IJMS

Vol 39, No 2, Supplement March 2014 Review Article

Peripheral Lymphadenopathy: Approach and

Diagnostic Tools

Shahrzad Mohseni1, MD; Abolfazl Abstract

Shojaiefard2, MD; Zhamak Khorgami2,
MD; Shahriar Alinejad1, MD; Ali
Peripheral lymph nodes, located deep in the subcutaneous tissue,
Ghorbani2, MD; Ali Ghafouri2, MD clean antigens from the extracellular fluid. Generally, a normal
sized lymph node is less than one cm in diameter. Peripheral
lymphadenopathy (LAP) is frequently due to a local or systemic,
benign, self-limited, infectious disease. However, it could be a
manifestation of underlying malignancy. Seventy-five percent
of all LAPs are localized, with more than 50% being seen in
the head and neck area. LAP may be localized or generalized.
Cervical lymph nodes are involved more often than the other
lymphatic regions. Generally, it is due to infections, but most
This article has Continuous of the supraclavicular lymphadenopathies are associated with
Medical Education (CME) malignancy. Based on different geographical areas, the etiology
credit for Iranian physicians is various. For example, in tropical areas, tuberculosis (TB) is
and paramedics. They may a main benign cause of LAP in adults and children. Complete
earn CME credit by reading history taking and physical examination are mandatory for
this article and answering the diagnosis; however, laboratory tests, imaging diagnostic methods,
questions on page 234. and tissue samplings are the next steps. Tissue diagnosis by fine
needle aspiration biopsy or excisional biopsy is the gold standard
evaluation for LAP.
We concluded that in patients with peripheral LAP, the patients
age and environmental exposures along with a careful history
taking and physical examination can help the physician to request
step by step further work-up when required, including laboratory
tests, imaging modalities, and tissue diagnosis, to reach an
appropriate diagnosis.

Please cite this article as: Mohseni Sh, Shojaiefard A, Khorgami Z, Alinejad Sh,
Ghorbani A, Ghafouri A. Peripheral Lymphadenopathy: Approach and Diagnostic
Tools. Iran J Med Sci. 2014;39(2):158-170.

Keywords Lymphadenopathy Localization Benign Malignant

Diagnosis
1
Department of Surgery, Shariati
Hospital, Tehran University of Medical
Sciences, Tehran, Iran;
2
Research Center for Improvement of
Surgical Outcomes and Procedures, Introduction
Department of Surgery, Shariati Hospital,
Tehran University of Medical Sciences, The human body has about 600 lymph nodes.1 Spleen, tonsils,
Tehran, Iran
adenoids, and Peyer's patches are parts of the lymphoid tissue, and
Correspondence: their role is to clean antigens from the extracellular fluid. Peripheral
Abolfazl Shojaiefard, MD; lymph nodes are those which are located deep in the subcutaneous
Department of General Surgery, tissue and can be palpated if any process causes them to enlarge.
Shariati Hospital,
North Kargar Street, Tehran, Iran.
Lymphadenopathy (LAP) is the term to describe the conditions in which
Tel: +98 21 84902450 lymph nodes become abnormal in size, consistency, and number.
Fax: +98 21 88220053 A normal sized lymph node is usually less than one cm in
Email: [email protected] diameter. Of course, there are exceptions in lymph nodes in
Received: 25 February 2012
Revised: 25 June 2013
different regions and at different ages have different sizes. For
Accepted: 4 August 2013 example, some authors have proposed that an inguinal lymph node

