymphocytic leukemia, Addison's disease, Adult t cell leukemia, Breast cancer, Chronic lymphatic leukemia, Chronic lymphocytic leukemia, Colorectal cancer, Cutaneous t cell lymphoma, Cystic hygroma, Epstein-barr virus, Gamma heavy chain disease, Granuloma inguinale, Hemangiopericytoma, Hodgkin's lymphoma, Inflammatory pseudotumor, Kikuchi's disease, Leukemia, Lip cancer, Lymphangioma, Lymphoma, Malignant lymphoma, Melanoma, Merkel cell carcinoma, Myeloproliferative disorder, Non-hodgkin's lymphoma, Pancoast tumor, Plasma cell leukemia, Primary autoimmune haemolytic anaemia, Pseudolymphoma, Reticuloendotheliosis, Rhabdomyosarcoma, Secondary deposits from a local malignancy, Stomach cancer, Systemic mastocytosis, Waldenström macroglobulinemia
Ophthalmologic	No underlying causes
Overdose/Toxicity	No underlying causes
Psychiatric	No underlying causes
Pulmonary	Congenital tuberculosis, Extrinsic allergic alveolitis, Histoplasmosis, Pancoast tumor, Pneumoconiosis, Tuberculosis
Renal/Electrolyte	No underlying causes
Rheumatology/Immunology/Allergy	Amyloidosis, Extrinsic allergic alveolitis, Hemangiopericytoma, Hemophagocytic lymphohistiocytosis, Hemophagocytic reticulosis, Juvenile chronic arthritis, Rheumatoid arthritis, Rheumatoid disease, Still's disease, Systemic lupus erythematosus
Sexual	Aids, Bejel, Chancroid, Herpes simplex, Herpes virus 2, Hiv-1 disease, Human immunodeficiency virus, Secondary syphilis, Sexually transmitted diseases, Syphilis
Trauma	Snake bite , Spider bite
Urologic	Granuloma inguinale
Miscellaneous	Tang hsi ryu syndrome

Causes in Alphabetical Order

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3

• Common causes of lymphadenopathy, include:

• Infections (acute suppurative)

• Fungal
• Mycobacterial
• Viral
• Protozoal (e.g. toxoplasma)
• Bacterial (e.g. chlamydia, rickettsia, bartonella)

• Reactive

• Follicular hyperplasia
• Paracortical hyperplasia
• Sinus histiocytosis
• Granulomatous
• Neoplastic
• Drugs (e.g. cyclosporin, phenytoin, methotrexate)
• Lipid storage diseases
• IgG4-related sclerosing disease

Differentiating Lymphadenopathy from other Diseases

• Lymphadenopathy must be differentiated from syphilis, which may present as fever, myalgias, weight loss, and lymph node enlargement.

Epidemiology and Demographics

• Lymphadenopathy is very common.
• The estimated incidence of lymphadenopathy among children in the United States ranges from 35%- 45%.

Age

• Patients of all age groups may develop lymphadenopathy.
• Lymphadenopathy is more commonly observed among children.

Gender

• Lymphadenopathy affects men and women equally.

Race

• There is no racial predilection for lymphadenopathy.

Risk Factors

• The most common risk factors in the development of lymphadenopathy, include:

• Local soft-tissue infections
• Upper respiratory tract infection
• Foreign travel

Natural History, Complications and Prognosis

• Patients with lymphadenopathy may be symptomatic or asymptomatic, depending on the aetiology.
• Early clinical features include palpable tenderness, pain, and fever.

• Common complications of lymphadenopathy, include:

Mediastinal lymphadenopathy

• Superior vena cava syndrome
  • Tracheal and bronchial obstruction
  • Dysphagia
  • Hemoptysis
• Uric acid nephropathy
• Hyperkalemia
• Hypercalcemia
• Hypocalcemia
• Hyperphosphatemia
• Renal failure

Abdominal lymphadenopathy

• Intestinal obstruction

Superficial lymphadenopathy

• Abscess formation
• Cellulitis
• Fistulas (seen in lymphadenitis that is due to tuberculosis)
• Sepsis
• Prognosis will depend on the aetiology of the underlying disease.

