Introduction¹

Generalised lymphadenopathy can be defined as enlargement of more than two noncontiguous lymph node groups.

Each lymph node consists of a fibrous capsule, enclosing a sinus stuffed with macrophages. The macrophages remove 99% of antigens delivered in this way. Deeper within the structure of the lymph node are B cells, T cells and small B lymphocytes which are involved in the production of immunoglobulins. Lymph nodes are thus ideal structures to deal with antigens entering lymph fluid via the skin, respiratory and gastrointestinal tract.

Lymph nodes have a considerable capacity to increase in size. Their size depends on the individual's age, their location and any immune activity in which they may be involved.

Most generalised lymphadenopathy is due to benign self-limited disease, such as viral or bacterial infection but it can be caused by a wide range of conditions (see 'Differential diagnosis', below).

Epidemiology

An annual incidence of 0.6-0.7% has been estimated for the general population.² Studies in the USA estimate the incidence of palpable adenopathy in childhood to be between 38-45%.¹ Lymphadenopathy is one of the most common clinical problems encountered in paediatrics.

In the UK, HIV ³ and tuberculosis (TB) remain conditions of continuing concern in patients presenting with generalised lymphadenopathy.⁴

Presentation⁵

History

All GPs will be familiar with the patient, who is often a child or adolescent, presenting with generalised lymph node enlargement. Most of these cases will be due to self-limiting infection but serious underlying causes must be quickly identified. A history should include the duration of the lymphadenopathy, whether any other household members are acutely ill and whether there are any accompanying symptoms. Persistent fever, night sweats, general malaise or weight loss may be pointers to significant disease. Bearing in mind the extensive list of differential diagnoses, it is important to keep the patient under review if spontaneous recovery does not occur. Presenting symptoms of more indolent diseases (e.g. TB, malignancy) may occur some time after the development of the initial lymphadenopathy.

In adolescents, a sexual history and history of intravenous drug use should be elicited.¹

Examination

Most children have palpable lymph nodes whose relative size could qualify for lymphadenopathy in an adult. These are most prominent in the anterior cervical, inguinal and axillary regions and continue to increase in size until the age of 8-12, after which atrophy occurs. For proper assessment of generalised lymphadenopathy it is necessary to familiarise oneself with what is normal at a particular age. Bilateral anterior cervical lymph nodes up to 2 cm in diameter often are found in older healthy children or in those experiencing or recently recovering from an upper respiratory tract infection. Axillary nodes up to 1 cm and inguinal nodes up to 1.5 cm in diameter are also usually normal. A 1.5 cm inguinal or a 2 cm anterior cervical node, for example, would be considered normal in a 7 year-old child but would warrant further investigation in a 2 month-old infant.¹

Supraclavicular nodes of any size at any age warrant further investigation as they can be associated with malignancy in the chest and abdomen. Epitrochlear nodes (just above the elbow crease) can signify Hodgkin's disease.

Erythema, warmth, tenderness and fluctuance of a node suggests lymphadenitis of infective origin. Nodes that are firm, non-tender and matted together increase the possibility of malignancy.¹ Measure the temperature to exclude pyrexia and check for any local sources of infection, including the scalp, skin, ears, nose, pharynx and chest. Perform a systematic examination to exclude signs of obvious malignancy and especially the abdomen to exclude hepatomegaly or splenomegaly.⁵

Differential diagnosis¹

Generalised lymphadenopathy may be caused by a wide range of conditions, as follows:
Viral:

• Common upper respiratory infections.
• Infectious mononucleosis, cytomegalovirus (CMV).
• Rubella, varicella, measles.
• HIV.
• Hepatitis A and hepatitis B.
• Roseola infantum - human herpesvirus type 6 (HHV-6).
• Dengue fever.
• Adenovirus.

• Septicaemia.
• Typhoid fever.
• Tuberculosis.
• Syphilis.
• Plague.
• Lyme disease.
• Tularaemia.
• Brucellosis.

• Toxoplasmosis, leishmaniasis, Chagas' disease.
• African trypanosomiasis (sleeping sickness).

• For example, coccidioidomycosis.

• Juvenile rheumatoid arthritis.
• Systemic lupus erythematosus (SLE).
• Drug reactions (e.g. phenytoin, allopurinol, primidone).
• Serum sickness.

• Gaucher's disease.
• Niemann-Pick disease.

• Acute leukaemias.
• Lymphomas (Hodgkin's, non-Hodgkin's).
• Neuroblastoma.
• Histiocytoses.

Investigations¹

In the vast majority of cases, once the history and physical examination are completed, the clinician will be able to determine that the condition is self-limiting and requires no further investigation. However, in the event of a worrying history or suspicious findings, the following investigations may be indicated:

Laboratory investigations

• FBC and white cell differential. An erythrocyte sedimentation rate is nonspecific but may be of help.
• Liver and renal function tests.
• Urine analysis.

If systemic infection is suspected, titres for CMV, Epstein-Barr virus, toxoplasmosis, Bartonella henselae (cat scratch disease) and HIV and skin testing for TB may be indicated, depending on prevalence.

If malignancy is suspected, uric acid,⁶ calcium and phosphate may be indicated.