158 Iran J Med Sci Supplement March 2014; Vol 39 No 2

 Lymphadenopathy

size up to 1.5 cm should be considered normal, in adults and children.4,5,17,18 In patients with TB,
while the normal range for the epitrochlear nodes the assessment of the human immunodeficiency
is up to 0.5cm.2 In general, normal lymph nodes virus (HIV) is advised because it increases the
are larger in children (ages 2-10), in whom a size incidence of extrapulmonary TB to more than
of more than 2 cm is suggestive of a malignancy 50%.19-21 Infectious mononucleosis affects patients
(i.e., lymphoma) or a granulomatous disease of all ages; however, it is more frequent before
(such as tuberculosis or cat scratch disease).3 adolescence. Approximately over 90% of adults all
It is important to take a careful history to over the world are seropositive for this viral disease,
consider a variety of disorders, which may be although only 25-30% of them have become
a clue to the underlying disorder. It might be a clinically ill.14,22
usual self-limited infection in younger adults or a In general practice, less than one percent of
malignancy in older patients. Based on different patients with LAP have malignant disease,12 often
geographical areas, the etiology varies. For due to leukemia in younger children and Hodgkin's
example, tuberculosis (TB) is the most common disease in adolescents.23 It has been reported
cause of cervical LAP in endemic areas such that the prevalence of malignancy is 0.4% in
as Africa.4-8 Nonetheless, in a large number of patients under 40 years and 4% in those over 40
studies, the most common benign etiologies are years of age in the primary care setting.14 The
non-specific reactive changes in lymph nodes.9-11 prevalence rises to 17% in referral centers15 and
Despite the low prevalence of malignancy soars to 40-60% in highly suspicious patients.14
among patients with LAP, it remains to be the main Be that as it may, the location of LAP changes
concern of both patients and physicians. Studies the possibility of malignancy.
have shown that its prevalence is less than one Hodgkin's disease is rare before 10 years
percent among patients with unexplained LAP in old and a small male dominance is present,
general practice.12 especially in childhood. The Epstein-Barr virus
Several aspects in the diagnosis of LAP infection in combination with immune deficiency
should be considered. In most cases, further is a risk factor for increasing Hodgkin's disease,
investigation is not required as the cause particularly in less-developed countries and
is obvious on primary evaluation (such as low socioeconomic conditions. Non-Hodgkin's
infection). In unexplained conditions, laboratory lymphoma, the fourth common worldwide
tests, imaging studies, and tissue biopsy are malignancy in males with a frequency of 6.1%,24
recommended. Imaging can identify the size is another cause.
and distribution of the node more accurately
than can physical examination. Ultrasound is History Taking
a noninvasive method to assess lymph nodes
in superficial regions like the neck.13 Computed Taking a complete history of the patient is necessary
tomography (CT) is useful to determine LAP in to determine the etiology of LAP. Age, time of
the thorax or abdominopelvic cavity.14,15 Tissue presentation, duration of symptoms, underlying
diagnosis by fine needle aspiration biopsy or diseases, and circumstances in which LAP was
excisional biopsy is the gold standard evaluation detected are of great value. Furthermore, a history
for LAP.16 of exposure to animals, ingestion of certain drugs
Several articles have discussed the and foods, risky behaviors, and history of recurrent
appropriate approach to the diagnosis and infection and immunodeficiency can help the
management of LAP. In this article, we discuss diagnosis.
various aspects of peripheral LAP and describe A history of environmental exposure to tobacco,
how a physician can approach it. In order to alcohol, and ultraviolet radiation increases the
provide a comprehensive review of various suspicion of the metastatic carcinoma of the
aspects of peripheral LAP, we performed internal organs, head, and neck as well as skin
comprehensive literature search and review malignancies. Immune deficient patients, like
through electronic databases, including those with AIDS, have wide differential causes
PubMed, Elsevier, Scholar Google, IranMedex, of LAP and malignancies like Kaposis sarcoma;
and Scientific Information Database (SID), using however, non-Hodgkin's lymphoma should
"peripheral lymphadenopathy, localization, always be taken into consideration.16
benign, malignant, and diagnosis for articles A family history of malignant disorders
published between 1984 and 2011. may raise the physicians suspicion to distinct
etiologies of LAP such as breast carcinomas,
Epidemiology melanoma, and dysplastic nevus syndrome.16
Also, if LAP lasts less than two weeks or over
In tropical areas, TB is a main benign cause of LAP one year without increasing in size, the probability

