The lymphatic system consists of a network of lymph nodes (LN) and interconnecting lymphatic vessels. It is a slow-flow, low-pressure system serving to return filtered interstitial fluid back to the blood. They collect and process antigens from the interstitial fluid and are the sites of primary immune response.

The body has approximately 600 lymph nodes and they are located around ports of entry and along blood vessels. The peripheral lymph nodal groups are easily palpable on clinical examination, and are routinely looked for, but those in the submandibular, axillary or inguinal regions may be normally palpable in healthy individuals.

Lymphadenopathy (LAP) refers to one or more nodes that are abnormal in consistency, number or size.

The cause of LAP is usually due to an immune response to infective agents, inflammatory cells in immune disease involving the lymph node or a primary or secondary neoplastic process, causing infiltration in the node.

Since there are lots of potential causes for LAP, it is challenging as well as important to differentiate the benign processes from the malignant ones. This article summarises the broad clinical approach to an adult presenting with LAP in primary care.

In a population-based Dutch study, about 10% of patients with unexplained LAP presenting to primary care required referral to a specialist but only 1% had a malignancy. There have been many retrospective studies suggesting different percentages of risk of malignancies in patients presenting with unexplained LAP but the simple conclusion is that it increases with age, especially above 40 years.

In primary care settings, patients 40 years of age and older with unexplained LAP have about a 4% risk of cancer versus a 0.4% risk in patients younger than age 40.

CLINICAL FACTORS TO CONSIDER FOR A PATIENT WITH LAP

1. HISTORY CONSIDERATIONS FOR LAP

The onset, duration and progression of the LAP – Nodes that last less than 4 weeks or those that have been persistent without any size increase for a year or more are unlikely to be neoplastic. This rule should not be considered absolute and patients who have other risk factors must be considered for further testing if in doubt.

Presence or absence of systemic symptoms – When present, systemic symptoms including pruritus, autoimmune-type symptoms like rash/arthritis, etc, significant weight loss (5% over 3 months or 10% over 6 months), fever (in the absence of infection) or drenching night sweats usually indicate an underlying systemic cause for LAP.

The last 3 of the above are classed together as ’B‘ symptoms in the staging system of lymphomas. Although usually associated with lymphoproliferative disorders, together or separately, they may be present in many other diseases, one of which is tuberculosis.

Suffice to say, the presence of any of these or other systemic symptoms in most situations might indicate the need for an expeditious referral to a specialist centre for further evaluation – especially a lymph node biopsy.

Generalised vs localised LAP – Generalised LAP is defined as LAP in 2 or more non-contiguous lymph node regions and it usually indicates a systemic cause that will need evaluation. In contrast, for localised LAP the cause is likely to be in the draining area of the enlarged nodes – for example, dental/ scalp/ENT lesions could explain the cause of cervical LAP and a careful examination of these areas is warranted in patients presenting with cervical LAP.

Recent exposure to certain drugs and the onset of LAP that temporally correlates with the start of such drugs (phenytoin, methyldopa, hydralazine, allopurinol, etc) might indicate them to be the cause, especially when associated with eosinophilia/ skin rash.

History of sexual exposure or intravenous drug use (IVD) might serve as a clue to retroviral disease. Past history of TB, lymphoma, etc should be taken into consideration as the LAP could signify a recurrence.

2. EXAMINATION FINDINGS

Site: As mentioned above, certain nodes can be felt ’normally‘ in a patient. In a thinly-built person, even a normal size lymph node could become palpable. Epitrochlear, supraclavicular or popliteal LAP should always be considered pathological and suspected for malignancy.

 There is no one uniform size above which a node is considered abnormal. By consensus most nodes in any site ≤1 cm are likely to be ’normal‘ and those ≥2 cm are likely to be pathological and need to be evaluated further.

An exception might be inguinal nodes which are commonly ’enlarged‘ >1 cm and may be insignificant – it has to be interpreted in the clinical context. Size of nodes also depends on age (smaller sizes that might be significant for kids) and the size and build of the patient. Size does not give any clues as to the aetiology of the LAP.

Consistency: The following can serve as a rough guide to differentiate between a benign vs malignant process.

