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Clinical approach to Lymphadenopathy

Article  in  Annals of Nigerian Medicine · January 2012

DOI: 10.4103/0331-3131.100201

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Review Article

Clinical approach to lymphadenopathy

Abdullah A. Abba, Mohamed Z. Khalil1
Department of Medicine, Division of Pulmonology, Ahmadu Bello University, Zaria, Nigeria, 1Department of Medicine, King Khalid University
Hospital & College of Medicine, King Saud University, Riyadh, Saudi Arabia

ABSTRACT Access this article online

Website:
Lymphadenopathy (LAP) is a common clinical finding that may be localized, limited or generalized. The www.anmjournal.com
enlargement of a lymph node, due to primary disease or secondary cause, is of concern to both patients and DOI:
clinicians, particularly, if the underlying pathology is a malignant disease. Lymph node aspiration or biopsy for 10.4103/0331-3131.100201
histopathological evaluation may not reveal the diagnosis due to several factors. However, a methodological Quick Response Code:
approach to LAP can disclose the accurate diagnosis with minimal discomfort to the patient and in a short time.
In this review article, we provide evidence-based clinical evaluation of LAP, guided by the probability of the
underlying disease to assist clinicians in establishing the proper cause and hence offer appropriate management.

Key words: Approach, diagnosis, enlarged lymph nodes, lymphadenopathy

Introduction 75 percent of patients presenting with LAP, whereas

25 percent of those patients had generalized LAP.[4,5] In our
study of 258 adults who presented with LAP as a presenting
L ymph nodes (LNs) are group of specialized cells
that represent a division of the defense system in
the human body. The body has approximately 600 LNs,
feature, localized LAP occurred in 54.7%, limited in 11.6%
and generalized in 33.7%.[6] Distinguishing between
the extensions of LAP is important in formulating a
and their locations are scattered around ports of entry as
differential diagnosis. Generalized LAP is almost always
well as major vessels.[1] The peripheral groups are those
due to a significant systemic illness.
readily palpable by clinical examination, and routinely
looked for, but only those in the submandibular, axillary
The cause of LAP is essentially due to either an immune
or inguinal regions may normally be palpable in healthy
response to infective agents, or inflammatory cells in
individuals. Studies have shown that as many as 56%
infections involving the LN. Moreover, it may be due
of patients examined for other reasons may be found
to infiltration of neoplastic cells carried to the node by
to have lymphadenopathy (LAP).[2]
lymphatic or blood circulation. Alternatively, primary
neoplastic proliferation of lymphocytes may be the
Lymphadenopathy can be defined as LNs that are
underlying pathology of LAP. Table 1 gives the list
abnormal in size, consistency or number. Fortunately,
of causes of LAP. It is not exhaustive but considering
the majority of patients presenting with peripheral
the causes as classified may be helpful in arriving
LAP have easily identifiable causes that are benign or
at a diagnosis in a timely manner. Furthermore, the
self-limiting.
epidemiological pattern in a particular locality may
Lymphadenopathy is considered to be localized if only also determine which causes to put uppermost in the
one group of LN is involved, limited if 2–3 groups of differential diagnosis.
LN are involved and generalized if more than three
The prevalence of malignancy, the most serious of the
noncontiguous groups are involved.[3] Localized LAP is
causes of LAP, is quite low among the general population
more common and it has been reported to affect nearly
with LAP being as low as 1.1 percent or even lower.[4,5,7]
This, however, is not true among patients seen in referral
Corresponding Author: Prof. Abdullah A. Abba,
centers where LN biopsies have revealed malignancy in
Department of Medicine, Ahmadu Bello University Teaching
Hospital, Shika, Zaria, Kaduna State, Nigeria. as many as 40–60% of cases.[8] Lyimphatic metastasis
E-mail: abbaiya@yahoo.com of tumor cells represents a series of extremely complex

Annals of Nigerian Medicine / Jan-Jun 2012 / Vol 6 | Issue 1 11

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Abba and Khalil: Clinical approach to lymphadenopathy