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Mohseni Sh, Shojaiefard A, Khorgami Z, Alinejad Sh, Ghorbani A, Ghafouri A

of malignancy is quite low.16 Nodes that are associated with malignancy

tend to involve several groups of nodes. 34
Related Symptoms and Signs LAP in the supraclavicular area has the
highest risk of malignancy; this risk is 90% in
A recent upper respiratory infection can cause patients more than 40 years old and 25% in
cervical LAP, which is usually self-limited. A triad of those under 40 years old.12 The Virchow node,
moderate to high fever, pharyngitis, and moderately in the left supraclavicular area, suggests intra-
tender lymph node with splenomegaly (>50%) abdominal malignancies (e.g., gastric carcinoma),
characterizes classic infectious mononucleosis.25 while in the right side suggests intra-thoracic
Cytomegalovirus, toxoplasmosis, HIV, and human malignancies.
herpes virus type 1 can cause mononucleosis-like
syndrome.25 The typical symptoms of toxoplasmosis Size
are flu-like symptoms, with a single swollen cervical It is suggested that palpable supraclavicular,
lymph node.14,16 HIV in the acute phase presents iliac and popliteal nodes, epitrochlear greater
with mononucleosis-like syndrome. Its presentation than 0.5cm, and inguinal nodes larger than 1.5
consists of fever, fatigue, pharyngitis, rash, malaise, cm are abnormal.16 The nodes in other areas are
arthralgia, and LAP, which appear 2-6 weeks after considered as abnormal if their diameter exceeds
exposure to the HIV virus.26,27 one cm.2 However, there is no uniform nodal size
A recent travel to an endemic area or at which the greater diameter can raise suspicion
exposure to an infected patient with TB along of a neoplastic etiology.
with painless, gradually progressive, single or
matted lymph nodes can suggest mycobacterium Pain and Tenderness
TB involvement.28 The coexistence of LAP and Pain and tenderness on a lymph node is a
symptoms like arthralgia, muscle weakness, non-specific finding. It is typically due to infection.
unusual rash, and anemia may direct the diagnosis In some cases, pain is induced by hemorrhage
of autoimmune diseases, including rheumatoid into the necrotic center of a neoplastic node,
arthritis, systemic lupus erythematous, and immunologic stimulation of pain receptors, or
dermatomyositis.1,16 On the other hand, whenever rapid tumor expansion.12
dermatomyositis is diagnosed, the underlying
malignancy should be ruled out. Consistency
Significant fever, night sweats, and Acute inflammation by infiltrating the node
unexplained weight loss (more than 10% in may make it more consistent, with concomitant
less than 6 months) are the B symptoms of tenderness due to the tension on the capsule.
lymphoproliferative disorders, but they may also Chronic inflammation also leads to fibrotic
be seen in TB or collagen vascular diseases.29 changes, making the node hard in palpation.
Petechiae and purpura associated with Stony-hard and painless nodes are usually signs
LAP and splenomegaly may be detected in of metastatic cancer or granulomatous disease.
acute leukemias.30 Pain may occur in involved Firm and rubbery nodes can imply lymphoma.
nods with Hodgkin's disease following alcohol Matted lymph nodes are described when a
consumption. 29 Generalized pruritus is a group of nodes are conglomerated. They can
concerning symptom because it manifests in 30% be either due to benign (mycobacterial infection
of patients with Hodgkin's disease31 and 10% of and sarcoidosis) or malignant (lymphoma and
patients with non-Hodgkin's lymphoma.32 metastatic carcinoma) disorders.1,16,35

Physical Examination Mobility

LAPs resulting from infections and collagen
All patients with LAP should undergo a complete vascular diseases are usually freely movable in
and systematic physical examination. Any palpable the subcutaneous region. Rubbery mobile nodes
lymph node should be evaluated for its location, are associated with lymphoma. Nodes that are
size, consistency, fixation, and tenderness. associated with malignancy are often fixed to the
skin or surrounding tissues.36,37
Location Organomegaly (especially splenomegaly) is
Determining whether LAP is localized or sometimes associated with LAP, as in infectious
generalized makes the differential range narrower. mononucleosis, acute lymphoma, Hodgkin's disease,
An enlarged node in a lymphatic-rich region non-Hodgkin's lymphoma, and sarcoidosis.29
mostly presents a local disease. The presence of Skin should also be examined for unusual
a red lymphangitic streaking (lymphangitis) may lesions suggesting malignancy such as melanoma,
be detected in a localized infection.33 and for traumatic lesions that potentially can be

