Lymphadenopathy

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Lymphadenopathy


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Differentiating Lymphadenopathy from other Diseases

Epidemiology and Demographics

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Natural History, Complications and Prognosis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1],Shyam Patel [2];Associate Editor(s)-in-Chief: Amandeep Singh M.D.[3], Raviteja Guddeti, M.B.B.S. [4] Ogechukwu Hannah Nnabude, MD


Synonyms and keywords: Lymph nodes enlarged; Enlarged lymph nodes; Lymphadenitis; Swollen lymph nodes; Swollen/enlarged lymph nodes
For patient information, click here

Overview

Lymphadenopathy, also called adenopathy, refers to any disease process that involves lymph nodes that are abnormal in consistency and size. This condition has multiple causes, the most common of which include neoplasia, autoimmune diseases, and infection. Lymphadenitis refers to lymphadenopathies that are due to inflammatory processes. It is characterized by nodal swelling, pain, skin changes, fever, edema, and/or purulent collections. [1]

Classification

Lymphadenopathy may be classified as follows:

  • By size, where lymphadenopathy in adults is often defined as a short axis of one or more lymph nodes is greater than 10mm.[2][3] However, there is regional variation as detailed in this table:
Upper limit of lymph node sizes in adults
Generally 10 mm[2][3]
Inguinal 10[4] – 20 mm[5]
Pelvis 10 mm for ovoid lymph nodes, 8 mm for rounded[4]
Neck
Generally (non-retropharyngeal) 10 mm[4][6]
Jugulodigastric lymph nodes 11mm[4] or 15 mm[6]
Retropharyngeal 8 mm[6]
Mediastinum
Mediastinum, generally 10 mm[4]
Superior mediastinum and high paratracheal 7mm[7]
Low paratracheal and subcarinal 11 mm[7]
Upper abdominal
Retrocrural space 6 mm[8]
Paracardiac 8 mm[8]
Gastrohepatic ligament 8 mm[8]
Upper paraaortic region 9 mm[8]
Portacaval space 10 mm[8]
Porta hepatis 7 mm[8]
Lower paraaortic region 11 mm[8]

Pathophysiology

Lymph nodes are a part of the reticuloendothelial (RES) system, which includes lymphatic vessels, the lymphatic fluid found in interstitial fluid, monocytes of the blood, macrophages of the connective tissue, bone marrow, thymus, spleen, bone, and mucosa-associated lymphoid tissue (MALT) of visceral organs [9]

Lymphatic fluid moves throughout the lymphatic system and enters lymph nodes for filtration of foreign antigen. Foreign antigens are presented to the lymphoid cells, which lead to cellular proliferation and enlargement. Under microscopy, cellular proliferation in lymphoid follicles may be identified as several mitotic figures.[10] Increased activity leads to stretching of the lymphatic capsule and this may cause localized tenderness.

The development of B-cells originates from pluripotent stem cells from the bone marrow. B cells that successfully build their immunoglobulin heavy chains migrate to the germinal centers to allow for antibody diversification by somatic hypermutation.[11] The current school of thought is that B-cell lymphomas occur as a result of alternations in chromosomal translocations and somatic hypermutation.

T-cell development also begins from pluripotent stem cells, which mature within the thymic cortex. [12] While they are in the thymic cortex, specific rearrangements occur at the T-cell receptor. It is understood that chromosomal translocations at the level of T-cell receptors lead to T-cell lymphomagenesis.

Lymph nodes follicle necrosis may occur due to inflammatory, infectious, or malignant conditions. The neutrophil-rich infiltrates suggests bacterial infection, while lymphocyte-rich predominance may suggest viral infection. However, clinicians must remember that etiologies may vary; lymphomas, leukemias, tuberculosis, or even systemic lupus erythematosus (SLE) may be more appropriate diagnoses in the appropriate clinical context [13]

Histopathology

Histology can provide more information regarding the cause of lymphadenopathy when etiology is not clear during initial history taking, physical examination, and laboratory evaluation.