Table 1: Causes of lymphadenopathy certain drug intake such as phenytoin, carbamazepine,

Infections captopril, allopurinol, and atenolol.
Bacterial Streptococcal pharyngitis, skin infections,
cat scratch disease, tularemia*, diphtheria, Generalized LAP is more likely to occur in patients
Brucellosis*, Leptospirosis*, lymphogranuloma with malignancy. It is frequently seen in patients
venereum, typhoid fever*, hyme disease*,
charicroid, plague, syphilis with leukemias and lymphomas, or metastatic solid
Viral HIV*, E-B Virus*, Herpes Simplex, tumors. Lymphomas and most metastatic carcinomas
Cytomegalovirus*, mumps, measles*, characteristically progress through nodes in anatomic
rubella*, Hepatitis B*, Dengue fever*
Mycobacterial Mycobacterium tuberculosis, atypical
sequence. Patients who are immunocompromised
mycobacteria and those with human immunodeficiency virus (HIV)
Fungal Histoplasmosis, Coccidiomycosis, have a wide differential for generalized LAP, including
Cryptococcosis
Protozoal Toxoplasmosis*, Leishmaniasis*
early infection with HIV, activated TB, cryptococcosis,
Neoplastic Lymphoma* cytomegalovirus, toxoplasmosis, and Kaposi’s sarcoma,
Leukemia* which can present with LAP before visible skin lesions
Squamous cell cancer of head and neck
Metastasis
appear.
Lymphoproliferative Angioimmunoblastic lymphadenopathy*
Auto-immune lymphoproliferative disease Clinical Evaluation
Rosai-Dorfman’s Disease
Hemophagocytic Lymphohistiocytosis
Connective Tissue Systemic Lupus Erythematosus* Reaching an accurate diagnosis for a patient presenting
Diseases Rheumatoid Arthritis* with LAP may not be an easy task for clinicians with the
Still’s Disease*
Dermatomyositis* background of massive number of differential diagnosis.
Churg-Strauss Syndrome* A methodological approach guided by educated
Kawasaki Disease evidence-based evaluation is therefore necessary from
Immunologic Serum Sickness*
Drug Reactions*
the outset. Table 2 gives the salient points in the history
Endocrine Hypothyroidism and physical examination of patients presenting with
Addison’s Disease LAP that may aid in the process of reaching a correct
Miscellaneous Sarcoidosis
Lipid Storage Disease
diagnosis.
Amyloidosis*
Histiocytosis Most patients can be diagnosed on the basis of a careful
Chronic granulomatous disease history and physical examination. Thorough history and
Kikuchi’s Disease
Kimura’s Disease meticulous physical examination will identify a readily
Castleman’s Disease diagnosable cause of the LAP, such as upper respiratory
Inflammatory pseudotumor tract infection, pharyngitis, periodontal disease,
*Cause generalized lymphadenopathy, Although the rest of the conditions conjunctivitis, insect bites, recent immunization, cat-
often cause localized lymphadenopathy, they can also present with generalized
lymphadenopathy scratch disease or dermatitis. Where the cause and course
of LAP is obvious, no further assessment is necessary.
and sequential processes that include dissemination
Furthermore, getting a clear history of exposure to
and invasion into surrounding stromal tissues from certain risk factors may suggest the cause of LAP, such
primary tumors, penetration into lymphatic walls and as history of animal contact or raw milk ingestion may
implantation in regional LNs. Recent developments suggest brucellosis, or intravenous drug abuse and high
in lymphatic biology and research, especially the risk sexual practices may suggest HIV. Environmental
application of unique molecular markers specific for exposures such as tobacco, alcohol, and ultraviolet
lymphatic endothelial cells have provided exciting new radiation as well as occupational exposures to silicon or
insights into the tumor microenvironment.[7,9-11] beryllium may raise suspicion for metastatic carcinoma
of the internal organs, the head and neck, and skin.
Non-malignant causes of LAP are numerous and diverse, Family history may raise suspicion for certain neoplastic
ranging from infections such as tuberculosis (TB), causes of LAP, such as carcinomas of the breast or
brucellosis, mononucleosis syndromes, and cat-scratch familial dysplastic nevus syndrome and melanoma.
disease; extending to connective tissue disease such as Moreover, associated symptoms such as mouth ulcers,
systemic lupus erythematosus (SLE), and rheumatoid photosensitivity, arthralgias, early morning stiffness,
arthritis (RA); or it may be iatrogenic as a result of muscle weakness, or butterfly rash may indicate the