160 Iran J Med Sci Supplement March 2014; Vol 39 No 2

 Lymphadenopathy

an inoculation site for microbial germs. as atypical TB.21 Cat scratch disease, also known
as sub-acute regional lymphadenitis, is caused by
Classification and Etiology Bartonella henselae, a Gram-negative bacterium.
LAP is seen in more than 80% of these patients.40
Seventy-five percent of all LAPs are localized, and Hodgkin's disease, non-Hodgkin's lymphoma, and
more than 50% are detected in the head and neck squamous cell carcinoma of the head and neck and
area. They are often caused by a specific pathology metastatic carcinomas are common malignancies
in the region of the lymphatic drainage, which can be in the cervical region.16,41 Papillary and follicular
diagnosed without additional assessment. Twenty- thyroid cancer and nasopharyngeal carcinomas can
five percent of LAPs are generalized and are often also involve and metastasize to the cervical lymph
a sign of a significant systemic underlying disease.14 nodes.38 Clinical cervical LAP has been found in
There are a variety of etiologies which can lead 15-30% of the cases of papillary thyroid carcinoma.42
either to localized or generalized LAP (table 1).16,29,36 Supraclavicular LAPs, associated with
malignancy in all ages, should always be
Localized Adenopathy investigated even in children. The right
supraclavicular lymph nodes drain the
Cervical lymph nodes are involved more often than mediastinum, lungs, and esophagus, while the
are other lymphatic regions. They also have an left nodes drain the gastrointestinal tract and
extensive range of differential diagnoses, making genitourinary tract, which can be involved with the
the approach more important. Bacterial or viral malignancy of these organs. Hodgkin's disease,
infection of the face, nasopharynx, or oropharynx non-Hodgkin's lymphoma, breast carcinoma,
is the most common cause of cervical LAP.38 mycobacterial, and fungal infections can also
Generalized LAP caused by viruses like Ebstein- involve the lymph nodes of this region.29
Barr Virus and cytomegalovirus, may also present Axillary LAP is most commonly non-specific
with acute bilateral cervical lymphadenitis.39 Acute or reactive.16 The anterior and central axillary
pyogenic lymphadenitis, usually due to skin infection lymph nodes may be palpable due to breast
by Staphylococcus aureus or pharyngitis by group A cancer metastasis even before the main lesion is
Streptococci, is more common in children. TB also detected. Hodgkin's disease and non-Hodgkin's
involves the cervical lymph node in 60% to 90% of lymphoma are seldom seen solely in the auxiliary
cases;21 they are firm and non-tender and are known nodes.16 Cat scratch disease also is a common

Table 1: Differential Diagnosis of Peripheral Lymphadenopathy

Localized Peripheral
Lymphadenopathy
Infections:
Viral: Upper respiratory tract infections, mononucleosis, herpes virus, coxsackie
virus, cytomegalovirus, HIV
Cervical Bacterial: Staphylococcus aureus, Streptococcus pyogenes (group A),
mycobacterium, dental abscess, cat scratch disease
Malignancy: Hodgkin's disease, non-Hodgkin's lymphoma , thyroid cancer,
squamous cell carcinoma of the head and neck
Malignancy: Abdominal/thoracic neoplasm, thyroid cancer, Hodgkin's disease, non-
Supraclavicular Hodgkin's lymphoma, breast carcinoma
Infections: Mycobacterial, fungal
Infections: Staphylococcal and Streptococcal skin infections, cat scratch disease,
Axillary sarcoidosis
Malignancy: Breast cancer, lymphomas, luekemias
Benign Reactive Lymphadenopathy
Infections: Sexually transmitted disease, cellulitis
Inguinal
Malignancy: Lymphomas, squamous cell carcinoma of the penis and vulva,
metastatic melanoma
Generalized Peripheral
Lymphadenopathy
Infections Mononucleosis, HIV, miliary tuberculosis, typhoid fever, syphilis, plague
Malignancy Lymphomas, acute leukemias
Autoimmune Disorders Systemic lupus erythematosus, rheumatoid arthritis, Sjgrens syndrome,
sarcoidosis
Drug Reactions Phenytoin, Allopurinol, Atenolol
Lipid Storage Diseases Gusher's disease, Neiman-Peak
The data of the table are derived from references cited in the text.