Common causes of lymphadenopathy with their associated histological findings include:

Causes

Lymph node enlargement can be of viral, bacterial, malignant, protozoan origin and can even be caused by live vaccines [18] Examples of infections that can cause lymph node enlargement include:

  • Viral infections such as Epstein-Barr Virus and cytomegalovirus which cause infectious mononucleosis, [19] and CMV mononucleosis respectively.[20]

as well HHV8 [21] and HIV.[22]

  • Yersinia pestis, which causes the bubonic plague, causes lymph node swelling so large that it can be seen under the skin. These lymph nodes are called buboes and may become necrotic. [23]
  • Other bacterial infections such as cat-scratch disease, [24] cutaneous anthrax, [25] and tuberculous lymphadenitis [26]
  • Protozoal infections including African sleeping sickness, [27] Chagas' Disease, [28] and toxoplasmosis. [29]

Examples of malignancies that cause lymphadenopathy are:

  • Primary: Hodgkin lymphoma [30] and non-Hodgkin lymphoma give lymphadenopathy in all or a few lymph nodes.[31]
  • Secondary: metastasis, Virchow's Node, neuroblastoma, [32] and chronic lymphocytic leukemia.[33]

Autoimmune causes include: systemic lupus erythematosus [34] and rheumatoid arthritis may have a generalized lymphadenopathy.[31]

Benign lymphadenopathy

Examples include:

  • Reactive Follicular hyperplasia [35]
  • Atypical Follicular Hyperplasia [35]
  • IgG4-related sclerosing disease-associated lymphadenopathy [35]
  • Paracortical hyperplasia/Interfollicular hyperplasia: It is seen in viral infections, skin diseases, and nonspecific reactions. [35]
  • Sinus histiocytosis: It is seen in lymph nodes draining limbs, inflammatory lesions, and malignancies. [35]
  • Benign lymphadenopathy with extensive necrosis [35]


Axillary lymphadenopathy can be defined as solid nodes measuring more than 15 mm without fatty hilum.[36] Axillary lymph nodes may be normal up to 30 mm if consisting largely of fat.[36]

In children, a short axis of 8 mm can be used.[37] However, inguinal lymph nodes of up to 15 mm and cervical lymph nodes of up to 20 mm are generally normal in children up to age 8–12.[38]

Lymphadenopathy of more than 1.5 cm - 2 cm increases the risk of cancer or granulomatous disease as the cause rather than only inflammation or infection. Still, an increasing size and persistence over time are more indicative of cancer.[39]


Differentiating Lymphadenopathy from other Diseases

After a thorough history and physical examination, lymphadenopathy can be initially categorized as:

Diagnostic: where in the practitioner has a proximal cause for the lymph nodes and can go on to treat them. Examples would be strep pharyngitis or localized cellulitis. The lymphadenopathy pattern history and physical examination can be suggestive an example would be mononucleosis wearing the practitioner has strong clinic index of suspicion can perform a confirmatory test which if positive he can go on and treat the patient.

Unexplained lymphadenopathy. Unexplained lymphadenopathy can be generalized into localized or generalized lymphadenopathy. Unexplained localized lymphadenopathy is further divided into patterns at no risk for malignancy or serious illness in which case the patient can be observed for 3 to 4 weeks and if response or improvement can be followed. The other alternative is if the patient is found to have a risk for malignancy or serious illness biopsy is indicated

Unexplained generalized lymphadenopathy can be approached after review of epidemiological clues and medications with initial testing with a CBC with manual differential and mononucleosis serology if either is positive and diagnostic proceed to treatment. If both are negative, the second workup approach would be a PPD, and RPR, a chest x-ray, and ANA, hepatitis BS antigen serology, and HIV. Additional testing modalities and lab tests may be indicated depending on clinical cues. If the results of this testing are conclusive, the practitioner can proceed on to diagnosis and treatment at the illness. If the results of the testing are still not clear, proceed onto biopsy of the most abnormal if the nodes.The most functional way to investigate the differential diagnosis of lymphadenopathy is to characterize it by node pattern and location, obtained pertinent history including careful evaluation of epidemiology, and place the patient in the appropriate arm of the algorithm to evaluate lymphadenopathy.