Diagnosis

Diagnostic Criteria

Malignant Lymphadenopathy

• Node > 2 cm
• Node that is draining, hard, or fixed to underlying tissue
• Atypical location (e.g. supraclavicular node)
• Risk factors (e.g. HIV or TB)
• Fever and/or weight loss
• Splenomegaly

Benign Lymphadenopathy

• Node < 1 cm
• Node that is mobile, soft-or tender, and is not fixed to underlying tissue
• Common location (e.g. supraclavicular node)
• No associated risk factors
• Palpable and painful enlargement

Symptoms

• Symptoms of lymphadenopathy may include the following:

• Constitutional symptoms

• Fever
• Weight loss
• Fatigue
• Night sweats

• Malaise
• Nausea and vomiting
• Cachexia

• A directed history should be obtained to ascertain:

• Use of drugs causing lymphadenopathy
• Travel to endemic areas
• Occupational risk (e.g. Fishermen, slaughterhouse workers, hunters, trappers)
• High risk behavior or high risk sexual behaviors (e.g. I.V drug abuse, multiple partners)

Physical Examination

• Patients with lymphadenopathy may have a pale or normal appearance.
• Physical examination may be remarkable for:

Vitals

• Temperature

• High grade fever
• Low grade fever

• Pulse

• Rapid (e.g. acute infections)

Skin

• Rash may be present
• Color change (indicative of inflammation)
• Skin fistula draining pus may be present
• Ulcers

Head

Palpating Anterior Cervical Lymph Nodes

Lymph nodes should be examined in the following order:

• Anterior Cervical
• Posterior Cervical
• Tonsillar
• Sub-Mandibular
• Sub-Mental
• Supra-clavicular

Characteristics to be noted while palpating lymph nodes:

• Size
• Pain/ tenderness

• Increased tenderness (e.g infected lymph nodes)

• Consistency
• Matting

Gallery

• 
  Cervical adenopathy: massive right side cervical adenopathy and facial asymmetry due to metastatic, intraoral squamous cell cancer. Images Courtesy of Charlie Goldberg, M.D., UCSD School of Medicine and VA Medical Center, San Diego, CA.
• 
  Cervical adenopathy: massive right side cervical adenopathy and facial asymmetry due to metastatic, intraoral squamous cell cancer. Images Courtesy of Charlie Goldberg, M.D., UCSD School of Medicine and VA Medical Center, San Diego, CA.
• 
  Cervical adenopathy: large right anterior cervical lymph node. Images Courtesy of Charlie Goldberg, M.D., UCSD School of Medicine and VA Medical Center, San Diego, CA.
• 
  Cervical lymphadenopathy. Images Courtesy of Charlie Goldberg, M.D., UCSD School of Medicine and VA Medical Center, San Diego, CA.
• 
  Cervical Adenopathy: multiple right sided cervical lymph nodes. Images Courtesy of Charlie Goldberg, M.D., UCSD School of Medicine and VA Medical Center, San Diego, CA.

Laboratory Findings

• Laboratory findings consistent with the diagnosis of lymphadenopathy, may include:

Complete Blood Count

• Elevated lactate dehydrogenase (LDH)
• Mild neutropenia
• Leukocytosis
• Elevated markers of inflammation and acute phase reactants (e.g. ESR, C-reactive protein, ferritin)

Imaging Findings

Ultrasonography

• On ultrasound, characteristic findings of lymphadenopathy, include:

• Increased lymph node size.

CT

• On CT, characteristic findings of lymphadenopathy, include:

• Most nodes: 10 mm in short-axis
• Sub-mental and sub-mandibular: 15 mm
• Retropharyngeal: 8 mm
• Loss of fatty hilum
• Focal necrosis
• Cystic necrotic nodes
• Long-to-short axis ratio (>2cm - usually benign)

• The upper limit in size of a normal node varies with location.

Treatment

• There is no treatment for lymphadenopathy; the mainstay of therapy is treating the underlying condition.
• For instance, infectious lymphadenopathy responds well to prompt treatment with antibiotics, and usually leads to a complete recovery. However, it may take months, for swelling to disappear. The amount of time to recovery depends on the cause.

References

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