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Mohseni Sh, Shojaiefard A, Khorgami Z, Alinejad Sh, Ghorbani A, Ghafouri A

cause of axillary LAP.40 Leukemia

Benign reactive inguinal LAP is seen in Metastatic: Breast tumor, Lung, Kidney, others
patients who walk barefooted outdoors. Localized HHypersensitivity syndromes: Serum
LAP is typically caused by infection and is due sickness, Drugs
to sexual transmitted diseases (herpes simplex IInfections: Viral (Epstein-Barr virus,
virus, gonococcal infection, syphilis, chancroid, cytomegalovirus, HIV), Bacterial (TB,) Fungal,
granuloma inguinale, and lymphogranuloma Protozoan, Rickettsial (Typhus), Helminthes
venereum). Malignancy rarely presents itself CConnective Tissue disorders: Systemic
only in the inguinal lymph nodes. Occasionally, lupus erythematosus, Rheumatoid arthritis,
Hodgkin's disease, non-Hodgkin's lymphoma, Dermatomyositis
melanoma, and squamous cell carcinoma of the AAtypical lymphoproliferative disorders:
penis, vulva, and anus can involve the lymph Castlemans Disease, Wegener
nodes of this region.16 GGranulomatous: Histoplasmosis,
Mycobacterial infections, Cryptococcus,
Generalized Adenopathy Berylliosis, Cat scratch disease, Silicosis
OOthers
The etiology of generalized adenopathy may 2) Using the letters of alphabet, although it
sometimes overlap with localized LAP (table 1)16,29,36 makes the categorization too long.29
and almost always indicates an underlying disease. 3) Using the region of lymph node enlargement
Some important and common causes are as follows: and its localization provides useful information
The Epstein-Barr virus typically involves the about causes.29
bilateral posterior cervical, axillary, and inguinal
lymph nodes, distinguishing it from the other Diagnostic Approach
causes of pharyngitis. LAP appears in the first
week of exposure and then gradually subsides Following comprehensive history taking and
over two to three weeks. Low-grade fever, fatigue, physical examination, the existing algorithm (figure
and prolonged malaise are the other symptoms.25 1) can guide the physicians for a further evaluation
HIV infection is frequently associated with of patients with peripheral LAP.1,14,16
generalized LAP. It may also increase the risk
of TB. The HIV initially involves the cervical, Laboratory Diagnostic Methods
auxiliary, and occipital nodes and is not tender.43 If more work-up is needed, the first step is to
In this situation, lymph nodes enlargement obtain complete blood count (CBC).
lasts more than 2-3 months.14 Drug reaction In bacterial pharyngitis, a throat culture
is characterized by fever, rash, arthralgia, and or rapid antigen detection tests is helpful.
generalized LAP.16,29 Lymphocytosis (>50% of leukocytes) with the
Generalized lymph node enlargement is a presence of at least 10% atypical lymphocytes
common and is usually a non-specific aspect of and a positive serologic test of the Epstein-
systemic lupus erythematosus. It is frequently Barr virus are typical laboratory findings in the
detected in the cervical, axillary, and inguinal Epstein-Barr virus involvement.14 However, the
regions. Whereas lymph node necrosis is the presence of atypical lymphocytes in a peripheral
characteristic histological finding, reactive blood smear can be due to acute leukemia,35
follicular hyperplasia is the most frequent which mandates further evaluations such as
histopathologic finding in lymph node lesions in bone marrow biopsy.16Anti-cytomegalovirus IgM
systemic lupus erythematosus patients.44 antibodies or cytomegalovirus polymerase chain
Generalized LAP is rarely seen in reaction (PCR) are laboratory tests for diagnosing
malignancies; however, it is usually seen in non- cytomegalovirus.14 Anti-HIV antibodies reach
Hodgkin's lymphoma, whereas Hodgkin's disease detectable levels about two weeks after infection,
is distinguished by the localized involvement of and HIV PCR can be helpful in this phase.14
the lymph nodes.30 IgM toxoplasma antibody is the diagnostic
serologic test for the acute phase infection of
Differential Diagnosis toxoplasmosis.1
If autoimmune diseases are suspected, CBC,
Three models are available to categorize peripheral antinuclear antibody, dsDNA antibody, ESR,
LAP. and rheumatoid factor and complement level
1) Using the acronym "CHICAGO" helps to should be checked. Lymphocytosis can be seen
consider all causes.29 in leukemia, autoimmune disorders, Epstein-
CCancers: Hematologic malignancies: Barr virus, cytomegalovirus, and TB. Increased
Hodgkin's disease, Non-Hodgkin's lymphoma, neutrophil count in CBC is detected in acute