Generalized Lymphadenopathy

Common Infective Causation

  • Mononucleosis
  • HIV
  • Tuberculosis
  • Typhoid fever
  • Syphilis
  • Plague

Malignancies

  • Acute leukemia
  • Hodgkin's lymphoma
  • Non-Hodgkin's lymphoma

Metabolic Storage Disorders

  • Gaucher disease
  • Niemann-Pick disease

Medication Reactions

  • Allopurinol
  • Atenolol
  • Captopril
  • Carbamazepine
  • Cephalosporin(s)
  • Gold
  • Hydralazine
  • Penicillin
  • Phenytoin
  • Primidone
  • Pyrimethamine
  • Quinidine
  • Sulfonamides
  • Sulidac

Autoimmune Disease

  • Sjogren syndrome
  • Sarcoidosis
  • Rheumatoid arthritis
  • Systemic lupus erythematosus

Localized Peripheral Lymphadenopathy

Head and Neck Lymph Nodes

Viral infection

  • Viral URI
  • Mononucleosis
  • Herpes virus
  • Coxsackievirus
  • Cytomegalovirus
  • HIV

Bacterial infection

  • Staphylococcal aureus
  • Group A Streptococcus pyogenes
  • Mycobacterium
  • Dental abscess
  • Cat scratch disease

Malignancy

  • Hodgkin disease
  • Non-Hodgkin lymphoma
  • Thyroid cancer
  • Squamous cell carcinomas of the head and neck

Inguinal Peripheral Lymphadenopathy

Infection

  • STDs
  • Cellulitis

Malignancy

  • Lymphoma
  • Squamous cell carcinoma of genitalia
  • Malignant melanoma

Axillary Lymphadenopathy

Infection

  • Localized Staphylococcal aureus
  • Cat-scratch disease
  • Brucellosis

Malignancy

  • Lymphoma
  • Breast cancer
  • Melanoma
  • Reaction to breast implants

Supraclavicular Adenopathy

  • Infections
  • Mycobacteria
  • Fungi
  • Malignancy

Thoracic and abdominal neoplasms

  • Hodgkin disease
  • Non-Hodgkin lymphoma

Epidemiology and Demographics

Generalities can safely be made about the epidemiology of lymphadenopathy. [40] [41] [42]

First, both generalized and localized lymphadenopathies are fairly equally distributed without regard to gender.

Second, lymphadenopathy is more prevalent in the pediatric population than in the adult population secondary to the greater number of viral infections. It would follow that the majority of the time, lymphadenopathy in the pediatric population is of less consequence again secondary to the prevalence of viral and bacterial infections in that age group. Three-quarters of all lymphadenopathy observed are localized, and of those three-quarters, half of these are localized to the head and neck area. All remaining localized lymphadenopathy is found in the inguinal area, and the remaining lymphadenopathy is found in the axilla in the supraclavicular area. Of note, the differential diagnosis of lymphadenopathy changes significantly with the age of the patient.

Third, the patient's location and circumstance are very revealing and lymphadenopathy. For example, in the developing world (sub-Saharan Africa, Southeast Asia, Indian subcontinent), exposure to parasites, HIV, and miliary TB are far more likely to be causes of generalized lymphadenopathy then in the United States and Europe. Whereas, Epstein-Barr virus, streptococcal pharyngitis, and some neoplastic processes are more likely candidates to cause lymphadenopathy in the United States and the remainder of the localized industrial world. An exposure history is very important for diagnosis.