• Soft -> Inflammation/Infective
• Firm/Rubbery -> Lymphomatous process
• Hard/Fixed -> Carcinomatous/Metastasis
• Fluctuant -> Suppurative
• Matting -> Infection/Malignant
• Pain -> Due to stretching of capsule/inflammation, but can also be due to rapid growth/haemorrhage or necrosis within the enlarging node, hence this feature is not very useful to differentiate benign from malignant.

Shape: Several studies have reported that one of the most important and sensitive (but less specific) predictive factors for malignant lymph node is the Long/Short axis ratio (L/S) where if that ratio is less than 2.0, malignancy is highly likely. That is, if the width of the lymph node approaches its length, malignancy should be suspected – however note that submandibular and parotid lymph nodes can normally be round in shape.

Though an ultrasound is a more objective technique for calculating this ratio, an initial clinical impression of the ratio might be gleaned and used for decisions on further evaluation in the light of the whole clinical picture. Since the sensitivity is high, L/S ratio less than 2 should be considered suspicious while a normal L/S ratio should not be taken for granted.

Generalised LAP: Most common causes of this picture is infectious mononucleosis syndromes, HIV infection, autoimmune diseases including Kikuchi’s disease, acute and chronic lymphoproliferative disorders like lymphomas and some leukaemias.

3. ASSOCIATED FINDINGS

See Tables 1 & 2

Splenomegaly: Splenomegaly in the presence of LAP is a rare occurrence in primary care (4.5% of the cases according to one study). The most likely causes for the splenomegaly and LAP appearing together are infectious mononucleosis, Hodgkin and non-Hodgkin lymphomas, chronic lymphocytic leukaemia and some acute leukaemias. The presence of splenomegaly is relatively rare in metastatic solid cancers.

Skin lesions: Autoimmune disorders, some lymphomas, cutaneous cancers with secondary lymph nodes, and drug-induced LAP are potential possibilities.

4. INVESTIGATIONS

Full blood count: A full blood count (FBC) with examination of a peripheral blood film (PBF) is a useful and simple tool in patients with LAP. Abnormalities in the FBC including anaemia, and raised white cell count with either neutrophilia or lymphocytosis can point towards infection or immune causes.

In particular if lymphocytosis is present, it might point towards an underlying low-grade lymphoproliferative disorder like chronic lymphocytosis leukaemia/marginal zone lymphoma.

It is important to note this finding, as a referral to a Haematologist can help to confirm this diagnosis by performing a flow cytometry on the peripheral blood rather than subjecting a patient to an unnecessary biopsy.

Chest X-ray: Another simple investigation that can be performed in primary care is a chest X-ray (CxR) which will help to pick up mediastinal widening caused by LAP.

Serology: In the presence of corroborative history, a HIV serology or an autoimmune work-up like ANA, etc might also be considered while the appropriate specialist referral is being initiated. If there are features suggestive of a mononucleosis syndrome (fever, sore throat, fatigue, swollen tonsils, LAP, headaches), a serology for common viruses like CMV or EBV (IgM anti-CMV or EBV antibody) could be performed and increasing titres documented on paired samples over 2 to 4 weeks could be suggestive of such infections.

APPROACH TO LAP IN PRIMARY CARE

Below is a suggested pathway for managing patients with LAP, but Haemato-oncologists at the SingHealth Duke- NUS Blood Cancer Centre (SDBCC) would be happy to discuss referrals and provide guidance if you are in doubt.

GPs can call for appointments through the GP Appointment Hotlines at 6321 4402 (SGH) or 6436 8288 (NCCS).

By: Dr Chandramouli Nagarajan, Consultant, Department of Haematology, Singapore General Hospital; SingHealth Duke-NUS Blood Cancer Centre

Dr Chandramouli Nagarajan is a Consultant at the Department of Haematology, Singapore General Hospital (SGH) and the SingHealth Duke-NUS Blood Cancer Centre (SDBCC). He is a Clinical Lecturer at the NUS Yong Loo Lin School of Medicine and an Adjunct Assistant Professor at the Duke-NUS Medical School. He served as a Consultant Haematologist in the Northwest of England for 2½ years before joining SGH in 2014.

His main area of interest is malignant haematology, especially lymphomas, myeloma, as well as immune and laboratory haematology. His other area of interest is clinical/medical education and he has been involved in teaching undergraduate and postgraduate students throughout his career. He has contributed as a member of several committees, was the clinical lead for blood transfusion services and has been involved in research, serving as Principal Investigator in clinical trials, during his tenure in the United Kingdom.