162 Iran J Med Sci Supplement March 2014; Vol 39 No 2

 Lymphadenopathy

bacterial infection. An extreme increase in the total peripheral LAP.1,14,16

number of leukocytes (more than 50000 WBC/
mm3) is a leukemoid reaction. It can be found Imaging
in response to an infection (such as acquired
immune deficiency syndrome), inflammation, and Imaging can identify node characteristics more
rarely in myeloproliferative disorders (i.e., chronic accurately than can physical examination.
myelocytic leukemia).45 Ultrasonography is a useful imaging tool in the
The existence of anemia (or other cytopenias) assessment of the number, size, site, shape,
implies a significant underlying illness.35 margins, and internal structure in patients with
Leukemia, HIV, and systemic lupus erythematous peripheral LAP, whereas CT scan and magnetic
may be accompanied by pancytopenia. Full resonance imaging (MRI) are more useful in the
blood count with hemogram, ESR, CRP, and evaluation of the thoracic and abdominopelvic cavity
LDH are helpful in diagnosing malignancies and and their accuracy mainly depends on the size of
autoimmune processes. the lymph nodes.13,46 Color Doppler ultrasonography
Since thorough history taking and physical has been used in the assessment of lymph node
examination can lead to request for further enlargement since the beginning of the 1970s.47,48
work-up, figure 1 shows a step-by-step It can evaluate the vascular pattern, displacement
evaluation of and approach to patients with of vascularity, vascular resistance, and pulsatility

Figure 1: Algorithm for the diagnosis and evaluation of patients with peripheral lymphadenopathy. The data of the algorithm are
derived from references cited in the text.

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Mohseni Sh, Shojaiefard A, Khorgami Z, Alinejad Sh, Ghorbani A, Ghafouri A