Exposure to blood and blood-borne products either through transfusion, unsafe sexual practices, intravenous drug abuse, or vocation Exposure to infectious disease whether it be travel, in the workplace, or the home Medication exposure-prescription, nonprescription, or supplements Exposure to animal-borne illness either via pets or the workplace Exposure to arthropod bites

Natural History, Complications and Prognosis

The prognosis of lymphadenopathy depends on its etiology. While many are treatable are have a good prognosis, malignancies, HIV, active tuberculosis, have less favorable prognoses. Localized lymphadenopathies often have a better prognosis than the majority of generalized lymphadenopathies secondary to etiologies. Also, earlier detection is a crucial determinant of prognosis

Diagnosis

Laboratory Evaluation of Lymphadenopathy

  • CBC with manual differential: This is a foundational test in the diagnosis of both generalized and regional lymphadenopathy. The number and differential of the white blood cells can indicate bacterial, viral, or fungal pathology. In addition, characteristic white blood cell (WBC) patterns are observed with several of the hematological neoplasms producing lymphadenopathy
  • EBV serology: Epstein-Barr viral mono is present causing regionalized lymphadenopathy
  • Sedimentation rate: A measure of inflammation though not diagnostic, it can contribute to diagnostic reasoning
  • Cytomegalovirus titers: This viral serology is indicative of possible of CMV mononucleosis
  • HIV serology: This serology can be used to diagnose acute HIV syndrome-related lymphadenopathy or to infer the diagnosis of secondary HIV-elated pathologies causing lymphadenopathy.
  • Bartonella henselae serology: used for the diagnosis of cat-scratch lymphadenopathy
  • FTA\RPR: These tests can diagnose syphilis as the cause of lymphadenopathy
  • Herpes simplex serology: can determine if the lymphadenopathy is herpes-related. Herpes simplex can produce symptoms that are similar to mononucleosis.
  • Toxoplasmosis serology: can be used to diagnose toxoplasmosis
  • Hepatitis B serology: Serological tests for hepatitis B to establish it as a contributing factor for lymphadenopathy
  • ANA: this is a screening test for SLE that can help establish it as a cause for generalized lymphadenopathy

Diagnostic Radiological Testing

  • Chest x-ray: can reveal tuberculosis, pulmonary sarcoidosis, and pulmonary neoplasm.
  • Chest CT scan: This modality of radiological imaging can define the above processes and reveal hilar adenopathy.
  • Abdominal and pelvic CT scan: These images, in combination with chest CT scan, can be revealed in cases of supraclavicular adenopathy and the diagnosis of secondary neoplasm.
  • Ultrasonography: can be used in the assessment of number, size, size, shape, the marginal definition, and internal structures in patients with lymphadenopathy. Color Doppler ultrasonography is of use in distinguishing the vascular pattern between more established, pre-existing lymphadenopathy and acute lymphadenopathy. Studies have indicated that a low long axis to short axis ratio of lymphadenopathy as measured by ultrasound can be a significant indicator of lymphoma and metastatic cancer as a cause of lymphadenopathy.
  • MRI scanning: useful in the evaluation of thoracic, abdominal, and pelvic masses.
  • PPD: can be used in the diagnosis of tuberculosis
  • Tissue diagnosis of the node: this is done by incisional biopsy and remains the gold standard for diagnosis of lymphadenopathy.

Treatment

Treatment of lymphadenopathy is based on the etiology. Generally, treatment of lymphadenopathy is as follows:

  • Infectious causes of lymphadenopathy can be treated with antibiotic therapy, antiviral therapy, or antifungal therapy.
  • Immune therapy, systemic glucocorticoids can be used for autoimmune causes of lymphadenopathy
  • For malignancies, any combination of surgery, chemotherapy, and radiation therapy can be used.
  • If medication is the suspected cause, discontinue the medication if possible.[43]

References

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