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Abba and Khalil: Clinical approach to lymphadenopathy
possibility of autoimmune diseases such as systemic
lupus erythematosus (SLE), or rheumatoid arthritis (RA).
History of painful LAP is commonly reassuring; as
it is indicative of underlying benign pathology such
as an inflammatory process or suppuration. Pain or
tenderness is explained by stretching of the LN capsule
as a result of rapid increase in size; nonetheless, pain
may also result from bleeding into a necrotic center
of a malignant node and therefore does not always
necessarily suggest a benign cause.
Lymphadenopathy that lasts less than two weeks or
more than one year with no progressive size increase has
a very low likelihood of being neoplastic. The precise
timing of the onset of LAP is however elusive as most
patients are unable to say with certainty as to when the
enlargement started. Normal nodes are generally less
than 1 cm in diameter. In one series, no patient with
a LN smaller than 1 cm had cancer, compared with 8
and 38 percent of those with nodes 1 to 2.25 cm and
greater than 2.25 cm, respectively.[12] Some authors have
however suggested that epitrochlear nodes of size 0.5 cm
or more and inguinal nodes of size 1.5 cm or more should
be considered abnormal.[13,14] It has been shown that
benign or self-limited causes were found in 79 percent of
patients younger than 30 years of age, versus 59 percent
in patients 31 to 50 years of age and 39 percent in those
older than 50 years. In primary care settings, patients
40 years of age and older with unexplained LAP have
about a4 percent risk of cancer versus a 0.4 percent risk
in patients younger than age 40.[7]
In our study of 258 adults who presented with LAP,
multivariate logistic regression model revealed that age
over 40 years, male gender, generalized LAP, presence of
Table 2: Salient points in the clinical assessment of a patient
with lymphadenopathy
A. History 1. Localizing Symptoms/Signs – local infection/
malignancy
2. Constitutional Symptoms – infectious; lymphoma
3. Exposure/Risk – high risk sexual behaviour (HIV);
cat (cat scratch disease)
4. Drug – e.g. Phenytoin, serum sickness
5. Travel – consider diseases other than local
6. Occupational – hunters (tularemia); fishermen
(erysipeloid)
B. Examination: 1. Location – Generalized – Systemic disease –
Localized
2. Size – cancer unlikely if ≤1 cm2
3. Consistency – Hard – cancer or fibrosis; rubbery –
lymphoma, chronic leukemia
4. Fixation – Abnormal nodes, cancer or inflammation
5. Tenderness – recent rapid enlargement, typically
inflammatory
Annals of Nigerian Medicine / Jan-Jun 2012 / Vol 6 | Issue 1 13
other physical signs, abnormal liver function tests and
negative Mantoux test to be statistically significantly
associated with nodal malignancy.[15]
Other studies have also demonstrated that an increased
likelihood of malignancy was associated with age over 40
years, male gender, white ethnicity, supraclavicular and
epitrochlear locations, fixed nodal character, duration
of greater than two weeks, and larger size.[8,13,16-22] The
clinical features highlighted in Table 3 are helpful in
determining the possibility of malignancy and hence
the speed, nature and extent of further investigations.
When LAP is localized, the clinician should examine
the region drained by the nodes for evidence of
infection, skin lesions or tumors. The anatomic
location of localized LAP may be helpful in suggesting
the diagnosis; cervical LAP may be secondary to
infectious mononucleosis, axillary LAP are seen in
patients with cat-scratch disease, whereas inguinal
LAP may point towards sexually transmitted diseases.
Supraclavicular LAP has the highest risk of malignancy,
estimated as90 percent in patients older than 40 years
and25 percent in those younger than age 40.[7] Having
the patient perform a Valsalva’s maneuver during
palpation of the supraclavicular fossae increases the
chance of detecting a node. Right supraclavicular LAP
is associated with cancer in the mediastinum, lungs or
esophagus while left supraclavicular (Virchow’s) node