index. Hence, it can distinguish between an old LAP fusion tendency, and strong internal echoes (due
and a recent LAP that is still active.49-51 A normal or to calcification) are the ultrasound characteristics
reactive node is usually oval with a hilum, whereas of tubercular lymphadenitis.51,69
metastatic and lymphomatous lymph nodes
generally emerge as round lesions.46,52 Several Tissue Diagnosis
studies have indicated that a low long axis to short
axis of lymph nodes (L/S ratio) is a significant sign Tissue diagnosis is the gold standard in the
of lymphoma and metastatic cancer.50,53-55 evaluation of LAP. Fine needle aspiration
Steinkamp HJ et al.56 detected the L/S ratio cytology (FNAC) is a simple and safe procedure
less than 2 was indicative of metastatic lymph and is proved to be accurate in the diagnosis of
nodes with 95% accuracy. But there is not any reactive hyperplasia, infections, granulomatous
cut-off value for distinguishing the exact cause. lymphadenopathies, lymphomas, and metastatic
Therefore, the L/S ratio is one of the parameters malignancies. It is most helpful when looking for
in the evaluation of lymph nodes and as such the recurrence of a previously diagnosed cancer. It
should be considered with other findings to is easily performed in both inpatient and outpatient
reach a diagnosis.51 Metastatic nodes are settings and yields results promptly.70 The accuracy
often hypoechoic50,51,57,58 in comparison to the of diagnosing metastatic carcinoma in lymph nodes
adjacent tissues. The absence of hilum has been by FNAC is 82-96%.71-73 Using ancillary techniques
reported in 76-96% of malignant nodes.46,59,60 The like immunohistochemistry and flow cytometry
ultrasonographic characteristics of benign and improves the accuracy of FNAC for the diagnosis of
neoplastic LAPs are summarized in table 2.46,56,61 lymphomas.74 FNAC has the maximum sensitivity
The resistive index and the pulsatility index, and specificity for detecting metastatic cancers.
vascular resistance indices measured by spectral Prasad et al.72 reported sensitivity of 97% and
Doppler ultrasound, are useful to distinguish specificity of 98.9% in diagnosing metastatic lymph
malignant from benign node disorders. Some node by FNAC. The most important limitations of
studies have reported that malignancies in FNAC are inadequate specimen75 and high rate
nodes tend to have a higher resistive index of false-negative diagnoses in Hodgkin's disease
(>0.8) and pulsatility index (>1.5) than do reactive and incomplete classification of non-Hodgkin's
nodes.47,61,62 However, other reports have posited lymphoma.70
that metastatic nodes have lower or similar In patients suspected of LAP resulting
vascular resistance compared with benign from skin neoplasms (such as squamous cell
nodes.50,63 According to these various reports, carcinoma or melanoma), biopsy of the skin
the role of vascular resistance in the assessment lesion is helpful.16
of LAP is still controversial. Ultrasonography-guided FNAC gives more
Some studies have suggested using patterns precise information than does blinded FNAC
of vascular distribution within the nodes to because it guides the needle to the most
distinguish benign from malignant nodes.64-66 suspicious area of the lymph node. Whenever
Normal nodes usually have hilar vascularity. physical examination and imaging techniques
Reactive nodes tend to have more prominent suggest malignancy, ultrasonography-guided
hilar vascularity due to an increase in the blood FNAC can identify metastasis in the lymph node.76
flow.61,67Metastatic lymph nodes often have a Core needle biopsy, as another tissue
peripheral perfusion pattern and abnormal hilar diagnosis method, provides more specimen
structure.53,66,68 from the tissue than does FNAC. If an imaging
In ultrasound assessment, microcalcification technique guides the procedure, the results will be
may be detected in 50-69% of the cases of more accurate, and it may prevent unnecessary
papillary thyroid carcinomas.53 Microcalcification excisional biopsy.77 The accuracy of image-guided
in metastatic axillary nodes is rare, but it strongly core needle biopsy in diagnosing lymphoma has
suggests breast cancer.46 Multiple lymph nodes, been reported in the range of 76-100%.41,78-84

Table 2: Ultrasonographic Criteria of Benign and Neoplastic Lymphadenopathy

L/s Internal Blood Flow
Shape Border Hilum RI** PI***
Ratio* Echogenicity Distribution
Benign Present- Low<0.8 Hilar
ovoid various High>2 Isoechoic <1.5
Disorders Normal
Neoplastic Peripheral or
Round sharp Low<2 Hypoechoic Absent High> 0.8 >1.5
Disorders miscellaneous
*Long axis to short axis (L/S); **Resistive index (RI); ***Pulsatility index (PI); In matted lymph nodes, the border is not sharp.
The data of the table are derived from references cited in the text.