Imaging¹

• CXR may detect mediastinal adenopathy or pulmonary disease such as TB, lymphomas, coccidioidomycosis, neuroblastoma, histiocytoses and Gaucher's disease.
• CT scan of the chest and abdomen may be indicated, particularly if supraclavicular adenopathy is present.
• Ultrasonography may be helpful in evaluating the extent of lymph node involvement in patients with lymphadenopathy and may be more sensitive than CT scanning in some instances.^1,7
• Newer imaging modalities such as ¹⁸F-fluorodeoxyglucose positron emission tomography (¹⁸F-FDG PET) and magnetic resonance lymphography are increasingly being used in the diagnosis and monitoring of lymphomas and other conditions involving generalised lymphadenopathies.⁸

Other tests

The decision to proceed to more invasive tests should not be taken lightly, particularly where a child is involved and should only be considered at first presentation if supraclavicular nodes are present, the nodes are large and generalised, or the history or examination are strongly suggestive of malignancy. Indications for further investigation include systemic symptoms despite normal laboratory findings and imaging, documented increase in lymph node size and failure to respond to treatment for presumed infection.¹ Such investigations might include:

• Fine needle aspiration (FNA) - this can be performed in the outpatient department, has low morbidity, is cost-effective, produces minimal scarring and does not require a general anaesthetic.However, it has its limitations and most pathologists prefer lymph node excision if further tests such as chromosomal analysis are required.⁸
• Core needle biopsy - this uses a wider needle and can obtain more tissue. Guidance with ultrasound or CT is sometimes used as a refinement.⁹
• Excision biopsy - this has the advantage over needle biopsy in that sufficient tissue is obtained for oncology studies where malignancy is suspected.⁸ Inadequate specimen size, improper handling or preparation and a poor choice of node sampling can affect results. Inguinal nodes should not be sampled in this way because their architecture frequently is distorted by chronic inflammatory changes.¹

Management¹

The most important aspect of management is the recognition and exclusion of serious disease, which can often mimic trivial self-limiting conditions in the early stages. Patients and parents should be advised to seek further advice if lymph node enlargement does not resolve, new enlargements develop, old symptoms persist or new ones appear.

Treatment depends on the causative agent and may include the following:

• Expectant management - e.g. viral infections, most cases of cat-scratch disease.
• Antimicrobial therapy - in the case of bacterial infection, the most likely culprits include Staphylococcus spp. and Streptococcus spp.; therefore, a beta-lactamase resistant antibiotic is chosen.⁸ In patients with TB, follow local guidelines.
• Chemotherapy.
• Radiotherapy.
• Surgical care - apart from the diagnostic procedures outlined above, lymphadenitis may require aspiration or incision and drainage of large suppurative nodes to relieve discomfort, as well as obtaining aspirate for culture.
• Depending on the suspected underlying condition, referral to a paediatric infectious disease specialist, a surgeon, a haematologist or an oncologist may be required.

Complications¹

Complications depend to a large extent on the underlying aetiology. Two complications which may develop independently of the individual pathology are:

• Superior vena cava syndrome - insidious compression of the superior vena cava from mediastinal lymphadenopathy, presenting with cough, wheezing and respiratory tract obstruction.¹⁰
• Abdominal lymphadenopathy presenting with abdominal or back pain, urinary frequency and constipation. Intussusception can lead to intestinal obstruction and can be life-threatening.

Prognosis¹

This depends almost entirely on the underlying aetiology. Malignancies such as lymphoma, leukaemia and neuroblastoma carry a poor prognosis. Nonmalignant conditions with significant mortality and morbidity include HIV, juvenile rheumatoid arthritis and SLE. The onset of complications such as abdominal lymphadenopathy or superior vena cava syndrome can alter the prognosis independent of the primary disease process.

Document references

1. Kanwar VS et al; Lymphadenopathy, Medscape, Mar 2010
2. Chau I, Kelleher MT, Cunningham D, et al; Rapid access multidisciplinary lymph node diagnostic clinic: analysis of 550 Br J Cancer. 2003 Feb 10;88(3):354-61. [abstract]
3. HIV and STIs, Health Protection Agency
4. Gilbert RL, Antoine D, French CE, et al; The impact of immigration on tuberculosis rates in the United Kingdom compared Int J Tuberc Lung Dis. 2009 May;13(5):645-51. [abstract]
5. Shaikh U et al; Lymphadenitis, Medscape, Apr 2010
6. Abu-Alfa AK, Younes A; Tumor lysis syndrome and acute kidney injury: evaluation, prevention, and Am J Kidney Dis. 2010 May;55(5 Suppl 3):S1-13; quiz S14-9. [abstract]
7. van Overhagen H, Brakel K, Heijenbrok MW, et al; Metastases in supraclavicular lymph nodes in lung cancer: assessment with palpation, US, and CT.; Radiology. 2004 Jul;232(1):75-80. Epub 2004 May 27. [abstract]
8. Gow K; Lymph Node Disorders, Medscape, Mar 2010
9. Yuan J, Li XH; Evaluation of pathological diagnosis using ultrasonography-guided lymph node Chin Med J (Engl). 2010 Mar 20;123(6):690-4. [abstract]
10. Holme H, Nanduri V; Superior vena cava obstruction: Dangers of a missed diagnosis. J Paediatr Child Health. 2011 Mar;47(3):150-1. doi: [abstract]

Internet and further reading

• Richner S, Laifer G; Peripheral lymphadenopathy in immunocompetent adults. Swiss Med Wkly. 2010 Feb 20;140(7-8):98-104. [abstract]
• Moor JW, Murray P, Inwood J, et al; Diagnostic biopsy of lymph nodes of the neck, axilla and groin: rhyme, reason or Ann R Coll Surg Engl. 2008 Apr;90(3):221-5. [abstract]

Acknowledgements