may indicate pathology in the testes, ovaries, kidneys,
pancreas, prostate, stomach or gallbladder. Although
rarely present, a paraumbilical (Sister Joseph’s) node
may be a sign of an abdominal or pelvic neoplasm.[23]
Tables 1 and 2 detail the common causes of localized
LAP according to region involved and drugs known to
cause LAP, respectively.
Another clinical feature that is of diagnostic importance
is the consistency. Fluctuant nodes usually indicate
suppuration while rubbery, firm nodes suggest
lymphoma. Metastatic nodes are usually stony hard
Table 3: Clinical features to differentiate benign from malignant
lymphadenopathy
Feature Malignant Benign
Size >2 cm <2 cm (<1 cm)
Consistency Hard, firm or rubbery Soft
Duration >2 weeks <2 weeks
Mobility Fixed Mobile
Surroundings Attached (invasion) Not attached
Location Supraclavicular, epitrochlear, or Inguinal,
generalized submandibular
Tenderness Usually non-tender Usually tender
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Abba and Khalil: Clinical approach to lymphadenopathy
while softer nodes indicate inflammatory or infective
conditions. Small shotty nodes are felt in childhood viral
infections. LNs that are matted (feels connected to each
other without ability to palpate separate boundaries
to each node, and seems to move as a unit) are highly
suggestive of TB. This finding may however be seen in
other benign conditions (e.g. sarcoidosis) or malignancy
(e.g. metastasis or lymphoma).
In patients with generalized LAP, the emphasis is on
finding clues to a systemic illness in the history and
physical examination. The presence of joint symptoms
and rash or mouth ulcers may suggest connective
disease as a cause.
Splenomegaly or hepatosplenomegaly and LAP may
occur concomitantly, that may suggest mononucleosis
syndromes, adult onset Stills disease, chronic
lymphocytic leukemia, lymphoma and sarcoidosis.
Moreover, certain clues detected by clinical examination
may direct the next step such as the presence of
erythema nodosum may suggest the presence of
sarcoidosis consequently; a chest X ray may reveal
mediastinal LAP.
Fine-Needle Aspiration
Fine-needle aspiration (FNA) biopsy is a safe, simple and
cost-effective technique that provides rapid information
directing further approach to a patient presenting
with LAP. Its findings are especially beneficial for
verification of lymphoid origin of the enlarged growth
and in differentiating between metastatic, infectious,
reactive and lymphomatous causes of LAP. It also
helps in the determination of the extent of tumor;
detection of recurrence; monitoring of the course of
disease; obtaining of material for special studies such
as microbiological cultures, immunological or genetic
studies as well as electron microscopy. Furthermore,
FNA is a rapid way of allaying the fears of a patient in
the event of identifying a benign cause of the growth.
The diagnostic value of FNA cytology in the assessment
of palpable supraclavicular LNs as a first line of
investigation has been shown by one study, to be cost-
effective procedure and the overall sensitivity was
92.7%, specificity 98.5%, positive predictive value
97.3% and the negative predictive value was 94.8%.[24]
Another study of 627 FNA of LNs of which 218 were
available for cytohistological correlation, revealed that
there were three (1.88%) false-negative and two (1.25%)
false-positive cases. Accuracy tests revealed 97.41%
14 Annals of Nigerian Medicine / Jan-Jun 2012 / Vol 6 | Issue 1
sensitivity, 95.45% specificity, and 96.88% efficacy,
with cytohistological agreement being almost perfect
(kappa = 0.92). The high accuracy of this study based
only on cytomorphological criteria demonstrates its
relevance in patient care, especially in areas of limited
financial resources.[25] Similarly, in a study of 135 patients
who had FNA, O’Donnell et al. demonstrated that FNA
provided sufficient pathological diagnosis to avoid day
case surgery in 57 patients (42.2%), and inpatient surgery
in 65 patients (48.1%).[26] If the LN are not palpable,
endoscopic ultrasound-guided fine-needle aspiration
(EUS-FNA) has been shown to accurately diagnose