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 Lymphadenopathy

Percutaneous image-guided core needle the germinal center.

biopsy is a safe and useful method for the diagnosis 2) Paracortical hyperplasia is detected in
and classification of malignant lymphomas viral infections, skin diseases, drug reactions,
presenting with enlarged peripheral lymph nodes and non-specific reactions. The extension of the
and superficial masses. It can be used as the first T-cells in the paracortical region is the pathologic
step for tissue sampling in a patient suspicious pattern.
of lymphomas.41,80 Nevertheless, its strength for 3) Sinus hyperplasia is seen in lymph nodes
the diagnosis of lymphoma is still controversial draining limbs due to inflammatory lesions
and excisional biopsy of enlarged lymph nodes and malignancies. The histopathologic pattern
is regularly recommended as the gold standard includes the expansion of the histiocyte cells in
procedure.85,86 the medullary and cortical sinuses.
Several approaches have been developed 4) Granulomatous inflammation is mainly seen
to recognize which patient with peripheral LAP in TB and sarcoidosis. The pathologic feature
needs excision biopsy. Vassilakopoulos et al.87 is the formation of histiocytic granuloma in the
evaluated 475 patients older than 14 years old lymph nodes.
with LAP. They found that 6 variables among 5) Acute lymphadenitis is usually seen in the
23 examined clinical covariates independently lymph nodes of the affected tissues involved in
predicted the need for lymph node biopsy, bacterial infection. Follicular hyperplasia and
including age above 40 years, lack of tenderness infiltration of polymorphonuclear (PMN) cells
on the lymph node, lymph node size, generalized is the pathologic pattern. Suppurative adenitis
pruritus, supraclavicular location, and hard smears show PMN and few lymphoid cells in a
texture of the lymph node. Ninety-six percent of necrotic background.
the patients who needed biopsy were properly Certain pathogens cause typical findings.
categorized by this model. Large transformed B immunoblasts, surrounded
Oliver S. Soldes et al.34 suggested that some by some plasma cells with basophilic cytoplasm,
parameters increased the risk of malignancy in are detected in Epstein-Barr virus infection.
children more than 8 years old; these parameters The features of the lymph node in Epstein-
were node size greater than one cm, multiple Barr virus involvement can be mistaken with
sites of adenopathy, supraclavicular lymph nodes, Hodgkin's disease.90 The histological findings of
fixed nodes, and abnormal chest X-ray. Moreover, cytomegalovirus lymphadenitis are similar to those
the authors recommended that younger children of the Epstein-Barr virus, but large eosinophilic
with a single small node be preferably managed intranuclear inclusions are characteristically seen
by laboratory tests and clinical follow-up because in cytomegalovirus. Mycobacterium TB produces
of the low risk of malignancy (5%). a chronic specific granulomatous inflammation
Australian Cancer Network Diagnosis and in which Langerhans' giant cells, caseating
Management of Lymphoma Guidelines, approved necrosis, and calcification can be seen.91 Satellite
by the National Health and Medical Research micro-abscesses, surrounded by granulomatous
Council (NHMRC), identified the following factors inflammation, are the hallmark of cat scratch
useful in determining the need for a lymph node disease.92 Non-necrotizing epithelioid granuloma
biopsy:88 age more than 40 years; supraclavicular is a characteristic of sarcoidosis.93 The presence
lymph node location; nodal diameter greater than of Reed-Sternberg cells (a large cell with plentiful
2.25 cm; firm-hard texture; and lack of pain. basophilic cytoplasm and prominent eosinophilic
nucleoli) in a varied inflammatory cell infiltration
Histopathology background characteristically is seen in classical
Hodgkin's disease.88
Based on the etiology, the histopathology of lymph The histological patterns of Hodgkin's disease
nodes differs. We present a review of the salient according to the World Health Organization
points of some common diseases with regard to (WHO) classification are:94 1) nodular sclerosis;
their histopathology. 2) lymphocyte-rich; 3) mixed cellularity; 4)
Reactive LAP, which is the most common lymphocyte-depleted; and 5) nodular lymphocyte-
cause of lymph node enlargement, is a non- predominant. The principal histological subtypes
neoplastic and reversible enlargement of the vary by geographic location and economic level.
lymphoid tissue secondary to antigen stimulus. In developed countries such as the US, nodular
There are five distinct patterns of benign LAP:89 sclerosis Hodgkin's disease is the most common
1) Follicular hyperplasia is seen in infections, form of Hodgkin's disease (80%). It is most
autoimmune disorders, and non-specific common in young adults, especially in women
reactions. The histopathologic pattern is an in poor economic areas.94 Mixed cellularity
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