mediastinal LN pathology with diagnostic accuracy of
84%.[27] This method and the more recently introduced
endobronchial ultrasound-guided transbronchial needle
aspiration (EBUS-TBNA) have been shown to be highly
sensitive and specific in the diagnosis of mediastinal
and hilar lesions.[28-30] Fine-needle aspiration of a
representative node in either the abdominal or thoracic
cavity or peripherally by any of these techniques in
patients with TB, malignancy, or HIV infection may allow
prompt diagnosis of LAP as shown by many studies.[31-42]
Open thoracic surgery, laparotomy, and other invasive
diagnostic procedures such as mediastinoscopy and
laparoscopy can now be avoided.
Transesophageal and transbronchial, ultrasound-
guided, FNA of enlarged mediastinal LNs have become
popular and provide accurate results. One study
reported that in experienced hands, the transbronchial
or transesophageal approach are nonsurgical approaches
and have similar diagnostic yields, although the
transbronchial approach is superior for right-sided
LNs; however, both approaches provides results similar
to those of mediastinoscopy.[43] The use of contrast-
enhanced EUS has been shown to improve the specificity
in diagnosing benign LNs as compared to B-mode
EUS. It does not improve the correct identification of
malignant LNs and cannot replace EUS-guided FNA.[44]
FNA is simple, rapid and does not require a general
anesthetic. The procedure of FNA can be performed in the
outpatient department. Most patients who have a benign
diagnosis on FNA do not require further evaluation.
The limitations of FNA remain in the lack of proper tissue
sample to run special studies including cytogenetics,
flow cytometry, electron microscopy, and special stains.
Additionally, the potential risk of seeding a tract with
malignancy as a result of FNA procedure is always a
consideration.
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Abba and Khalil: Clinical approach to lymphadenopathy
Excisional Biopsy
Obtaining a proper representative tissue for pathological
diagnosis can be made by excisional surgical biopsy.
Ideally, the most accessible node is selected for biopsy.
The diagnostic yields are reported to be quite different
based on the site of nodal biopsy obtained, as it has been
shown that inguinal nodes offer the lowest yield, and
supraclavicular nodes have the highest.[45,46]
Although less commonly used because of the advent
of new immunohistochemical analytic techniques that
have increased the sensitivity and specificity of FNA,
excisional biopsy remains the diagnostic procedure of
choice in delivery of timely and appropriate medical
care to patients presenting with LAP. The preservation
of nodal architecture is critical to the proper diagnosis
of LAP, particularly when differentiating lymphoma
from benign reactive hyperplasia.[36,39-42] While FNA
may be the initial approach for most patients, certain
parameters may indicate malignancy and therefore a
more aggressive approach is needed. In a study of 60
patients, Matsumoto et al. identified advanced age, large
swollen LNs, high levels of serum soluble interleukin-2
receptor (sIL-2r) and high lactate dehydrogenase LDH)
to be indicative of malignancy and suggested early
LN biopsy in such cases.[47] Ultrasound or computed
tomography (CT)-guided percutaneous LNs biopsy often
do not supply sufficient tissue for the histopathologic
diagnosis of intra-abdominal LAP compared to surgical
removal of the LN. Laparoscopic LN biopsy (LLB) has
the advantage of obtaining the entire LN and avoiding
potential complications of a laparotomy. It was recently
shown that LLB is a safe and effective procedure.
Its diagnostic accuracy is superior to percutaneous
techniques, and can be proposed as the procedure of
choice to sample deep lymphatic tissues in patients
with intra-abdominal LAP at a very low morbidity.[48]
Lymph node biopsy is essential in making a definitive
diagnosis in certain conditions. In Kikuchi’s disease, for
example, where the overall accuracy of FNA diagnosis
of Kikuchi’s lymphadenitis was found to be only
56.25%,[49] an LN biopsy is necessary even in patients
with typical presentations such as young women with
cervical LAP, fever, neutropenia who are otherwise in
excellent condition. This is because this condition can
be easily confused with malignant lymphoma.
With the more widespread application of molecular
techniques, and the development of improved minimally
invasive procedures, percutaneous and endoscopic
techniques may come to dominate and the surgeon
Annals of Nigerian Medicine / Jan-Jun 2012 / Vol 6 | Issue 1 15
may have a diminishing role in the management of
LAP. There is however a need to know when and how
quickly an excisional biopsy is indicated. A recent study
has shown that there was no evidence for the use of
explicit protocols for referral or management and that
biopsy was often delayed.[50] The study suggested the
introduction of coordinated problem-based referral and
management pathways for the management of patients
with enlarged superficial LNs supported by regular
audits of practice.
Suggested Approach
Guidelines and suggested approaches in handling
different medical problems are based on pooled evidence
from the medical literature, aided by the expert opinions
of practicing physicians. However, it is important to
emphasize that patients are different; not only because
of variability in their response to diseases, but they are
different in the way of presenting and perceiving their
illness. Therefore, it is of paramount importance to rely
mainly on proper history and physical examination to
reach the appropriate clinical diagnosis.
The evidence provided to us in the medical literature
clearly indicates that there is a need to critically review
all evidence in the evaluation of patients presenting
with LAP. We need to exercise care in order not to miss
a potential treatable lesion while at the same time not
to subject patients to unnecessary discomfort. While
the duration of LAP is extremely helpful in guiding
clinicians to the aggressiveness of the underlying disease,
this aspect of history is subject to individual bias. We
suggest using an algorithm as depicted in Figure 1 in such
assessment after obtaining a reliable history.
For patients presenting with short duration of LAP
and low clinical risk to suggest malignancy or serious
illness, probably, the diagnosis can be made based on
analyzing the clinical data obtained from the patient.
Simple confirmatory investigations may be reassuring
to both patients and clinicians. On the other hand, if
the duration of LAP is long (>2 weeks), this indicates
persistent LAP but not necessary serious or malignant
disease. Consequently, obtaining clinical data to
differentiate between high or low clinical risk would
be an imperative next step in clinical evaluation. The
presence of alarming symptoms and signs of LAP
warrants further investigation to establish the diagnosis
and to initiate the proper treatment.
Among the investigations needed to reach the diagnosis
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Abba and Khalil: Clinical approach to lymphadenopathy

Figure 1: Clinically Oriented Approach to Lymphadenopathy. *Clinical risk: As judged by clinician based on age, history and physical examination

are imaging studies such as plain chest X ray, CT
scan of the chest and abdomen, magnetic resonance
imaging, radioisotope scan, ultrasound scan, and
echocardiography.
Obtaining a tissue from the diseased LN for diagnosis
is the gold standard of establishing the pathological
diagnosis. This can be done by either FNA or excisional
biopsy. The obtained tissue should be processed for
histological examination as well as microbiological,
histochemical, immunofluorescence and polymerase
chain reaction when appropriate.
Certainly, despite running all available tests, small
percentage of patients with LAP remains undiagnosed.
Probably, referral to more specialized centers for
reviewing the histopathology may be fruitful.
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Cite this article as: Abba AA, Khalil MZ. Clinical approach to Lymphadenopathy.
Ann Nigerian Med 2012;6:11-7.
Source of Support: Nil. Conflict of Interest: None declared.